Systems for ex vivo organ care

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DESCRIPTION

Procedures for ex vivo organ care

Field of the invention

The invention relates generally to ex vivo organ care procedures. More particularly, in various embodiments, the invention relates to the care of an organ ex vivo under physiological or quasi-physiological conditions.

Background of the invention

Current organ preservation techniques typically involve hypothermic storage of the organ in a chemical preservation solution on ice. These techniques use a variety of solutions, none of which sufficiently protects the organ from damage resulting from ischemia. Such injuries are particularly undesirable when an organ is intended to be transplanted from a donor to a recipient.

Using conventional approaches, such lesions increase as a function of the length of time an organ is maintained ex vivo. For example, in the case of a lung, it can normally be preserved ex vivo for only about 6 to about 8 hours before it becomes unusable for transplantation. A heart can normally be preserved ex vivo for only about 4 to about 6 hours before it becomes unusable for transplantation. These relatively short time periods limit the number of recipients that can be reached from a given donor site, thereby restricting the pool of recipients for a harvested organ. Even within time limits, organs can nevertheless be significantly damaged. A significant problem is that there may be no observable indication of damage. Because of this, organs can be transplanted under sub-optimal conditions, resulting in dysfunction or other post-transplant organ injury. Thus, it would be desirable to develop techniques that can extend the time during which an organ can be preserved in a healthy state ex vivo. Such techniques would reduce the risk of post-transplant organ failure and expand potential donor-recipient pools.

The effective preservation of an organ ex vivo would also provide numerous other benefits. For example, prolonged ex vivo storage would allow for more careful monitoring and functional testing of the harvested organ. This, in turn, would allow earlier detection and potential repair of defects in the removed organ, further reducing the likelihood of post-transplant organ failure. The ability to perform simple organ repairs would also allow many organs with minor defects to be saved, whereas current transplantation techniques require them to be discarded.

Furthermore, a more efficient match between the organ and a particular recipient can be achieved, further reducing the probability of eventual organ rejection. Current transplantation techniques rely primarily on the matching of donor and recipient blood types, which, by itself, is a relatively unreliable indicator of whether or not the organ will be rejected by the recipient. A more preferred assay for organ compatibility is a human leukocyte antigen (HLA) concordance assay, but current cold ischemic organ preservation approaches preclude the use of this assay, which often requires 12 hours or more to complete.

Long-term and reliable ex vivo organ care would also provide benefits outside the context of organ transplantation. For example, a patient's body as a whole can normally tolerate much lower levels of chemotherapy, biotherapy, and radiation therapy than many particular organs. An ex vivo organ care system would allow an organ to be removed from the body and treated in isolation, reducing the risk of damage to other parts of the body.

Published PCT Patent Application No. 99/15011 relates to maintaining a harvested organ in a functional and viable state prior to implantation. The organ perfusion apparatus includes a preservation chamber for storing the organ during the preservation period. A perfusion circuit is provided having a first pathway for providing oxygenated fluid to the organ, and a second pathway for extracting depleted fluid from the organ. The perfusion apparatus also includes a device operatively associated with the perfusion circuit to maintain the organ at a substantially normothermic temperature.

United States Patent Application No. 5,656,420 refers to the prolongation of the survival time of

ES 2 625 850 T3 mammalian lung tissue subjected to ischemia, whereby said tissue is perfused with a preservation solution comprising a therapeutic dose of the delta opioid DADLE ([D-Ala², D-Leu⁵] -encephalin) under hypothermic conditions.

NC Wright's published article; DN Hopkinson; TE Shaw; and TL Hooper entitled: A porcine ex vivo paracorporeal model of lung transplantation describes a technique that allows perfusion of a ventilated and isolated pig lung with an extracorporeal veno-venous circuit from a support animal. The publication details of this article are: Laboratory animals, vol, 34, no. 1, 2000, pages 56-62, XP002450330 UK.

The published article of MACCHIARINI P; MAZMANIAN GM; ORIOL R; OF MONTPREVILLE V; DULMET E; FATTAL S; And COL entitled Ex vivo lung model of pig-to-human hyperacute xenograft rejection refers to hyperacute rejection of the lung in the combination of pig-to-human xenotransplantation. Publication details are JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, vol 114, no. 3, 1997 pages 315-325, XP002450331 United States.

The EGAN Y COL published article refers to the ex vivo evaluation of human lungs for suitability for transplantation. Publication details are: THE ANNALS OF THORACIC SURGERY, ELSEVIER, UNITED STATES, vol. 81, no. 4.1 April 2006, pages 1205-1213, XP005350148.

In view of the foregoing, improved systems, procedures and devices are needed for ex vivo organ care.

Summary of the invention

Accordingly, a method for perfusing a lung is provided as detailed in claim 1. Advantageous embodiments are described in the dependent claims.

The invention addresses deficiencies in the state of the art by providing, in various embodiments, improved systems, procedures, solutions and devices related to portable ex vivo organ care.

In one aspect of the invention, the invention includes a method of perfusing one or more lungs ex vivo for an extended period of time in a steady state maintenance mode. The procedure generally includes the step of connecting the lungs within a fluid perfusion circuit, which includes a pump, a fluid source, and a fluid flow interface that allows fluid to flow into and out of the lungs. The procedure also includes the steps of flowing a perfusion fluid into the lungs through a pulmonary artery interface and flowing the perfusion fluid out of the lungs through a pulmonary vein interface, ventilating the lungs through through a tracheal interface, providing periodic breaths including alternate inspiration and expiration of gas into and out of the lungs, similar to in-vivo lung inspiration and expiration, and providing a respiratory gas, having a predetermined composition of gaseous components, to the lungs for use in metabolism by the lungs. In this procedure, the perfusion system is brought to a state of equilibrium, where the perfusion fluid that flows into the lungs includes gaseous components in a first composition that is substantially constant over time, and the perfusion fluid that flowing out of the lungs includes gaseous components in a second composition that is substantially constant over time. Since the lungs are separated from the rest of the donor body, there is no need to supply metabolic requirements for the rest of the body, so less gas exchange is used during perfusion in the systems described herein than in the lungs. in-vivo, and the requirement for oxygen and carbon dioxide exchange is reduced. The composition of gaseous components in the respiratory gas is therefore selected to provide adequate oxygen and carbon dioxide to the lungs for metabolism and control of the pH of the perfusion fluid in an amount approaching physiological levels.

In one embodiment, a tracheal oxygen delivery approach is used to implement maintenance mode. In accordance with this approach, one or more explanted lungs are instrumented within the perfusion circuit and perfused by a perfusion fluid that is oxygenated to a desired level prior to initiating perfusion of the lungs. During perfusion, the oxygenated perfusion fluid flows into the explanted lungs through the pulmonary artery interface and flows out of the lungs through the pulmonary vein interface. In addition, the respiratory gas is supplied to the lungs by the first gas source through the tracheal interface, so that the explanted lungs are ventilated by a respiratory gas in periodic breaths through the tracheal interface with periods of inspiration and expiration. alternate. In particular, the ventilation / respiratory gas supplies a predetermined composition of gaseous components to

ES 2 625 850 T3 through the tracheal interface. In certain implementations, the gas flowing through the tracheal interface is a combination that has at least oxygen, carbon dioxide, and nitrogen. In certain embodiments, oxygen is from about 10% to about 20% and carbon dioxide is from about 2% to about 8% of the blend. In one embodiment, the ventilation / respiratory gas combination is about 14% oxygen and about 5% carbon dioxide, with the balance being nitrogen. In this mode, gas leaving the lungs is withdrawn from the lungs via the tracheal interface, for example, through an outlet valve located along a conduit extending from the tracheal interface. After perfusing the lungs for a period of time in this mode, the steady state occurs when the first and second gaseous compositions are substantially the same. After reaching the steady state, the oxygen and carbon dioxide components in the perfusion fluid flowing into the lungs and in the perfusion fluid flowing out of the lungs reach a substantially constant composition. In addition, the lungs are perfused with the perfusion fluid and ventilated through the tracheal tube, while oxygen, carbon dioxide, and other gases are kept in the perfusion fluid at a substantially constant composition of gaseous components, and the gas delivered to the lungs through the tracheal interface differs from the second gaseous composition by an amount sufficient to supply the metabolic requirement of the lungs, and, In certain embodiments, the two gaseous compositions differ by an approximate amount to support the metabolic requirement.

In another embodiment, an isolated tracheal volume again breathing approach is used to implement maintenance mode. In this embodiment, one or more explanted lungs are first instrumented within the perfusion circuit and perfused with a perfusion fluid that flows into the lungs through the pulmonary artery interface and flows out of the lungs through the pulmonary vein interface. A source of ventilating gas is provided to the lungs through the tracheal interface, and one or more respiratory gas mixtures, each containing a predetermined composition of gaseous components, are delivered to the perfusion fluid via a gas exchange device. (for example, an oxygenator) in the perfusion circuit. In an exemplary embodiment, a gas supplied to the gas exchange device is premixed to include a desired gas composition for infusion into the perfusion fluid. In another embodiment, gases having different compositions are controllably released from the appropriate gas sources to the oxygenator 1042 at rates and volumes that allow the desired gas mixture composition to be obtained.

In certain embodiments, a source of respiratory gas may be supplied to the gas exchange device that includes a gaseous composition of from about 3% to about 7% carbon dioxide, from about 11% to about 14% oxygen, and the remainder being nitrogen. In this mode, the source of ventilation gas is provided in an isolated volume that interfaces with other fluids and is exchanged with other gases only through the alveoli of the lungs. In certain embodiments, the isolated gas volume is provided by a flexible bag. In certain embodiments, the isolated gas volume is provided by a hose. The gaseous components in the isolated gas volume are able to achieve a constant composition by exchange with the gaseous components in the perfusion fluid. The expired carbon dioxide is entrained from the lungs by the circulating perfusion fluid and is substantially removed from the perfusion fluid by mixing with the one or more oxygen-containing gas mixtures supplied through the gas exchange device. In operation, the lungs are ventilated during perfusion in this mode by applying a compressive force to the isolated volume. As the isolated volume is compressed, its components flow through the tracheal interface and into the lungs, where the lungs swell and the gaseous components are exchanged with gaseous components in the perfusion fluid through the alveoli in swollen lungs. As the compressive force is removed from the flexible hose or bag, the lungs breathe out. The application and removal of the compression force is repeated until the gaseous components flowing into the tracheal interface reach equilibrium with the components in the perfusion fluid.

After reaching a state of equilibrium in the isolated tracheal volume breathing approach again, the oxygen and carbon dioxide components in the perfusion fluid flowing into the lungs include a substantially constant composition and the gaseous components in the lungs. Perfusion fluid flowing out of the lungs also includes a substantially constant composition. In certain embodiments, a constant composition of a component is achieved when the composition of the component varies over time by less than about 3%, less than about 2%, less than about 1% over time. time at a given sampling location within the system. Although in a steady state in the isolated tracheal volume technique, the composition of oxygen and carbon dioxide in the perfusion fluid flowing into the lungs may differ from the composition of these components in the flowing perfusion fluid. out of the lungs. In certain embodiments, the compositions of said

The components in the incoming fluid differ from the compositions in the outgoing fluid in amounts substantially equivalent to the amount resulting from pulmonary metabolism. In certain embodiments, the oxygen component is maintained during perfusion at a steady state partial pressure that is higher in perfusion fluid flowing into the lungs than in perfusion fluid flowing out of the lungs. In certain embodiments, the carbon dioxide component is maintained during perfusion at a steady-state partial pressure that is lower in perfusion fluid flowing into the lungs than in perfusion fluid flowing out of the lungs. .

In certain embodiments of the maintenance mode, the composition of gaseous components in the perfusion fluid is selected to provide equilibrium partial pressures of the gaseous components within the circulating fluid in a range between a predetermined arterial gaseous composition and a venous gaseous composition. default. In certain embodiments, the predetermined arterial gaseous composition is physiological arterial blood gaseous composition, and the predetermined venous gaseous composition is physiological venous blood gaseous composition. For example, the composition of the oxygen component in the perfusion fluid may be at a partial pressure that is greater than a composition of the physiological venous blood oxygen component and less than a composition of the physiological arterial blood oxygen component. More specifically, this partial pressure of the oxygen component in the perfusion fluid can be between about 60 mmHg and about 100 mmHg, between about 80 mmHg and about 90 mmHg, or between about 83 mmHg and about 85 mmHg. In addition, the composition of the carbon dioxide component in the perfusion fluid is at a partial pressure that is less than a composition of the carbon dioxide component in physiological venous blood and greater than a composition of the carbon dioxide component in arterial blood. physiological. More specifically, this partial pressure of the carbon dioxide component in the perfusion fluid can be between about 40 mmHg and about 50 mmHg, or between about 42 mmHg and about 50 mmHg.

In certain embodiments of the maintenance mode, one or more therapeutic substances are delivered to the lungs during perfusion. The one or more therapeutic substances can be selected from antimicrobial, vasodilator and anti-inflammatory drugs. The one or more therapeutic substances can also be selected from isuprel, flolan, prostacyclin, and nitric oxide donors. In addition, the one or more therapeutic substances can be delivered to the lungs through the tracheal interface by means of a nebulizer, or to the infusion fluid through a maintenance solution bag, or by injection directly into the infusion fluid reservoir. at the point of use.

In certain embodiments of the maintenance mode, the perfusion fluid is maintained and delivered to the lungs at a temperature close to physiological. According to one implementation, the perfusion fluid employs a blood product-based perfusion fluid to more accurately mimic normal physiological conditions. In alternative embodiments, a synthetic blood substitute solution is used, while in other embodiments, the solution may contain a blood product in combination with a blood substitute product. The perfusion fluid can include a blood product, such as whole blood, and can be partially or completely depleted in leukocytes and / or platelets.

In certain embodiments, one or more tests can be performed on the lungs while they are kept in the perfusion circuit for ex vivo care. For example, the levels of an arteriovenous (AV) oxygen gradient between the perfusion fluid flowing into the lungs and that flowing out of the lungs can be measured.The oxygen saturation levels of blood hemoglobin in the Perfusion fluid flowing into the lungs and fluid flowing out of the lungs can also be measured, as can pulmonary vascular resistance ventilation rate, tidal volume, maximum respiratory pressure and positive pressure at the end of expiration (PEEP).

In accordance with another aspect of the invention, the invention includes a lung care system for perfusing one or more lungs ex vivo. The exemplary system includes a portable multipurpose module and a single-use disposable frame that is sized and shaped to engage with the multipurpose module. The single-use module also includes a lung chamber assembly mounted on the disposable frame. The exemplary system also includes a pump adapted to deliver a perfusion fluid to the lung chamber assembly. The lung chamber assembly includes a pulmonary artery interface to allow flow of perfusion fluid into the lungs, a tracheal interface to allow ventilation of the lungs, and a pulmonary vein interface to allow perfusion fluid to flow. out of the lungs. In addition, the single-use module may include a source of respiratory gas having a predetermined gaseous component composition. In certain embodiments, the source of respiratory gas is included in the multipurpose module.

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In certain embodiments, the Lung Care System Pulmonary Vein Interface includes a portion of the donor Left atrium, which is amputated from the donor at the time of lung explantation. A part of the left atrium, known as the left atrial cuff, is left hanging freely from the lungs and is exposed to the lung chamber assembly to allow perfusion fluid to flow from the lungs to the lung chamber assembly. In certain embodiments, the pulmonary vein interface includes a cannulation to the left atrial cuff. In an example of cannulation to the left atrial cuff, a semi-sealable connection is formed between the left atrial cuff and a cannula that directs perfusion fluid to a reservoir. The semi-sealable connection can be formed by a connector device that pairs the cannula with the left atrial cuff, and the connection can be releasable. In one aspect, the connector device includes a first surface for engaging the left atrial cuff and a second surface for engaging the cannula. In one aspect, the first surface of the connector device includes a plurality of perforations for engaging a plurality of parts of the left atrial cuff. The left atrial cuff can also extend vertically above the lungs and fit semiseably within a vertically extending cannula, where the cannula has a cross section with a diameter that is greater than a diameter of the left atrial cuff. The cannula can fit loosely around the left atrial cuff. In other practices, the cannulation of the left atrial cuff can be formed by sealing a tip portion of the cannula substantially within a pocket formed by the left atrial cuff. In yet another embodiment, the pulmonary vein interface includes the left atrial cuff disposed in a cup-shaped interface within the lung chamber assembly to allow perfusion fluid to flow from the lungs and out of the lung chamber assembly via an outlet conduit coupled to the cup-shaped interface. The cup-shaped interface may further include multiple openings at respective heights along a side wall of the interface, and the openings are in fluid communication with a selector valve. The selector valve is used to controllably draw the perfusion fluid at the cup-shaped interface out of the lung chamber assembly through a selected one of the multiple openings and through the outlet conduit. Therefore, the perfusion fluid is able to fill the cup-shaped interface to a height where the selected opening is located, in order to create a desired level of back pressure on the pulmonary veins.

In certain embodiments of the lung chamber assembly, a housing is mounted within the lung chamber assembly to support the lungs. The housing substantially prevents the lungs from contacting at least one wall of the lung chamber assembly. The housing can be rigid or flexible, and is configured to distribute the weight of the lungs as evenly as possible around the surface of the lungs. In this way, it is believed that the pressure on the alveoli of the lungs can be reduced. In one practice, the housing includes a flexible membrane, such as a drape, mesh, or other fabric, that suspends the lungs within the lung chamber assembly. In another practice, the shell is in the form of a rigid or flexible rib cage optionally having a diaphragm and / or padding structure.

The system may also include a heater to maintain perfusion fluid delivered to the lung at a temperature close to physiological. The system may further include a gas exchange device in fluid communication with at least one gas supply and the perfusion fluid, the gas exchange device being adapted to controllably modulate the composition of a gas component in the perfusion fluid. In certain embodiments, the gas exchange device (eg, an oxygenator) includes a gas selection switch for selecting from a plurality of gas supplies to modulate the composition of a gas component in the perfusion fluid. The system may further include a breathing device to provide a supply of gas through the tracheal interface. To operate the system in isolated tracheal mode, a volume compartment can be cannulated to a tracheal tube of the lungs and adapted to ventilate the lungs during perfusion,

In another aspect, a method of operating a perfusion circuit in an evaluation mode is described. One or more lungs can be evaluated for suitability for transplantation during the evaluation mode. The procedure includes positioning the lungs in an ex vivo perfusion circuit, flowing perfusion fluid into the lungs through a pulmonary artery interface, and flowing perfusion fluid out of the lungs through an interface. pulmonary vein, the perfusion fluid being at a physiological temperature. In addition, the procedure includes providing oxygen-containing gas to the lungs through a tracheal interface. The oxygen levels in the gas can be adjusted to allow evaluation at various oxygen composition levels. The gas may comprise about 100% oxygen, less than 100% oxygen, less than about 75% oxygen, less than about 50% oxygen, less than about 25% oxygen, or no oxygen. In certain embodiments, this gas can be of the same composition as ambient air.

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The evaluation mode is useful, for example, to perform tests to evaluate the gas transfer capacity of the lungs by determining the oxygen or carbon dioxide saturation or the partial pressure of oxygen in the perfusion fluid both before and after it. flow through the lungs. To perform this assay in the evaluation mode, a low oxygen gas source is used to adjust the gas content of the perfusion fluid so that the fluid resembles that of peripheral venous blood. The gaseous blood composition of the perfusion fluid is then monitored by taking oxygen saturation or partial pressure sample measurements of gas components in the perfusion fluid flowing into the lungs through the pulmonary artery interface and flowing out of the lungs via the pulmonary vein interface. The resulting pulmonary artery and pulmonary vein oxygen saturation or partial pressure measurements, collected over a period of time after ventilation begins, are then compared with each other to identify a maximum difference that is representative of the ability to breathe. gas transfer from the lungs.

Other evaluations can be done on instrumented lungs. These evaluations include measuring a fractional inspired oxygen concentration, measuring an arterio-venous (AV) oxygen gradient between the perfusion fluid flowing into the lungs and the perfusion fluid flowing out of the lungs, measuring a gradient of alveolar arterial oxygen (AA), measure a tidal volume, measure the saturation or oxygen of blood hemoglobin or the partial pressure of oxygen in the perfusion fluid flowing into and out of the lungs, and measure PEEP.

In certain examples of the evaluation mode, a suction force is applied across the tracheal interface to clear the alveoli of the lungs of debris. Debris from the pulmonary alveoli can also be cleared by having the lungs breathe in breaths that are of variable volume. For example, in sigh breathing, the breaths include a first breath that has a volume that is greater than the volume of at least two subsequent breaths.

In another aspect, compositions and solutions for infusion in a perfusion fluid that is used to perfuse the lungs prior to transplantation are described. The solutions include a substantially cell-free composition, where the compositions comprise one or more carbohydrates that include dextran, and a plurality of amino acids that do not include asparagine, glutamine, or cysteine.

In addition, they are described: a lung chamber assembly sized and configured to contain one or more lungs during ex vivo care; a reservoir for containing and optionally defoaming and / or filtering a volume of perfusion fluid; a perfusion fluid pump for pumping / circulating perfusion fluid to and from the removed lungs; a heater assembly for maintaining the temperature of the perfusion fluid at or near physiological temperatures; a gas exchange device for exchanging gases with the perfusion fluid in the system; a nutritional subsystem to replenish nutrients in the perfusion fluid as they are metabolized by the lungs and to provide preservatives to the perfusion fluid to reduce, for example, ischemia, edema, and / or other reperfusion-related injuries to the lungs; a sensor subsystem for monitoring, for example, temperature, pressure, flow rate and / or oxygenation of the perfusion fluid, and / or the various components used to maintain proper flow conditions to and from the lungs; an operator interface to assist an operator in operating the lung status and / or monitoring system, and / or to allow the operator to adjust various operating parameters; a power subsystem for providing fault tolerant power to the organ care system; and a control subsystem for controlling the operation of the organ care system.

Operationally, in one practice, the lungs are removed from a donor and instrumented for the lung chamber assembly by processes described above. The perfusion fluid pump pumps perfusion fluid from a reservoir to the heater assembly. The heater assembly heats the perfusion fluid to or near a normal physiological temperature. According to one embodiment, the heater assembly heats the perfusion fluid to between about 30 ° C and about 37 ° C, or between about 34 ° C and 37 ° C. From the heater assembly, the perfusion fluid flows to a first interface on the lung chamber assembly. Also referred to as the pulmonary artery interface, the first interface is cannulated to the vascular tissue of the pulmonary artery through a conduit located within the lung chamber assembly. The perfusion fluid then flows out of the lungs through the pulmonary vein through a second interface in the lung chamber assembly. The second interface, also called the pulmonary vein interface, connects to the rest of the perfusion circuit as described above. Optionally, the pulmonary vein is allowed to drain directly into the lung chamber assembly without cannulation. From the pulmonary vein interface, the perfusion fluid flows back to a fluid reservoir, where it can be infused with nutrients prior to recirculation through the perfusion circuit.

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When applicable (eg, during isolated tracheal volume mode), a gas exchange device is positioned within the perfusion circuit between the fluid reservoir and the lung chamber assembly. The gas exchange device receives a gas from an external or built-in gas source and applies gas (for example, oxygen, a mixture of oxygen and carbon dioxide, or a mixture of oxygen, carbon dioxide, and nitrogen) to the fluid. infusion before the fluid is flushed into the lungs. Alternatively, the levels of oxygen and other blood gases can be determined by drawing fluid samples from the perfusion fluid and analyzing the samples on a commercially available blood gas analyzer or using partial pressure sensors built into the system. The system may include one or more oxygen saturation sensors to measure the oxygen saturation level of the perfusion fluid to ensure that the perfusion fluid is maintained at physiological or other user-defined oxygen levels. In embodiments where the perfusion fluid is based on a blood product, it contains red blood cells (ie, cells that carry oxygen). Optionally, the oxygen sensors also provide a hematocrit measurement of the concentration of red blood cells in the perfusion fluid.

The nutritional subsystem infuses the perfusion fluid with a supply of maintenance solutions as the perfusion fluid flows through the system, and in some embodiments, while in the reservoir. According to one characteristic, maintenance solutions include nutrients, such as glucose. According to another feature, maintenance solutions include a supply of therapeutics, vasodilators, endothelial stabilizers, and / or preservatives to reduce edema and provide endothelial support to the lungs.

In accordance with another practice, the perfusion fluid includes blood collected from the donor through a process of exsanguination during removal of the lungs. Initially, donor blood is loaded into the reservoir and cannulation locations in the lung chamber assembly are bypassed with a bypass conduit to allow normal mode flow of the perfusion fluid through the system without it being present. a lung. Before cannulating the removed lungs, the system can be primed by circulating the blood of the exsanguinated donor through the system to heat and / or filter it, and, if desired, oxygenate it.

In one embodiment, the portable multipurpose module includes a portable housing constructed on a portable frame, and the disposable single-use module includes a disposable structure, such as a housing or a frame. To reduce weight, in one configuration, the disposable frame along with various components of the single-use module are formed of molded plastic such as polycarbonate, and the frame of the multi-use module is formed of molded materials such as polycarbonate or composite materials. carbon fiber. According to one feature, the loaded single-use disposable frame weighs less than about 12 pounds and the loaded single-use module weighs less than about 18 pounds. According to another feature, the component-unloaded multipurpose housing and frame weighs less than about 50 pounds, and when loaded with a multipurpose module, batteries, gas, maintenance solutions, perfusion fluid, and an organ, weighs approximately 85 pounds or less. According to another advantage, the system of the invention that includes both single use and multiple use modules, exclusive of any perfusion fluid, nutrient, preservative or other, batteries and gas supply, weighs less than about 65 pounds.

The single-use disposable structure (eg, frame or housing) is sized and shaped to engage with the portable frame of the multipurpose module for electrical, mechanical, gas, and fluid interoperation with the multipurpose module. According to one characteristic, the single-use and multipurpose modules communicate with each other via an optical interface, which automatically enters optical alignment the moment the single-use disposable module is installed in the use module. multiple notebook. According to another feature, the portable multipurpose module provides power to the single-use disposable module through spring-loaded connections, which are also automatically connected the moment the single-use disposable module is installed in the module. portable multipurpose. According to one feature, the optical interface and spring-loaded connections ensure that the power and data connection between individual and multiple modules are not lost due to jostling, for example during transportation over rough terrain.

In various configurations, the lung chamber assembly mounts to the disposable frame.

In one configuration, the various sensors associated with the heater assembly, gas exchange device, and / or perfusion fluid pump are included in the disposable single-use module. However, this is not necessarily the case, for example, with regard to sensors that do not contact the fluid.

ES 2 625 850 T3 perfusion. According to one example, the single-use disposable module employs an oxygen sensor that includes an in-line cuvette through which the perfusion fluid passes, an optical source to direct light into the perfusion fluid that passes through of the cuvette, and an optical sensor to measure an optical quality of the perfusion fluid passing through the cuvette. Preferably, the in-line cuvette is continuously or substantially continuously attached to a perfusion fluid flow conduit to reduce turbulence in the perfusion fluid and provide one or more accurate measurements. The continuous or substantially continuous configuration also reduces damage to any blood-based components of the perfusion fluid.

According to a further configuration, the disposable single-use module includes the aforementioned plurality of in-line compliance chambers located, for example, at an outlet of the perfusion fluid pump, an outlet of the gas exchange device or a heater assembly outlet. In a further configuration, the disposable single-use module includes a plurality of ports for sampling fluids from the lung chamber assembly.

In a further aspect, a method of transporting one or more lungs ex vivo is disclosed, which includes the steps of placing the lungs for transplantation in a protective chamber of a portable organ care system, pumping a perfusion fluid into the the lungs via a pulmonary artery in the lungs, provide a flow of perfusion fluid out of the lungs via a pulmonary vein in the lungs, and transporting the lungs in the portable organ care system from a donor site to a recipient site while pumping the perfusion fluid into an artery in the lungs.

These and other features and advantages of the invention are described in more detail below with respect to illustrative embodiments of the invention.

Brief description of the drawings

The following figures represent illustrative embodiments of the invention in which like reference numerals refer to like elements. These depicted embodiments may not be drawn to scale and are to be understood as illustrative of the invention and not as limiting, the scope of the invention being defined by the appended claims instead.

Figure 1 is a schematic diagram of a portable organ care system in accordance with an illustrative example.

Figure 2 is a diagram depicting a removed heart.

Figure 3 is a conceptual diagram depicting the removed heart of Figure 2 interconnected with the organ care system of Figure 1 in a normal flow mode configuration.

Figure 4 is a conceptual diagram depicting the removed heart of Figure 2 interconnected with the organ care system of Figure 1 in a retrograde flow mode configuration.

Figures 5A-5F show various views of an organ chamber assembly of the type used in the organ care system of Figure 1.

Figures 6A-6F show various views of a perfusion heater assembly of the type used in the organ care system of Figure 1.

Figure 7 shows a more detailed view of an exemplary resistive heater element of the type used in the heater assembly of Figures 6A-6F.

Figures 8A-8C show various views of a perfusion fluid pump interface assembly.

Figure 9 shows a perspective view of one side of the pump driver of a perfusion fluid pump assembly of the type shown in Figure 1, together with a bracket for mounting with the perfusion pump interface assembly.

Figure 10 shows a side view of the perfusion fluid pump interface assembly of Figures 8A-8C paired with the pump driver side of the perfusion fluid pump assembly of Figure 9.

Figure 11 depicts a block diagram of an illustrative control scheme for controlling the operation of the organ care system of Figure 1.

Figure 12 is a block diagram of an exemplary data acquisition subsystem of the type that may be used with an illustrative organ care system of Figure 1.

Figure 13 is a block diagram of an exemplary heating control subsystem of the type that may be used to maintain the temperature of the perfusion fluid in the illustrative organ care system of Figure 1.

Figure 14 is a block diagram of an exemplary power management subsystem of the type that may be employed in the illustrative organ care system of Figure 1.

Figure 15 is a block diagram of an exemplary pump control subsystem of the type that

ES 2 625 850 T3 may be used to control the operation of a perfusion fluid pump assembly in the illustrative organ care system of Figure 1.

Figure 16 is a graph representing an r-wave with which the pump control subsystem of Figure 15 is synchronized.

Figures 17A-17J depict exemplary display screens of the type that may be employed with an operator interface.

Figures 18A and 18B show an exemplary implementation of the system of Figure 1.

Figures 19A-19C show various views of the system of Figures 18A and 18B with its top removed and its front panel open.

Figure 20A is a front perspective view of the system of Figures 18A and 18B with the top removed, the front panel open, and the single-use disposable module removed.

Figure 20b is a side view of a slot formed in a basin of the multipurpose module of Figure 20A to mate with a corresponding projection on the single-use disposable module.

Figure 21A shows a mounting bracket for receiving and locking in place the single-use disposable module within the multi-use module of Figure 20A.

Figures 21B and 21C show the installation of a single use disposable module in the multipurpose module using the mounting bracket of Figure 21A.

Figures 22A-22C show exemplary mechanisms for automatically establishing electro-optical interconnections between the single-use disposable module and the multi-use module during the installation of Figures 21B and 21C.

Figures 23A-23C show various views of the system of Figures 18A and 18B with all external walls removed.

Figure 23D is a conceptual diagram showing the interactions between the circuit boards of Figures 23A-23C.

Figures 24A-24E show various top perspective views of a single use disposable module.

Figures 25A-25C show various bottom perspective views of the illustrative single-use disposable module of Figures 24A-24D.

Figures 26A and 26B depict the operation of a flow mode selector valve.

Figures 27A and 27B show various top views of the single use disposable module of Figures 19A-19C with the top of the illustrative organ chamber removed.

Figures 28A-28C show various views of an exemplary hematocrit and oxygen saturation sensor of the type employed in the illustrative single-use disposable module of Figures 19A-19C.

Figure 29A is a flow chart depicting a donor-side process for removing a donor organ and placing it in the organ care system of Figure 1.

Figure 29B is a diagram depicting a harvested heart with suture and cannulation sites.

Figure 30 is a flow chart depicting a recipient side process for removing an organ from the organ care system of Figure 1 and transplanting it into a recipient.

Figure 31 represents a graph demonstrating electrolyte stability for an organ that is undergoing direct mode perfusion.

Figure 32 represents a graph demonstrating electrolyte stability for an organ undergoing retrograde perfusion.

Figure 33 represents a graph demonstrating the arterial blood gas profile for an organ that is undergoing perfusion.

Figure 34 is a schematic diagram of a portable lung care system with a disposable module configured.

Figure 35A is a diagram showing a pair of lungs removed.

Figure 35B is a diagram depicting a single lung removed.

Fig. 36 is a diagram showing a part of the lung circuit of a body from which at least one lung can be removed.

Figure 37 is a flow chart depicting an exemplary process for implementing a maintenance mode of operation within the lung care system of Figure 34.

FIG. 38 is a flow chart depicting another exemplary process for implementing a maintenance mode of operation within the lung care system of FIG. 34.

FIG. 39 shows exemplary measurement data collected during a lung care system maintenance mode of operation.

Figure 40 is a flow chart depicting an exemplary process for implementing an evaluation mode of operation within the lung care system of Figure 34.

Figure 41 shows one embodiment of the disposable module configured to preserve the removed lungs of Figure 35A.

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Figure 42 shows another embodiment of the disposable module configured to preserve the removed lungs of Figure 35A.

Figure 43 shows yet another embodiment of the disposable module configured to preserve the removed lungs of Figure 35A.

Figure 44 depicts a top view and profile view of an exemplary lung chamber assembly employed in the illustrative single-use disposable module of Figures 41-43.

Figure 45 depicts a top view and profile view of another exemplary lung chamber assembly employed in the illustrative single-use disposable module of Figures 41-43.

Figure 46 depicts a top view and profile view of another exemplary lung chamber assembly employed in the illustrative single-use disposable module of Figures 41-43.

Figure 47 depicts a top view and profile view of yet another exemplary lung chamber assembly employed in the illustrative single-use disposable module of Figures 41-43.

Figure 48A and Figure 48B show various views of an exemplary connector device used to cannulate the extracted pair of lungs of Figure 35A.

Figure 49A and Figure 49B show various views of another exemplary connector device used to cannulate the extracted pair of lungs of Figure 35A.

Figure 50A and Figure 50B show various views of another exemplary connector device most used to cannulate the removed pair of lungs of Figure 35A.

Figure 51A depicts an illustrative arrangement for cannulating the removed pair of lungs of Figure 35A.

Figure 51B depicts an exemplary cup-shaped interface.

Figure 52 depicts an illustrative screen for viewing and graphing real-time data collected from the lung care system of Figure 34.

Fig. 53 is a flow chart depicting a process on the donor side for donor lungs and placing them in the lung care system of Fig. 34.

Figure 54 is a flow chart depicting a recipient side process for removing lungs from the lung care system of Figure 34 and transplanting them into a recipient.

Detailed description

As briefly described above, the invention generally provides improved approaches to ex vivo organ care. More particularly, in various embodiments, the invention is directed to improving systems and procedures for maintaining an organ in an ex vivo portable environment. According to one improvement, the organ maintenance system keeps a heart beating at or near normal physiological conditions. To this end, the system circulates a nutrient-enriched, oxygenated perfusion fluid to the heart at a temperature, pressure and flow rate close to physiological. In other embodiments, the system maintains other organs, such as one or more lungs, at or near normal physiological conditions. According to one implementation, the system employs a perfusion fluid solution that more closely mimics normal physiological conditions. In one example, the perfusion fluid is a blood-based product. In alternative examples, the solution is based on a synthetic blood substitute. In other embodiments the solution may contain a blood product as compared to a blood substitute product. The blood product can be derived from donor blood or blood from a blood bank.

In accordance with various illustrative embodiments, the improvements of the invention allow an organ to be maintained ex vivo for extended periods of time , for example, exceeding 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or more hours. Such long ex vivo holding times expand the pool of potential recipients for donor organs, making the geographic distance between donors and recipients less important. The long ex vivo holding times of the invention also provide the time needed for a better genetic and HLA comparison between donor organs and organ recipients, increasing the likelihood of a favorable outcome. The ability to maintain the organ in a functioning condition close to physiological also allows a practitioner to evaluate the function of the organ ex vivo, further increasing the likelihood of transplant success. In some respects, the long maintenance time allows medical operators to perform repairs on donor organs with minor defects. In accordance with another advantage, the increased ex vivo organ maintenance times of the invention allow an organ to be excised from a patient, treated in isolation ex vivo, and then returned to the patient's body. Such treatment can include, without limitation, pharmaceutical treatments, gas therapies, surgical treatments, chemotherapies, biotherapies, genetic and / or radiation therapies.

Illustrative procedures of the invention are described below in the following order. First of all, it

ES 2 625 850 T3 describe the components of an Illustrative organ care system 100 for use with a heart. Second, illustrative operation of system 100 is described. Third, a subset of the components of system 100 is described in more detail. Fourth, illustrative control systems and procedures for system 100 are described. Fifth, an illustrative user interface is described. Sixth, the mechanical characteristics of system 100 are described in greater detail with respect to an exemplary implementation. Seventh, exemplary procedures for employing the system 100 during an organ harvesting, transport and transplantation procedure are described. Eighth, illustrative implementations of a system 1000 that adapt the system 100 to preserve lungs are described, and ninth, illustrative perfusion, nutritional and preservative solutions suitable for use with the system 1000 are presented.

Returning to illustrative examples, Figure 1 represents a schematic diagram of a portable organ care system 100. Figure 2 shows a conceptual drawing of a heart 102, which can be preserved / maintained ex vivo by the organ care system. organs 100 of the invention. Referring to Figures 1 and 2, illustrative system 100 includes an organ chamber assembly 104 for containing the heart 102 during ex vivo maintenance, a reservoir 160 for holding, defoaming and filtering perfusion fluid 108, a nozzle 774 for loading perfusion fluid 108 into reservoir 160 and a nozzle 762 for applying therapeutic substances to fluid 108 contained in reservoir 160, a perfusion fluid pump 106 for pumping / circulating perfusion fluid 108 to and from the withdrawn heart 102; a heater assembly 110 for maintaining the temperature of the perfusion fluid 108 at or near physiological temperatures; a flow mode selector valve 112 for switching between normal and retrograde aortic flow modes (also referred to as normal flow mode and retrograde flow mode, respectively); an oxygenator 114 for reoxygenating the perfusion fluid 108 after it is expelled from the heart 102; a nutritional subsystem 115 to replenish nutrients 116 in perfusion fluid 108 as they are metabolized by the heart 102 and to provide additional preservatives 118 to the perfusion fluid to reduce, for example, ischemia and / or other injuries related to reperfusion in the heart 102. Illustrative system 100 also includes a plurality of sensors, including without limitation: temperature sensors 120, 122, and 124; pressure sensors 126, 128, 130 and 132; perfusion flow sensors 134, 136 and 138; a perfusion fluid oxygenation sensor 140; and sensor electrodes 142 and 144, and a defibrillation source 143. System 100 further includes: various components used to maintain proper flow conditions to and from heart 102; an operator interface 146 to assist an operator in monitoring the operation of the system 100, and the status of the heart 102, and to allow the operator to select various operating parameters; a power subsystem 148 for providing fault tolerant power to system 100; and a controller 150 for controlling the operation of the organ care system 100.

Referring also to Figures 3 and 4, the system 100 can maintain the heart 102 in two modes of operation - a normal flow mode, shown in Figure 3, and a retrograde flow mode shown in Figure 4. In general, In the normal flow mode of FIG. 3, system 100 circulates perfusion fluid 108 toward heart 102 in the same way that blood would circulate in the human body. More particularly, referring to Figures 1-3, perfusion fluid enters left atrium 152 of heart 102 via pulmonary vein 168. Perfusion fluid 108 is flowed from right ventricle 154 via pulmonary artery 164 and from the left ventricle 156 through the aorta 158. In normal flow mode, system 100 pumps perfusion fluid to heart 102 at a near physiological flow rate of between about 1 liter / minute and about 5 liters / minute. This mode is useful, for example, to perform functional tests to verify that the heart 102 is free of defects, both before and after transport to a donor location.

Alternatively, in the retrograde flow mode, shown in Figure 4, system 100 flows perfusion fluid 108 into heart 102 through aorta 158, through coronary sinus 155 and other coronary vasculature of the heart, and outside the right ventricle 154 of the heart 102 via the pulmonary artery 164. As described in greater detail below with respect to Figures 24A and 24B, system 100 also provides drip flow 769 to left atrium 152 through drip valve 768. Drip flow is provided in a Sufficient amount to moisten the left atrium 152 and the left ventricle 156. In certain applications, the drip flow is less than about 5 ml / minute, less than about 1 ml / minute, or less than about 0.1 ml / minute. In this mode of operation, the system reduces the flow rate of the perfusion fluid 108 to between about 300 milliliters / minute and about 1 liter / minute. The inventors have discovered that the retrograde flow path of Figure 4, along with the reduced flow rate, reduces damage to the heart 102 during extended periods of ex vivo maintenance. In this way, heart 102 is transported to a donor site in retrograde flow mode.

ES 2 625 850 T3

Having briefly described the normal and retrograde flow modes, the system 100 will now be described in more operational detail. Referring once again to Figures 1-4, in one practice, heart 102 is removed from a donor and cannulated in organ chamber assembly 104. Perfusion fluid 108 is prepared for use within system 100 by being loaded into reservoir 160 through nozzle 774 and optionally being treated with therapeutic substances through nozzle 762. Pump 106 pumps the perfusion fluid charged 108 from reservoir 160 to heater assembly 110. Heater assembly 110 heats perfusion fluid 108 to or near normal physiological temperature. According to one example, heater assembly 110 heats the perfusion fluid to between about 32 ° C and about 37 ° C. Heater assembly 110 has an internal flow channel with a cross-flow area that is approximately equal to the internal cross-sectional area of ​​the fluid conduits that carry perfusion fluid 108 into and / or out of heater assembly 110, so that fluid flow disturbance is minimized. From heater assembly 110, perfusion fluid 108 flows to flow mode selector valve 112.

Initially, flow mode selector valve 112 is positioned in retrograde mode to direct perfusion fluid 108 from heater assembly 110 toward organ chamber assembly 104 via a first interface 162. Also referred to as an aortic interface or left ventricular interface, interface 162 includes cannulation to the vascular tissue of the left ventricle through an opening 228b located in organ chamber assembly 104 (as shown in Figures 5A-5B). As heart 102 warms up, it begins to beat causing heart 102 to pump perfusion fluid 108 through coronary vasculature 155 and out of heart 102 through right ventricle 154 via a second interface 166. The second interface 166, also referred to as the pulmonary artery interface or right ventricular interface, includes cannulation to the vascular tissue of the right ventricle through an opening 228c located on the organ chamber assembly 104 (as shown in Figures 5A-5B). As mentioned above, in retrograde flow mode, fluid is not actively pumped into or out of the left side of the heart, except for a relatively small drip of perfusion fluid, which is delivered to wet the left atrium. 152 and left ventricle 156, as described below with reference to Figures 24A-24E.

In response to the flow mode selector valve 112 being placed in the normal mode position, it directs perfusion fluid 108 to the left atrium 152 of heart 102 via a third interface 170. Third interface 170, also referred to as a pulmonary vein interface or left atrial interface, includes cannulation to the vascular tissue of the left atrium 152 through an opening 228A located in the organ chamber assembly 104 (as shown in the figures 5A-5B). Heart 102 then expels perfusion fluid 108 through left ventricle 156 via aorta interface 162 and through right ventricle 154 via pulmonary artery interface 166.

Each of interfaces 162, 166, and 170 can be cannulated up to heart 102 by pulling vascular tissue (eg, a section of aorta) over the end of the interface, then tying or otherwise securing the tissue to the interface. . Vascular tissue is preferably a short segment of a blood vessel (eg, aortic segment 158) that remains connected to heart 102 after heart 102 is separated and explanted from the donor. For example, the aorta interface 162 is cannulated to a small segment of the segmented aorta 158 that has been formed by segmenting the aorta 158 at a location downstream of the coronary sinus 155. In certain applications, the short vascular segments can be approximately 12 , 7 to about 25.4 cm (about 5 to about 10 inches) in length or longer. Segments can also be shorter than about 12.7 cm (5 inches). The segments can be from about 5.08 cm to about 10.16 cm (about 2 to about 4 inches) in length, or about 2.54 cm to about 5.08 cm (about 1 to about 2 inches) in length; in other applications the segments may be less than about 2.27 cm (about 1/2 inch), or less than about 0.635 cm (about 1/4 inch).

Alternatively, cannulation can occur by attaching the interface directly to the applicable atrium or ventricle, as may be preferred in applications where the heart 102 is prepared for explant by severing an entire blood vessel without leaving any segmented part of the vessel connected to the heart 102 . For example, left atrium cannulation 152 can be formed by inserting interface 170 directly into left atrium 152 and clamping interface 170 in place, without the need to tie to any pulmonary vein tissue 168.

Continuing with reference to FIG. 1, in both flow modes perfusion fluid 108 flows from pulmonary artery interface 166 into oxygenator 114. Oxygenator 114 receives gas from an external or on-board source 172 through a flow regulator. gas 174 and a gas flow chamber 176, which can be a pulse width modulated solenoid valve that controls gas flow, or any other control device

ES 2 625 850 T3 of gas that allows precise control of the gas flow. A gas pressure gauge 178 provides a visual indication of how full the gas supply 172 is. Transducer 132 provides similar information to controller 150. Controller 150 can automatically regulate the flow of gas into oxygenator 114 depending, by For example, the oxygen content in the perfusion fluid measured at sensor 140. According to various illustrative examples, the oxygenator 114 is a standard membrane oxygenator, such as the Liliput 2 manufactured by Dideco, a subsidiary of Sorin Biomedical, or the MINIMAX PLUS ™ manufactured by Medtronic, Inc. In the illustrative example, the gas It includes a mixture of oxygen and carbon dioxide. An example composition of such a mixture contains about 85% O2, about 1% CO2, with the balance being N2. Following reoxygenation, oxygenator 114 returns perfusion fluid 108 to reservoir 160. In accordance with the illustrative example, sensor 140 measures the amount of light absorbed or reflected by perfusion fluid 108 when applied to a length of waveform to provide an optical baseline measurement of oxygen saturation. Since the perfusion fluid 108 is a blood product based on certain examples, it may contain red blood cells (that is, cells that carry oxygen). Accordingly, sensor 140 also provides a signal 145 indicative of a hematocrit measurement of perfusion fluid 108. In alternate examples solution 108 is formed from a synthetic blood substitute, while in other examples solution 108 may contain a blood product in combination with a blood substitute product.

Also, in both flow modes, the nutritional subsystem 115, which includes a supply of maintenance solutions 116/118 and an infusion pump 182, infuses the perfusion fluid 108 with nutrients 116, such as glucose, as the solution Perfusion 108 flows through system 100, and in some embodiments, while in reservoir 160. Maintenance solutions 116/118 also include a supply of therapeutics and preservatives 118 to reduce ischemia and other reperfusion-related injuries to the heart 102.

Both the normal and retrograde flow modes are described in greater detail below with reference to Figures 24A-26B.

In accordance with the illustrative example, system 100 is primed prior to introducing an organ into organ chamber assembly 104. During priming, a priming solution (described below) is inserted into organ chamber 160 and pumped through system 100. In an example application, priming occurs over a period of between about 5 and about 20 minutes. Cannulation interfaces 162, 166, and 170 in organ chamber assembly 104 are bypassed to allow normal flow mode of perfusion fluid 108 through system 100, without donor heart 102 being present. The blood (or a synthetic blood substitute) is then loaded into reservoir 160. The blood may be the blood exsanguinated from the donor during extraction of the heart 102 or obtained from a typed and compared blood bank. System 100 then circulates the blood (or blood substitute) through system 100 to heat, oxygenate, and filter it. Nutrients, preservatives, and / or other therapeutic substances are provided through infusion pump 182 of nutritional subsystem 115. Various parameters can also be initialized and calibrated through operator interface 146 during priming. Once the system 100 is functioning properly, the pump flow rate can be decreased or brought to zero, and the heart 102 can be cannulated in the organ chamber assembly 104. The pump flow rate can then be increased. Priming of system 100 is described in greater detail below with reference to the flow chart of FIG. 29A.

As shown in Figure 1, system 100 also includes a plurality of compliance chambers 184, 186, and 188. The compliance chambers 184, 186 and 188 are essentially small in-line fluid accumulators with flexible, elastic walls designed to simulate the vascular compliance of the human body helping the system to more accurately mimic blood flow in the human body, providing back pressure. flow rate and / or filtering / reducing fluid pressure peaks due, for example, to changes in flow rate and / or pumping of pump 106. In accordance with the illustrative example, the compliance chamber 184 is located between an outlet 112a of a mode valve 112 and the reservoir 160 and operates in conjunction with an adjustable clamp 190 during normal flow mode to provide back pressure to the aorta 158 to cause perfusion fluid to flow into coronary sinus 155 to supply heart 102. In the illustrative example, the fluid back pressure provided to the aorta 158 is between about 55 mm Hg and about 85 mm Hg, which is within an acceptable range close to the physiological mean blood pressure in the aorta (which is normally between about 80 mm Hg and about 100 mm Hg). The back pressure of the aorta 158 helps the system 100 to simulate normal physiological conditions. The compliance chamber 186 is located between an outlet 112b of the mode valve 112 and the pulmonary vein cannulation interface 170 of the organ chamber assembly 104. The primary function of the compliance chamber 186 is to provide back pressure to the atrium. 152 and smooth the pressure / flow spikes caused by the pumping action of the perfusion fluid pump 106, which delivers blood to the heart without causing spikes in fluid pressure

ES 2 625 850 T3 substantial. In the Illustrative example, the fluid back pressure provided to Left atrium 152 is between about 0 mm Hg and about 14 mm Hg, which is about the same as left atrial pressure under normal physiological conditions. The compliance chamber 188 is located between an outlet of a one-way valve 310 and an inlet 110a of heater 110. The primary function of the compliance chamber 188 is also to smooth pressure / flow spikes caused by the pumping action of the perfusion fluid pump 106 and to provide fluid back pressure to the pulmonary artery 164. In the illustrative example, the fluid back pressure provided to pulmonary artery 164 is between about 0 mm Hg and about 25 mm Hg, which is within an acceptable range close to the physiological mean arterial blood pressure (between about 0 mm Hg and about 12 mm Hg).

The compliance chambers 188, 186 and 188 provide the benefits described above through their size and shape and the materials used in their design. Chambers 184, 186, and 188 are sized to hold from about 20 ml to about 100 ml of fluid 108, and are shaped in an oval configuration to allow them to receive fluid 108 and expand to dampen pressure spikes and to provide back pressure to the heart. 102. In certain applications, the material used for chambers 184, 186, and 188 includes at least one flexible membrane, selected so that the chambers have a Shore A durametric hardness (ASTM D2240 00) of about 10 (most flexible) to about 60 ( less flexible) with certain preferred embodiments having a hardness of between about 30 (+/- about 8) and about 50 (+/- about 8). In the illustrative embodiment, the compliance chamber 184 has a Shore A hardness of about 50 (+/- about 8) and the compliance chamber 186 has a Shore A hardness of about 30 (+/- about 8). In the illustrative embodiment, the compliance chamber 188 has a dual layer configuration with an inner chamber having a Shore A hardness of approximately 50 (+/- approximately 8) and an outer sleeve having a Shore A hardness of approximately 30 ( +/- about 8). Alternatively, the inner chamber can have a lower hardness (eg, about 30, +/- about 8) and the outer sleeve can have a higher hardness (eg, about 50, +/- about 8)).

Having provided an operational overview of system 1.00, organ chamber assembly 104, perfusion heater assembly 110, and pump head interface assembly 192 for interfacing with pump 106 are described in more detail below. . Figures 5A-5F depict various views of the illustrative organ chamber assembly 104 of Figure 1. As shown more clearly in Figures 5A5D, the organ chamber assembly 104 includes a housing 194, an outer lid 196, and an intermediate lid 198. The housing includes a bottom portion 194e and one or more walls 194a-194d to contain core 102. Middle cover 198 covers an opening 200 in housing 194 to substantially enclose core 102 within housing 194. As shown most clearly in Figures 5E and 5F, the intermediate cover 198 includes a frame 198a and a flexible membrane 198b suspended within the frame 198a. Flexible membrane 198b is preferably transparent but can be opaque, translucent, or substantially transparent. According to one feature, the flexible membrane includes sufficient excess membrane material to contact heart 102 when contained within housing 195. This feature allows a medical operator to touch / examine the heart 102 indirectly through the membrane 198b, or apply an ultrasound probe to the heart 102 through the membrane 198b, while maintaining the sterility of the housing 195. Membrane 198b can be made, for example, of any suitable flexible polymeric plastic material, for example polyurethane. The membrane 198b may also have integrated electrically conductive pads / contacts 199a and 199b through which the electrical activity of the heart can be measured by electrodes such as electrodes 142 and 144, and / or through which defibrillation signals can be delivered. or electrostimulation, as more fully described below. Alternatively, contacts 199a and 199b may be electrodes that include all or part of the functionality of electrodes 142 and 144. As shown in Figure 5C, outer cap 196 opens and closes on intermediate cap 198 independently of the intermediate cap 198. Preferably, the outer cap 196 is rigid enough to protect the heart 102 from physical contact, direct or indirect. Outer cap 196 and chamber 194 can also be made of any suitable polymeric plastic, for example polycarbonate.

According to one implementation, the housing 194 includes two hinge sections 202a and 202b, and the middle cover frame 198a includes two corresponding mating hinge sections 204a and 204b, respectively. Hinge sections 202a and 202b in housing 194 engage with hinge sections 204a and 204b in the frame of middle cover 198a to allow middle cover 198 to open and close relative to opening 200 of housing 194 . As shown more clearly in Figures 5D and 5F, the organ chamber assembly 104 also includes two pins 206b and 206b to secure the closed intermediate cover 198 over the opening 200. As shown in Figures 5E and 5F, Pins 206a and 206b are rotatably fitted in the pin hinge section 208a and 208b, respectively, on the wall 194c of the

ES 2 625 850 T3 housing 194. As shown most clearly in Figures 5a and 5E, the middle cover frame 198a also includes a hinge section 210. The hinge section 210 is rotatably adjusted with a mating hinge section 212 in outer cap 196 to allow outer cap 196 to open without opening intermediate cap 198. As best shown in Figures 5B, 5D, and 5F, outer cap 196 also includes two notches 214a and 214b to allow pins 206a and 206b to seat on edge 216 of mid-cap frame 198a. As shown in Figures 5B, 5D, and 5F, the organ chamber assembly 104 also includes a pin 218, which rotatably engages a hinge portion 220 of the wall 194c of the housing 194. In operation, latch 218 engages a flange 221 on edge 225 of outer cap 196 to secure outer cap 196 closed over intermediate cap 198.

As shown most clearly in Figures 5E and 5F, the intermediate cap also includes two gaskets 198c and 198d. Gasket 198d snaps between a periphery of mid-cap frame 198a and a periphery of outer cap 196 to form a fluid seal between mid-cap 198 and outer cap 196 when outer cap 196 is closed. Gasket 198c engages between an outer flange 194f of housing 194 and the frame of intermediate cover 198a to form a fluid seal between intermediate cover 198 and periphery 194f of housing 194 when intermediate cover 198 is closed.

Optionally, organ chamber assembly 104 includes a pad 222 or sack assembly sized and shaped to fit over an inner bottom surface 194g of housing 194. Preferably, pad 222 is formed from a material sufficiently elastic to protect the heart 102 from vibrations and mechanical shocks during transportation, for example, a closed cell foam. In accordance with one feature, pad 222 includes a mechanism for adjustably positioning a pair of electrodes, such as electrodes 142 and 144 of Figure 1. According to the illustrative example, the mechanism includes two through openings 224a and 224b. to route electrical leads from the underside of pad 222 to corresponding electrodes 142 and 144 on the heart contact surface of the pad. Passing electrical leads through pad 222 to electrodes 142 and 144 allows electrodes 142 and 144 to be adjustably positioned within pad 222 to accommodate hearts of varying sizes. In other examples, the mechanism may include, without limitation, one or more differently oriented slots, indentations, protrusions, through openings, partially through openings, hooks, eyelets, adhesive patches, or the like. In certain examples, pad 222 may be configured with one or more sleeve-like structures that allow an electrode to be inserted within pad 222, thereby providing a membrane-like surface of pad 222 positioned between the electrode and heart 102.

In some illustrative examples, pad 222 is configured as a pad assembly, the assembly including one or more electrodes, such as electrodes 142 and 144, adjustably located in or on pad 222. According to one advantage, the pad / electrode configuration facilitates contact between the electrodes and the heart 102 positioned on the pad 222, without temporarily or permanently suturing or otherwise mechanically connecting the electrodes to the heart 102. Weight The heart 102 itself can help stabilize the electrodes during transport. In accordance with the illustrative example, electrodes 142 and 144 include one or more sensors for monitoring one or more electrical signals from the heart and / or defibrillators to provide an electrical signal to the heart. As shown in Figures 1 and 5C, organ chamber assembly 104 includes electrical interface connections 235a-235b, which are mounted in openings 234a-234b, respectively, in wall 194b of housing 194. A cover 226 is provided to protect electrical interface connections 235a-235b when not in use.

As described in more detail below with reference to Figure 15, interface connections 235a and 235b couple electrical signals, such as ECG signals, from electrodes 142 and 144 outside of housing 194, for example, to the controller 194 and / or operator interface 146. As described in more detail below with reference to Figure 22A, interface connections 235a and 235b can also be coupled to a defibrillation source, which can be provided either by external instrumentation or through circuitry within system 100. , and that they can send a defibrillation or pacing signal 143 through electrodes 142 and 144 to heart 102.

As shown most clearly in Figures 5E and 5F, the organ chamber assembly 104 includes a resealable membrane interface 230, which mounts in an interface opening 232. The interface 230 includes a frame 230a and a resealable polymeric membrane 230b mounted on frame 230a. The membrane 230b can be made of silicone or any other suitable polymer. In operation, interface 230 is used to provide pacing signals, when needed, to heart 102, without having to open chamber lids 196 and 198. Membrane 230b is sealed around pacing leads to maintain a

ES 2 625 850 T3 closed environment around heart 102. Membrane 230b also reseals in response to removal of pacing leads.

As shown in Figures 5A and 5B, organ chamber assembly 104 includes openings 228a-228c for receiving aortic interface 162, pulmonary artery interface 166, and pulmonary vein interface 170, previously described with reference to Figures 1-4, and below with reference to Figures 24A-28C. As shown in Figure 5D, organ chamber assembly 104 also includes drain 201 for draining perfusion fluid 108 out of housing 194 back into reservoir 160, and mounting receptacles 203a-203d for mounting. the organ chamber assembly 104 on the single-use module (shown at 634 in FIG. 19A).

Figures 6A-6F depict various views of the perfusion fluid heater assembly 110 of Figure 1. As shown in Figures 6A and 6B, heater assembly 110 includes a housing 234 having an inlet 110a and an outlet 110b. As shown in both the longitudinal cross-sectional view of Figure 6D and the side cross-sectional view of Figure 6E, heater assembly 110 includes a flow channel 240 extending between inlet 110a and outlet 110b. Heater assembly 110 can be conceptualized as having symmetrical upper 236 and lower 238 halves. Accordingly, only the upper half is shown in an exploded view in Figure 6F.

Referring now to Figures 6D-6F, flow channel 240 is formed between a first 242 and a second 244 flow channel plates. Inlet 110a flows perfusion fluid into flow channel 240 and outlet 110b flows perfusion fluid out of heater 110. The first 242 and second 244 flow channel plates have substantially bio-inert perfusion fluid contact surfaces 108 (which may contain a blood product in certain embodiments) to provide direct contact with the perfusion fluid flowing through the channel. 240. The fluid contacting surfaces may be formed from a treatment or coating on the plate or it may be the surface of the plate itself. Heater assembly 110 includes first and second electric heaters 246 and 248 respectively. The first heater 246 is located adjacent to and couples heat to a first heater plate 250. The first heater plate 250, in turn, is heat coupled to the first plate of the flow channel 242. Similarly, the second heater 248 is located adjacent ay couples heat to the second heater plate 252. The second heater plate 252 couples heat to the second plate of the flow channel 244. In accordance with the illustrative embodiment, the first 250 and second 252 heater plates are formed from a material such as aluminum, which conducts and distributes the heat from the first and second electric heaters 246 and 248, respectively, relatively uniformly. The uniform heat distribution of the heater plates 250 and 252 allows the flow channel plates to be formed of a bio-inert material, such as titanium, reducing concern regarding their heat distribution characteristics.

Referring particularly to Figures 6E and 6F, heater assembly 110 also includes O-rings 254 and 256 for fluid sealing respective flow channel plates 242 and 244 to housing 234 to form flow channel 240.

Heater assembly 110 includes first mounting brackets 258 and 260. Mounting bracket 258 mounts on top side 236 of heater assembly 110 on a periphery of electric heater 246 to sandwich heater 246, heater plate 250, and heater plate. flow channel 242 between mounting bracket 258 and housing 234. Bolts 262a-262j fit through corresponding through holes in housing 258, electric heater 246, heater plate 250, and flow channel plate 242, and are threaded into corresponding nuts 264a-264j to secure all of these components. to casing 234. The mounting bracket 260 is mounted on the underside 238 of the heater assembly 110 in a similar manner to secure the heater 248, the heater plate 252, and the flow channel plate 244 to the housing 234. A resilient pad 268 fits within. of a periphery of support 258. Similarly, a resilient pad 270 fits within a periphery of support 260. A support 272 fits over pad 268. Bolts 278a and 278f fit through holes 276a-276f, respectively, in bracket 272 and screw into nuts 280a-280f to compress spring pad 268 against heater 246 to provide more efficient heat transfer to the heater plate 250. The elastic pad 270 is compressed against the heater 248 in a similar manner by the bracket 274.

As mentioned with respect to Figure 1, and also as shown in Figure 6A, the illustrative heater assembly 110 includes temperature sensors 120 and 122 and a dual sensor 124. The dual sensor 124 in practice includes a thermistor sensor. Dual to provide fault tolerance, it measures the temperature of the perfusion fluid 108 exiting the heater assembly 110, and provides these temperatures to the controller 150. As described in more detail below with respect to heater subsystem 149 of FIG. 13, the signals

ES 2 625 850 T3 from sensors 120, 122 and 124 can be used in a feedback loop to control Pulse signals from first heater 246 and / or second heater 248 to control the temperature of heaters 256 and 248. Additionally, to ensure that the heating plates 250 and 252 and therefore the blood-contacting surfaces 242 and 244 of the heating plates 250 and 252 do not reach a temperature that could damage the perfusion fluid, the assembly Illustrative heater 110 also includes temperature sensors / lead wires 120 and 122 to monitor the temperature of heaters 246 and 248, respectively, and provide these temperatures to controller 150. In practice, the sensors connected to the sensors / lead wires 120 and 122 are based on RTD (resistance temperature device). As also described in detail with respect to Figure 13, signals from sensors connected to sensors / lead wires 120 and 122 can be employed in a feedback loop to further control the pulse signals from first heater 246 and / or or second heater 248 to limit the maximum temperature of heater plates 250 and 252. As a protection against failure, there are sensors for each of the heaters 246 and 248, so that if one of them fails, the system can continue to operate with the temperature at the other sensor.

As described in more detail below with respect to FIG. 13, heater 246 of heater assembly 110 receives from controller 150 pulse signals 281a and 281b (collectively 281) on corresponding pulse wire 282a. Similarly, heater 248 receives from controller 150 pulse signals 283a and 283b (collectively 283) on pulse wire 282b. The pulse signals 281 and 283 control the current going to, and thus the heat generated by, the respective heaters 246 and 248. More particularly, as shown in Figure 7, the pulse cables 282a include a pair high and low, which are connected across a resistive element 286 of heater 246. The greater the current supplied through resistive element 286, the more resistive element 286 heats up. Heater 248 functions in the same way with respect to pulse wire 282b. According to the illustrative examples, element 286 has a resistance of approximately 5 ohms. However, in other illustrative examples, the element may have a resistance of between about 3 ohms and about 10 ohms. As described in more detail below with respect to Figures 11 and 13, heaters 246 and 248 can be independently controlled by processor 150.

In accordance with the illustrative example, the heater assembly housing components 110 are formed from a molded plastic, eg, polycarbonate, and weigh less than about one pound. More particularly housing 234 and brackets 258, 260, 272 and 274 are all formed from a molded plastic, for example polycarbonate. According to another feature, the heater set is a single-use disposable set.

In operation, the illustrative heater assembly 110 uses between about 1 Watt and about 200 Watts of power, and is sized and shaped so that the transition of perfusion fluid 108 flowing through channel 240 at a flow rate between about 300 ml / minute and about 5 L / minute from a temperature of less than about 30 ° C to a temperature of at least about 37 ° C in less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, or even less than about 10 minutes, without causing substantially hemolysis of cells, or denaturing proteins or otherwise damaging any blood product part of the fluid perfusion. In accordance with one feature, heater assembly 110 includes shell components, such as shell 234 and brackets 258, 260, 272, and 274, that are formed of polycarbonate and weigh less than about 5 pounds. In other examples, the heater assembly may weigh less than about 4 pounds, less than about 3 pounds, less than about 2 pounds, or even less than about 1 pound. In the illustrative embodiment, heater assembly 110 has a length 288 of approximately 6.6 inches, not including inlet ports 110a and outlet ports 110b, and a width 290 of approximately 2.7 inches. Heater assembly 110 has a height 292 of approximately 2.6 inches. The flow channel 240 of the heater assembly 110 has a nominal width 296 of approximately 3.81 cm (1.5 inches), a nominal length 294 of approximately 8.89 cm (3.5 inches), and a nominal height 298 of approximately 1,778 mm (0.070 inches).

Height 298 and width 296 are selected to provide uniform heating of perfusion fluid 108 as it passes through channel 240. Height 298 and width 296 are also selected to provide a cross-sectional area within channel 240 that is approximately equal to the interior cross-sectional area of ​​fluid conduits that carry perfusion fluid 108 into and / or out of heater assembly 110. In one configuration, height 298 and width 296 are selected to provide a cross-sectional area within channel 240 that is approximately equal to the interior cross-sectional area of ​​inlet fluid conduit 792 (shown below with reference to Figure 25C) and / or substantially equal to the interior cross-sectional area of ​​the fluid conduit

ES 2 625 850 T3 output 794 (shown below with reference to FIG. 24E).

Projections 257a-257d and 259a-259d are included in heater assembly 110 and are used to receive a heat activated adhesive to bond the heater assembly to multipurpose unit 650 (referenced in Figure 20A).

Figures 8A-8C show various views of a pump interface assembly 300. Figure 9 shows a perspective view of a pump drive end of the perfusion fluid pump assembly 106 of Figure 1, and Figure 10 shows the pump interface assembly 300 mated with the pump drive end of the perfusion fluid pump assembly 106. Referring to Figures 8A-10, the pump interface assembly 300 includes a housing 302 having an outer side 304 and an inner side 306. The interface assembly 300 includes an inlet 308 and an outlet 310. Also shown most clearly in the bottom view of Figure 8B and in the exploded view of Figure 8C, that the pump interface assembly 300 also includes internal 312 and external 314 O-rings, two deformable membranes 316 and 318, and a torus shaped bracket 320, and half rings 319a and 319b that fit within the O-ring 314 and bracket 320. The half rings 319a and 319b may be made of foam, plastic, or other suitable material.

The inner O-ring 312 fits into an annular track along a periphery of the inner side 306. The first deformable membrane 316 is mounted on the inner O-ring 312 in fluid-tight interconnection with the inner side 306 of the housing 302 to form a chamber between the inner side of the first deformable membrane 316 and the inner side 306 of the housing 302. A second deformable membrane 318 fits over the top of the first membrane 316 to provide fault tolerance in the event that the first deformable membrane 316 breaks or tears. Illustratively, the deformable membranes 316 and 318 are formed of a thin film of polyurethane (approximately 0.0508mm / 0.002 inches thick). However, any suitable material of any suitable thickness can be employed. Referring to Figures 8A and 8B, bracket 320 is mounted on second deformable membrane 318 and rings 319a and 319b and is fixed on housing 302 along a periphery of inner side 306. Threaded fasteners 322a-322i fix bracket 320 to housing 302 via respective threaded openings 324a-324i in bracket 320. As shown in Figure 8B, the outer O-ring 314 fits into an annular groove in the bracket 320 to provide a fluid tight seal with the pump assembly 106. Before inserting the O-ring 314 into the annular groove in the bracket 320, the half rings 319a and 319b are placed in the groove. O-ring 314 is then compressed and positioned within the annular groove in bracket 320. After being positioned within the annular groove, the O-ring 314 expands within the groove to secure itself and the half rings 319a and 319b in place.

The pump interface assembly 300 also includes heat bonding points 321a-321c, projecting from its outer side 304. As described in more detail with reference to Figures 21A-21C and 24A-24C below, the Points 321a-321c are given a hot glue to heat bond the pump interface assembly 300 to a C-shaped bracket 656 of the single-use disposable module frame 635.

As shown in FIG. 8C, the fluid outlet 310 includes an outlet housing 310a, an outlet connection 310b, a flow regulator ball 310c, and an outlet port 310d. Ball 310c is sized to fit within outlet port 310d, but does not pass through an internal opening 326 in outlet 310. Connection 310b is connected to outlet port 310d (eg, through epoxy or other adhesive) to capture ball 310c between internal opening 326 and connection 310b. Outlet housing 310a is similarly attached to connection 310b.

In operation, the pump interface assembly 300 is aligned to receive a pumping force from a pump driver 334 of the perfusion fluid pump assembly 106 and transfer the pumping force to the perfusion fluid 108, thereby circulating perfusion fluid 108 to organ chamber assembly 104. In accordance with the illustrative example, the perfusion fluid pump assembly 106 includes a pulsatile pump having an impeller 334 (described in more detail below with respect to FIG. 9), which contacts the membrane 318. Fluid inlet 308 draws perfusion fluid 108, for example, from reservoir 160, and provides the fluid into the chamber formed between inner membrane 316 and inner side 306 of housing 302 in response to movement of the pump impeller. the pump in a direction away from the deformable membranes 316 and 318, thereby deforming the membranes 316 and 318 in the same direction. As the pump impeller moves away from deformable membranes 316 and 318, the pressure head of fluid 108 within reservoir 160 causes perfusion fluid 108 to flow from reservoir 160 into pump assembly 106. A In this regard, pump assembly 106, inlet valve 191, and reservoir 160 are oriented to provide a gravity feed of perfusion fluid 108 into pump assembly 106. At the same time, the flow regulator ball 310c is drawn into the opening 326 to prevent the flow fluid from

ES 2 625 850 T3 perfusion 108 is also drawn into the chamber through outlet 310. It should be noted that outlet valve 310 and inlet valve 191 are one-way valves in the illustrated example, but in alternative examples the valves 310 and / or 191 are two-way valves. In response to movement of pump impeller 334 in a direction toward deformable membranes 316 and 318, flow regulator ball 310c moves toward connection 310b to open internal opening 326, allowing outlet 310 to expel fluid from the pump. perfusion 108 out of the chamber formed between the inner side 306 of the housing 302 and the inner side of the deformable membrane 316. A separate one-way inlet valve 191, shown between reservoir 160 and inlet 308 in FIG. 1, prevents any perfusion fluid from being expelled out of inlet 308 and flowing back into reservoir 160.

As described in more detail below with respect to Figures 18A-27B, in certain examples the organ care system 100 is mechanically divided into a disposable single-use unit (shown at 634 in Figures 19A-19C and 24A-25C) and a non-disposable multipurpose unit (shown at 650 in Figure 20A). In such examples, pump assembly 106 is rigidly mounted on multipurpose module 650, and pump interface assembly 300 is rigidly mounted on disposable single-use module 634. Pump assembly 106 and the pump interface assembly 300 have interlocking connections, which mate with each other to form a fluid tight seal between the two assemblies 106 and 300.

More particularly, as shown in the perspective view of Figure 9, the perfusion fluid pump assembly 106 includes a pump impeller housing 338 having a top surface 340, and a pump impeller 334 housed within a cylinder 336 of the casing 338. Pump impeller housing 338 also includes a mating hole 342, which includes a slot 332 sized and shaped to mate with a flange 328 projecting from pump interface assembly 300. As shown in Figure 10 , the upper surface 340 of the pump impeller housing 338 is mounted on a bracket 346 on the non-disposable multipurpose module unit 650. Bracket 346 includes features 344a and 344b to abut perforated projections 323a and 323b, respectively, of pump interface assembly 300. Bracket 346 also includes a notch 330 sized and shaped to align with mating hole 342 and slot 332 in pump impeller housing 338.

Operatively, the joint between the pump interface assembly 300 and the fluid pump assembly 106 is formed in two stages, illustrated with reference to Figures 9 and 10. In a first stage, the flange 328 is positioned within the orifice of coupling 342, while tapered projections 323a and 323b are positioned clockwise laterally adjacent to corresponding features 344a and 344b on bracket 346. A second stage, as shown by arrows 345, 347 and 349 in Figure 9, the pump interface assembly 300 and the fluid pump assembly 106 are rotated in opposite directions (for example, by rotating the assembly interface key 300 in a counterclockwise direction while holding the pump assembly 106 fixed) to slide the flange 328 into the slot 332 of the mating hole 342. At the same time, the tapered projections 323a and 323b slide under the support features 344a and 344b, respectively, engaging the inner surface of the support features 344a and 344b with the tapered outer surfaces of the tapered projections 323a and 323b to extract the inner side 306 of pump interface assembly 300 toward pump impeller 334 and to interlock flange 328 with mating holes 342, and tapered projections 323a and 323b with support features 344a and 344b to form the fluid tight seal between the two assemblies 300 and 106.

Having described illustrative organ care system 100 from a system, operating, and component standpoint, illustrative control systems and procedures for achieving system 100 operation are described below. More particularly, FIG. 11 depicts a Block diagram of an illustrative control scheme for system 100. As described above with reference to FIG. 1, system 100 includes a controller 150 to control the operation of system 100. As shown, controller 150 interoperably connects with the following six subsystems: an operator interface 146 to assist an operator in monitoring and controlling the system 100, and in monitoring the status of the heart 102; a data acquisition subsystem 147 having various sensors to obtain data relating to the heart 102 and the system 100 and to bring the data to the controller 150. A power management subsystem 148 for providing fault tolerant power to system 100; a heating subsystem 149 for providing controlled power to heater 110 to heat perfusion fluid 108; a data management subsystem 151 for storing and maintaining data related to the operation of the system 100 and with respect to the heart 102; and a pump subsystem 153 to control the pumping of perfusion fluid 108 through system 100. It should be noted that although the system 100 is conceptually described with reference to a single controller 150, the control of the system 100 may also be distributed across a plurality of controllers or

ES 2 625 850 T3 processors. For example, any or all of the described subsystems may include a dedicated processor / controller. Optionally, the dedicated processors / controllers of the various subsystems can communicate with and through a central controller / processor.

Figures 12-17J illustrate the interoperation of the various subsystems of Figure 11. Referring first to the block diagram of Figure 12, the data acquisition subsystem 147 includes sensors to obtain information pertinent to how the system is operating. 100 and the heart 102, and to communicate that information to the controller 150 for processing and use by the system 100. As described with respect to FIG. 1, the sensors of subsystem 147 include, without limitation: temperature sensors 120, 122, and 124; pressure sensors 126, 128 and 130; flow sensors 134, 136 and 138; oxygenation / hematocrit sensor 140; and electrodes 142 and 144. The data acquisition subsystem 147 also includes: a Hall sensor set 388 and a shaft encoder 390 from the perfusion pump assembly 106; battery sensors 362a-362c to detect if batteries 352a-352e, respectively, are sufficiently charged; an external available power sensor 354 to detect if an external AC power source is available; an operator interface module battery sensor 370 for detecting a state of charge of the operator interface module battery; and a gas pressure sensor 132 for detecting the flow of gases from the gas flow chamber 176. How the system 100 uses information from the data acquisition subsystem 147 will now be described with respect to the heating 149, power management 148, pumping 153, data management 151 and operator interface 146 subsystems, shown with greater detail in Figures 13-17J respectively.

Heating subsystem 149 is depicted in the block diagram of Figure 13. With continued reference also to Figure 1, heating subsystem 149 controls the temperature of perfusion fluid 108 within system 100 through a dual approach. feedback loop. In the first loop 251 (the perfusion fluid temperature loop) the perfusion fluid temperature thermistor sensor 124 provides two signals (fault tolerant) 125 and 127 to the controller 150. The signals 125 and 127 are indicative of the temperature of perfusion fluid 108 as it exits heater assembly 110. Controller 150 regulates pulse signals 285 and 287 to drivers 247 and 249, respectively. Drivers 247 and 249 convert corresponding digital level signals 285 and 287 from controller 150 to pulse signals from heater 281 and 283, respectively, which have current levels sufficient to drive first heater 246 and second heater 248 to heat perfusion fluid 108 within a temperature range selected by an operator. In response to controller 150 sensing that perfusion fluid temperatures 125 and 127 are below the operator-selected temperature range, it adjusts pulse signals 281 and 283 to first heater 246 and second heater 248, respectively, to a level sufficient to continue heating of the perfusion fluid 108. Rather, in response to controller 150 sensing that perfusion fluid temperatures 125 and 127 are above the temperature range selected by the operator, it decreases pulse signals 281 and 283 to first heater 246 and second heater. 248, respectively. In response to detecting that the temperature of the perfusion fluid 108 is within the temperature range selected by the operator, the controller 150 maintains the pulse signals 281 and 283 at constant or substantially constant levels.

Preferably, controller 150 varies pulse signals 281 and 283 in substantially the same way. However, this is not necessarily the case. For example, each heater 246 and 248 may respond differently to a particular voltage level or current pulse signal. In that case, controller 150 can drive each heater 246 and 248 to a slightly different level to obtain the same temperature from each. According to one characteristic, the heaters 246 and 248 each have an associated calibration factor, which the controller 150 stores and uses when determining the level of a particular pulse signal to allow a particular heater to achieve a result of particular temperature. In certain configurations, controller 150 defines one of the thermistors in dual sensor 124 as the default thermistor, and will use the default thermistor temperature reading in cases where the thermistors give two different temperature readings. In certain configurations, when the temperature readings are within a predefined range, the controller 150 uses the higher of the two readings. Drivers 247 and 249 apply heating pulse signals 281 and 283 to corresponding pulse wires 282a and 282b on heater assembly 110.

In the second loop 253 (the heater temperature loop), the heater temperature sensors 120 and 122 provide signals 121 and 123, indicative of the temperatures of the heaters 246 and 248, respectively, to the controller 150. According to the illustrated example, a temperature threshold is set for heaters 246 and 24s (for example, by default or by operator selection), above which the temperatures of heaters 246 and 248 are not allowed to rise. . As the temperatures of heaters 246 and 248 rise and approach the temperature threshold, sensors 121 and 123 indicate what

ES 2 625 850 T3 itself to controller 150, which then decreases pulse signals 281 and 283 to heaters 246 and 248 to reduce or stop the supply of power to heaters 246 and 248. Thus, while the low temperature signal 125 or 127 from the temperature sensor to the perfusion fluid 124 can cause the controller 150 to increase the power to the heaters 246 and 248, the temperature sensors of the heaters 120 and 122 ensure that heaters 246 and 248 are not being driven to a level that could cause their respective heater plates 250 and 252 to become so hot that they damage perfusion fluid 108. In accordance with various illustrative examples, controller 150 is adjusted to maintain the perfusion fluid temperature between about 32 ° C and about 37 ° C, or between about 34 ° C and about 36 ° C. In accordance with a further illustrative embodiment, controller 150 is defined to limit the maximum temperature of heater plates 250 and 252 to less than about 38 ° C, 39 ° C, 40 ° C, 41 ° C, or 42 ° C.

As can be seen, the second loop 253 is configured to override the first loop 251, if necessary, such that the temperature readings from the temperature sensors 120 and 122 indicative that the heaters 246 and 248 are approaching Maximum allowable temperature overrides the effect of any low temperature signal from the perfusion fluid temperature sensor 124. In this regard, subsystem 149 ensures that the temperature of the heating plates 250 and 252 will not rise above the maximum allowable temperature, even if the temperature of the perfusion fluid 108 has not reached the temperature value selected by the operator. This override feature is particularly important during fault situations. For example, if the perfusion fluid temperature sensors 124 both fail, the second loop 253 prevents the heater assembly 110 from overheating and damaging the perfusion fluid 108 by switching control exclusively to the heater temperature sensors. tadores 120 and 122 and dropping the temperature set point to a lower value. In accordance with one feature, controller 150 takes into account two time constants assigned to delays associated with temperature measurements from heaters 246 and 248 and perfusion fluid 108 to optimize the dynamic response of temperature controls.

Figure 14 depicts a block diagram of the power management system 148 for providing fault tolerant power to the system 100. As shown, the system 100 can be powered by one of four sources - by an external AC source 351 (for example, 60 Hz, 120 VAC in North America or 50 Hz, 230 VAC in Europe) or by one of three independent 352a-352c batteries. Controller 150 receives data from a line voltage availability sensor AC 354, which indicates if AC voltage 351 is available for use by system 100. In response to controller 150 detecting that AC voltage 351 is not is available, the controller 150 sends a signal to the power switching circuits 356 to provide high power to the system 358 from one of the batteries 352a-352c. Controller 150 determines from battery charge sensors 362a-362c which of the available batteries 352a-352c is most fully charged, and therefore switches that battery to operation via switching network 356.

Alternatively, in response to controller 150 sensing that external AC voltage 351 is available, it determines whether to use available AC voltage 351 (e.g., post rectification) to provide power to system 358 to provide power to the interface module. of user 146, to charge one or more of the batteries 352a-352c, and / or to charge the internal battery 368 of the user interface module 146, which also has its own internal charger and charge controller. To use the available AC 351 voltage, the controller 150 draws the AC 351 voltage to the power supply 350 by sending a signal through the switching system 364. The power supply 350 receives the AC 351 voltage and converts it to DC current for provide power to system 100. The 350 power supply is universal and can handle any line frequency or line voltages commonly used around the world. According to the illustrative example, in response to a low battery indication from one or more of the battery sensors 362a-362c, the controller 150 also sends power through the switching network 364 and the charging circuit 366 to the appropriate battery. In response to controller 150 receiving a low battery signal from sensor 370, it also or alternatively directs a charging voltage 367 to user interface battery 368. According to another feature, power management subsystem 148 selects batteries to power the system 100 in the order of least charged first, preserving the most charged batteries. If the battery that is currently being used to power system 100 is removed by the user, power management subsystem 148 automatically switches to the next less charged battery to continue powering subsystem 100.

In accordance with another feature, the power management subsystem 148 also employs a locking mechanism to prevent one or more of the batteries 352a-352c from being removed from the system 100 at any given time. If one battery is removed, the other two batteries are mechanically locked into position within system 100. In this regard, system 148 provides a level of fault tolerance to help ensure that a source of

ES 2 625 850 T3 358 power is always available for system 100.

The pumping subsystem 153 of Figure 11 will now be described in greater detail with reference to Figures 15 and 16. More particularly, Figure 15 is a conceptual block diagram depicting the illustrative pumping subsystem 153, and Figure 16 shows an exemplary ECG 414 of a heart 102 synchronized with an exemplary wave 385 representing the pump output of subsystem 153. The ECG 414 shown in FIG. 16 has peaks P, Q, R, S, T, and U. Pump subsystem 153 includes perfusion fluid pump 106 interoperably connected with pump interface assembly 300, as described in more detail above with reference to Figures 8A-10. As shown in FIG. 15, controller 150 operates pump subsystem 153 by sending a pulse signal 339 to a brushless three-phase pump motor 360 using Hall sensor feedback. Pulse signal 339 causes pump motor shaft 337 to rotate, thereby causing pump screw 341 to move pump impeller 334 up and / or down. According to the illustrative example, the pulse signal 339 is controlled to change a rotational direction and rotational speed of the motor shaft 337 to cause the pump impeller 334 to move up and down cyclically. This cyclical movement pumps perfusion fluid 108 through system 100.

In operation, controller 150 receives a first signal 387 from Hall sensors 388 positioned integrally within pump motor shaft 337 to indicate the position of pump motor shaft 337 for purposes of switching motor winding currents. Controller 150 receives a second higher resolution signal 389 from shaft encoder sensor 390 that indicates a precise rotational position of pump screw 341. From the current switching phase position of motor 387 and current rotational position 389, controller 150 calculates the appropriate pulse signal 339 (both magnitude and polarity) to make the necessary rotational change in motor shaft 337 to produce the appropriate vertical position change in pump screw 341 to achieve the desired pumping action. By varying the magnitude of the pulse signal 339, the controller 150 can vary the pump speed (that is, how frequently the pump cycle repeats) and by varying the rotational direction changes, the controller 150 can vary the displacement volume of pumping (eg by varying how far the pump impeller 334 moves during one cycle). In general terms, the cyclic pumping rate regulates the pulsatile flow rate at which perfusion fluid 108 is delivered to heart 102, while (for a given flow rate) the pumping displacement regulates the volume of perfusion fluid 108 delivered to heart 102. .

Both the flow rate and the displacement volume affect the flow rate, and indirectly the pressure of the perfusion fluid 108 to and from the heart 102. As mentioned with respect to Figure 1, the system includes three flow sensors 134, 136 and 138, and three pressure sensors 126, 128, and 130. As shown in Figure 15, sensors 134, 136, and 138 provide corresponding flow signals 135, 137, and 139 to controller 150. Similarly, sensors 126, 128, and 130 provide corresponding pressure signals 129, 131, and 133 to controller 150. Controller 150 uses all three of these signals in feedback to ensure that the commands it is providing to perfusion pump 106 have the desired effect on system 100. In some cases, and as described in more detail below with reference to Figures 17A-17J, controller 150 may generate various alarms in response to a signal indicating that a particular fluid flow rate or pressure is out of range. acceptable. Additionally, employing multiple sensors allows controller 150 to distinguish between a mechanical problem (eg, a blocked conduit) with system 100 and a biological problem with heart 102.

In accordance with one feature of the invention, pumping system 153 may be configured to control the position of the pump impeller 334 during each moment of the pumping cycle to allow for finely adjusted pump flow rate and volumetric profiles. This in turn allows pumping system 153 to deliver perfusion fluid 108 to the heart in any desired pulsatile pattern. In accordance with an illustrative example, the rotational position of shaft 337 is sensed by shaft encoder 390 and adjusted by controller 150 to at least 100 increments per revolution. In another illustrative example, the rotational position of shaft 337 is sensed by shaft encoder 390 and adjusted by controller 150 to at least 1000 increments per revolution. In accordance with a further illustrative example, the rotational position of shaft 337 is sensed by shaft encoder 390 and adjusted by controller 150 to at least 2000 increments per revolution. The vertical position of the pump screw 341 and therefore the pump impeller 334 is initially calibrated to zero or a home position, corresponding to a reference position of the pump screw 341.

In accordance with the illustrative example, the positional precision of the pump subsystem 153 allows the controller 150 to precisely regulate the pumping of the perfusion fluid 108 through the heart 102. This process of synchronizing the pulsatile flow of the perfusion fluid with the frequency natural heart is called in the

R-wave synchronization, which is described with continued reference to Figures 2, 15, and 16. A normally functioning heart has a two-phase pump cycle - diastole and systole. During the diastolic phase, also known as the resting phase, the heart's atria 157 and 152 contract, causing the valves to open between atria 157 and 152 and ventricles 154 and 156 to allow blood to flow in and out. Charge ventricles 154 and 156. During the systolic phase, the charged ventricles eject blood, and atria 157 and 152 open and fill with blood. The cyclical expansion and contraction of the heart 102 during this process can be represented by a graph of the heart's ventricular ECG waveform, shown at 414 in Figure 16. Figure 16 depicts the ECG waveform 414 synchronized with an exemplary waveform 385 representative of a pumping output by subsystem 153.

The pump subsystem 153 is configured to provide the maximum output at one time, which will result in the delivery of fluid 108 to the heart 102 at the most beneficial time. In the illustrated example, in retrograde mode, pump subsystem 153 is configured to pump fluid 108 through heart 102 such that maximum pump output 382 occurs during the diastolic phase of the heart, which begins after the S peak. shown in Figure 16 and is when the left ventricle 156 has finished expelling the perfused fluid 108 through the aorta 158. Timing of pump output in this manner allows the user to maximize injection of perfusion fluid 108 through aorta 158 and into coronary sinus 155. Timed pumping is achieved by initiating pumping at point 377 on the wave. 385, which is a point before point 382 and corresponds to the peak of the r-wave pulse of the heart 380 and the middle of ventricular systole. Point 377 is selected to account for the time delay between the time the signal from the controller 150 is provided to initiate pumping of the fluid and the actual delivery time of the pumped fluid at 108 to the heart 102. In another example, during normal flow mode where the left side of the heart fills and expels perfusion fluid (as described in more detail with reference to Figure 24A), controller 150 synchronizes pump subsystem 153 to initiate pumping in a fixed period of time after the r wave 380, so that it coincides with the natural filling cycle of the left atrium 152. Timing can be fine-tuned and fine-tuned by the operator through a pre-programmed routine in the operating software of system 100 and / or by manually operating the controls of the user interface display area 410, as described in more detail below with reference to Figures 17A-17J.

To achieve the synchronized pump output, the controller 150 predicts when the r-wave pulses from the heart 380 will present and cause the pump to pump at the appropriate time during the ECG 414. To make this prediction, the controller 150 measures the pulse pulses. r-wave of varying length 380 from electrical signals 379 and 381 provided by electrodes 142 and 144, respectively. From these pulses, controller 150 tracks the time elapsed from one pulse 380 to the next, and uses this information to calculate a sliding average of the length of time that separates two sequential r-wave pulses. From this information, controller 150 projects the time of the next r-wave (and from the projection determines the time before or after the projected r-wave when pumping must start to reach the optimal supply output) by adding the average time separating two r-wave pulses sequential to the time of the previous r-wave 380. Based on this sliding average r-wave separation time, controller 150 has the option of adjusting the pump output time with respect to subsequent r-waves, as reflected by the movement of wave 385 to the left or to the left. right along ECG 414 as indicated by arrow 383 in Figure 16. Adjusting wave 385 in this manner allows the user to adjust and customize the output time by pump 106 in a manner that optimizes filling of the heart. In addition, the pump 106 can also be adjusted to increase or decrease the displacement volume of the pump to customize the volume of fluid 108 provided by the pump 106, and this can be done either in concert with or independently of the timing of the r-wave. .

It should be noted that, although subsystem 153 particularly synchronizes with r-wave cycle 385, this is not necessarily the case. In alternative illustrative examples, subsystem 153 can pump in sync with any available heart characteristic, including fluid pressures into or out of a particular chamber or vessel. Also, subsystem 153 can be programmed to pump in any arbitrary pattern, whether periodic or not.

Referring again to FIG. 11, the data management subsystem 151 receives and stores the system data and information from the various other subsystems. Data and other information can be downloaded to a portable memory device and organized in a database, as desired by the operator. Data and information stored by an operator can be accessed and viewed through the operator interface subsystem 146.

Turning now to operator interface subsystem 146, Figures 17A-17J show various display screens.

ES 2 625 850 T3 illustrative displays of the operator interface subsystem 146. The display screen of Figures 17A17J allows the operator to receive information from and provide commands to the system 100. Figure 17A represents a level home page display screen upper 400 in accordance with an illustrative embodiment of the invention. From display screen 400, an operator can access all available data from data acquisition subsystem 147, and can provide any desired command to controller 150. As described in more detail with reference to Figures 17B-17J, the display screen 400 of Figure 17A also allows the operator to access more detailed display screens to obtain the information, provide commands, and define user-selectable parameters. the operator.

Continuing with reference to FIG. 1, the display screen 400 includes a display area 402, which displays a number of numerical and graphical indications pertinent to the operation of the system. In particular, display area 402 includes a numerical reading of the aortic outlet pressure (AOP) 404 of perfusion fluid 108 exiting the aorta interface 162 onto organ chamber assembly 104, a representation of waveform 406 of aortic fluid pressure (AOP) 404, and an AOP 408 alarm image indicating whether fluid pressure 404 is too high or too low (alarm 408 is shown as off in Figure 17A) . The display screen 400 also includes a display area 410 having a numerical indication 412 of the rate at which the heart is beating 102, an ECG 414 of the heart 102, a heart rate (HR) alarm image 416 indicating if the HR 412 exceeds or falls below the thresholds set by the operator, and a time record 418 that indicates how long the system 100 has been running, including priming time (described in more detail below with reference to FIG. 29A). A numeric display 419 shows the amount of time that the system 100 has been supporting the heart 102. The indicator alarm 413 indicates when a time limit preset by the operator has been exceeded.

Display screen 400 includes a number of additional display areas 420, 424, 432, 438, 444, 450, 456, 460, 462, 466, 472, 484, 482. Display area 420 shows a numerical reading of the pulmonary artery pressure (PAP) 422. PAP 422 is an indication of the pressure of perfusion fluid 108 flowing from heart pulmonary artery 164, as measured by pressure sensor 130. The display area 420 also provides a PAP alarm indicator 424, which signals when the PAP 422 is outside of an operator preset range. The display area 426 indicates the temperature (Temp) 428 of the perfusion fluid 108 as it exits the heater 110. Display area 426 also includes a Temp 430 alarm indicator, which sends a signal in response to Temp 428 falling outside of an operator preset range. The upper limit of the range preset by the operator is displayed at 427. The display area 432 shows a numerical reading on the hematocrit (HCT) 434 of the perfusion fluid 108, and an alarm indicator HCT 436 to indicate to the operator if the HCT 434 falls below a threshold preset by the operator. The display area 438 shows the oxygen saturation (SvO2) 440 of the perfusion fluid 108. The display area 438 also includes an SvO2 alarm to indicate if the SvO2 440 in the perfusion fluid 108 falls below a threshold preset by the operator. The display area 444 indicates the aortic outflow (AOF) 446 of the perfusion fluid 108 as it flows out of the aorta 158. The AOF 446 is measured by the flow sensor 134. The AOF alarm 448 indicates if flow rate 446 falls outside of an operator preset range. The display area 450 shows the flow rate of the organ chamber (CF) 452. The CF 452 is an indication of the flow rate of the perfusion fluid 108 as it exits the organ chamber 104, as measured by the flow sensor. flow rate 136. Display area 450 also includes an alarm indicator CF 454, which sends a signal in response to the CF 454 being outside of an operator preset range. Display area 456 includes a graph 458 to indicate when a file transfer to the memory card is occurring.

Display area 460 shows a graphical representation 459 of the degree to which batteries 352a-352c (previously described with reference to FIG. 14) are charged. The display area 460 also provides a numerical indication 461 of the amount of time remaining during which the batteries 352a-352c can continue to operate the system 100 in a current operating mode. Display area 462 identifies whether operator interface module 146 is operating wirelessly 464, along with a graphical representation 463 of the strength of the wireless connection between operator interface module 146 and the rest of system 100. The display area 462 also provides a graphical indication 467 of the remaining charge in the battery of the operator interface module 368 (previously described with reference to Figure 14) and a numerical indication 465 of the amount of time remaining during which the The operator interface module 368 battery can support it in a wireless mode of operation. Display area 466 indicates flow rate 468 of oxygen from gas flow chamber 176. It also provides a graphical indication 469 of how full the oxygen tank is, and a numerical indication 470 of the amount of time remaining before the oxygen tank is empty. The display area 472 shows the heart rate of the heart 102, and the

ES 2 625 850 T3 amount of time 476 during which the heart 102 has been cannulated with the system 100. The field is duplicative of the field 419 mentioned above. Display areas 480 and 482 show the current time and date, respectively, of system 100 operation.

Actuation of a rotary knob (or mouse, or other control device), such as the rotary knob 626 shown in Figure 18A, at the operator interface 146 opens a configuration menu 484, such as the one presented in Fig. display screen 401 of FIGS. 17B. As shown, accessing the setup menu 484 covers the display areas 402 and 410 such that they no longer show the graphical representations of pressure 406 and heart rate 414, but continue to display critical alpha / numeric information. Also as shown, all other display areas remain unchanged. The operator is allowed to adjust the operation of the system 100 while continuing to monitor critical information. According to one feature, the setup menu 484 allows the operator to pre-program desired operating parameters for the system 100. Using the display screen 401, the operator can view / edit the alarms, work mode and diastolic or (retrograde) selecting fields 488 and 490, respectively. The operator can define particular ECG and LAP graphing options by selecting fields 492 and 494. Additionally, the operator can define the oxygen flow rate and the perfusion fluid temperature by selecting fields 496 and 498, respectively. Selecting field 500 allows the operator to define the time and date, while selecting field 502 allows the operator to select the language in which the information is presented. At the bottom of the display field 484, the operator has the option of returning 504 to display screen 400, canceling 506 any changes made to the operational parameters, saving 508 the changes as new default values, or redefining 510 the parameters operating at factory settings.

Referring to Figures 17C and 17D, selecting the work mode alarm field 488 to view / edit 488 causes the work mode alarm dialog box 512 of Figure 17D to open within the display field 484 of Figure 17C. The work mode dialog box 512 displays the parameters associated with the normal flow mode (described above with reference to Figures 1 and 3) a field is included to define numerical thresholds for each of the normal flow mode alarms . More specifically, the dialog box 512 includes: CF alarm field 514; PAP alarm field 516; alarm field AOP 518; LAP 520 alarm field; perfusion fluid temperature alarm field 524; SvO2 alarm field 526; HCT 528 alarm field; and alarm field hR 530. By selecting a particular alarm field and operating arrows 532 up and / or 534 down, an operator can set the acceptable upper and / or lower thresholds for each of the parameters associated with each of the alarms. Dialog box 512 also includes alarm graphs 536a-536i, each of which is associated with a particular normal flow mode alarm. The operator can enable / disable any of the above normal flow mode alarms by selecting associated alarm graph 536a-536i. Any changes made using dialog box 512 are reflected in the corresponding fields on display screen 400 of FIG. 17A.

Referring to Figures 17A, 17B, and 17E, selecting non-working mode alarms field 490 to view / edit 488 causes the idle mode alarm dialog box 538 of Figure 17E to open within the display field. 484 of Figure 17C. The sleep mode dialog box 538 displays the parameters associated with the retrograde flow mode (described above with reference to Figures 1 and 4) and includes a field to define numerical thresholds for each of the retrograde flow mode alarms. According to the illustrative example, the alarms available for the normal and retrograde flow modes are similar, but not necessarily the same. Additionally, even for those that are the same, the thresholds may differ. Accordingly, the invention allows the operator to select different alarms and / or different thresholds for each flow mode of operation. More specifically, dialog box 538 includes: CF alarm field 540; PAP alarm field 542; alarm field AOF 544; alarm field AOP 546; LAP 548 alarm field; perfusion fluid temperature alarm field 550; SvO2 alarm field 552; HCT 556 alarm field; and HR 558 alarm field. By selecting a particular alarm field and actuating arrows 560 up and / or 562 down, an operator can set the acceptable numerical upper and / or lower thresholds for each of the parameters associated with each of the alarms. Dialog box 538 also includes alarm graphs 564a-564i, each of which is associated with a particular normal flow mode alarm. The operator can enable / disable any of the above normal flow mode alarms by selecting the associated alarm graph 564a-564i. As is the case with dialog box 512, any changes made using dialog box 538 are reflected in the corresponding fields on display screen 400 of FIG. 17A. In a redeployment, the system 100 may be configured to automatically switch between groups of alarm limits for a given flow mode when the flow mode changes.

ES 2 625 850 T3

With reference to Figures 17A, 17B, 17F, and 17G, the operator interface 146 also provides graphical mechanisms for adjusting the various parameters. For example, as noted above with reference to FIG. 16, an advantage of the user display area 402 is that it allows the operator to monitor (and adjust) the pumping of subsystem 153. The display area 410 identifies the ECG waveform 414 of the heart 102, and the display 402 shows in waveform 406 the pressure of the fluid flowing through the aorta. In these two displays, the operator can monitor the effect of the pump profile on the heart's ECG 414, allowing the user to adjust the scroll volume of pump subsystem 153, to adjust the frequency of pump subsystem 153 (and thus the flow rate of the fluid 108 that is being pumped through the system 100), to manually impose, or set a turn-on time of the subsystem (for example, imposing a fixed delay between the r-wave 380 and the start of the pump cycle), or to automatically program the pump subsystem 153 to pump at a predetermined time along the ECG shape 414 of the heart, as needed to properly fill the heart according to whether the heart is being perfused in retrograde or normal mode. These pump settings can be made using the various graphical frames of the operator interface 146. By way of example, in response to the operator selecting the ECG graph frame option 492 located in the display field 484 of the display screen 401, the operator interface 146 displays the dialog box 568 of FIG. 17F. The dialog box 568 displays a graphical representation 572 of the ECG 414 along with a cursor 570. The position of the cursor 570 indicates the point at which the pump subsystem 153 will initiate a displacement of the output pump (that is, the part of the pump cycle in which the motor of the pump 106 will push the perfusion fluid 108 towards the heart 102) relative to ECG 414 of heart 102. By rotating a rotary knob 626 (shown in Figures 18A 18B) on the operator interface 146, the operator moves the position of the cursor 570 to adjust when the pump subsystem 153 initiates the pump-out offset relative to a pulse. r-wave 380. As previously described with respect to Figures 15 and 16, pump subsystem 153 receives an r-wave signal 380 from ECG sensors 142 and 144. Pump subsystem 153 uses r-wave signal 380 in conjunction with pump setting information from cursor 570 to synchronize pumping of perfusion fluid with the heartbeat 102. In another example, in response to the operator pressing the pump setting button 652, operator interface 146 displays dialog box 574 of FIG. 17G. From dialog box 574, the operator can select pointer 576 and turn knob 626 to turn pump motor 106 on and off. Additionally, the operator can select bar graph 578 and rotate knob 626 to adjust the volume. of fluid being pumped, which is presented in liters / minute.

Operator interface 146 also provides a plurality of warning / reminder messages. By way of example, in FIG. 17H, the operator interface 146 displays a message to remind the operator to turn on AC power to recharge the batteries. This message appears, for example, in response to controller 150 detecting a low battery limiting condition. The operator interface 146 displays the message of Figure 17I to confirm that the user wishes to enter sleep mode and reminds the operator to insert a portable memory device, such as a magnetic or optical disk, portable disk, card. flash memory, or any other suitable memory device, to download and store information concerning a particular use of the system 100. The operator interface 146 displays error messages, such as the error message of FIG. 17J, in response to an identifiable fault occurring. The error messages in Figure 17J include, for example, 580 error information to assist a service technician in diagnosing and / or repairing the fault.

Having described an illustrative control system and procedures for achieving operation of the system 100, illustrative mechanical characteristics of the system 100 will now be described, along with an illustrative division of the components between the 634 single-use disposable module and the 634-module units. multiple uses 650. More particularly, Figures 18A-18B show a mechanical implementation 600 of the system of Figure 1. As shown, the illustrative implementation 600 includes a housing 602 and a carriage 604. The housing 602 is conceptually divided into two upper 602a and lower 602b housing sections and includes front 606a, rear 606b, left 606c, and right 606d sides. Cart 604 includes a platform 608 and wheels 610a-610d for transporting system 600 from site to site. A pin 603 secures the housing 602 to the carriage 604. To further aid portability, the system 600 also includes a handle 610 hingedly mounted on the upper section 602a of the left side 606c of the housing 602, along with two rigidly mounted handles 612a and 612b mounted on the lower section 602b. left side 606c and right side 606d of housing 602.

Housing 602 further includes a removable top 614, and a front panel 615 having a top panel 613, and a middle panel 616 hinged to a bottom panel 617 by hinges 616a and 616b. Top 614 includes handles 614a and 614b to aid in removal. In the illustrated embodiment, the top panel 613 is screwed, bolted, or otherwise attached to the top 614, such that removing the top 614 also removes the panel 613.

ES 2 625 850 T3

As shown in Figure 18A, the system 600 includes an AC power cord 618 along with a frame 620 to secure the power cord 618, both located in the lower section 602b of the left side 606c of the housing 602. A switch software reset button 622, also located in the lower section 602b of the left side 602c, allows the operator to reset the system software and electronics.

As shown in Figures 18A and 18B, the implementation 600 also includes the operator interface module 146, along with a recess 623 to support the operator interface module 146. The operator interface module 146 includes a display 624 to display information to the operator, for example, by means of the display screens of Figures 17A-17J. As mentioned above, the operator interface module 146 also includes a push-rotary button 626 for selecting from the various parameters and display screens of Figures 17A-17J. Button 626 can also be used to set parameters for automatic control of system 100, as well as to provide manual control over operation of system 100. For example, button 626 can be used to provide instructions to controller 150 to increase perfusion fluid flow rates, gas flow rates, etc. Also as previously described with respect to Figures 1, 14, and 17A-17J, the operator interface module 146 includes its own battery 368 and can be removed from recess 623 and used in a wireless mode. While in recess 623, power connections allow operator interface module 146 to be loaded. As shown, the operator interface module also includes 625 control buttons to control the pump, silence or disable alarms, enter or exit sleep mode, enter or adjust ECG sync mode, and start the perfusion clock. , which starts the visualization of data obtained during the care of the organ.

As shown in Figure 18B, the illustrative implementation 600 also includes a battery compartment 628 and an oxygen tank space 630, both located in the lower section 602b of the right side 606d of the housing 602. As shown, Battery compartment 628 houses the three battery systems 352a-352c, previously described in connection with FIG. 14. According to one feature, the battery compartment 626 includes three spaces for batteries 632a-632c. As described above with respect to FIG. 14, the battery spaces 632a-632c mechanically interoperate such that only one of the three batteries 352a352c can be removed at any one time.

The 634 Disposable Module and 650 Multipurpose Unit are constructed of a material that is durable yet lightweight. In some illustrative examples, polycarbonate plastic is used to form one or more of the components of the 634 and 650 units. To further reduce weight, the frame 635 and the frame of the multipurpose module 602 are formed of low weight materials, such as for example, carbon fiber epoxy composites, polycarbonate ABS plastic blends, glass reinforced nylon, acetal , Straight ABS, aluminum or magnesium. According to an illustrative configuration, the weight of the complete system 600 is less than approximately 38,555 kg (85 pounds), including the multipurpose module, core, batteries, gas tank, and priming, nutritional, preservative, and perfusion fluids, and less than approximately 50 pounds (22,680 kg) excluding such items. In accordance with another illustrative configuration, the weight of the disposable module 634 is less than about 5,443 kg (12 pounds), excluding any solutions. In accordance with a further illustrative embodiment, the multipurpose module 650, excluding all fluids, batteries 352a-352c, and oxygen supply 172 weighs less than about 50 pounds.

Continuing with reference to Figures 19A-19C, various views of the implementation 600 of Figures 18A and 18B are shown with the top 614 and the top front panel 613 removed and the front middle panel 616 open, in accordance with an example. illustrative.

With reference to Figures 19A-19C, system 100 is structured as a disposable single-use module 634 (shown and described in detail below with reference to Figures 24A-25C) and a multipurpose module 650 (shown without the single-use module in figure 20). As described in more detail below, in accordance with one feature of the illustrative example, all blood-contacting components of the system 100 are included in the single-use disposable module 634 so that after one use , the entire single-use module 634 can be scrapped, a new module 634 can be installed, and the system 100 will be available for use again in a very short time.

In accordance with the illustrative example, the single-use module 634 includes a frame 635 to support all components of the single-use module 634. As described in more detail with respect to Figures 24A25C, the components of the single-use module 634 include the organ chamber assembly 104, previously described in detail with respect to Figures 5A-5F, the fluid reservoir for infusion 160, oxygenator 114, infusion fluid pump interface 300, and all of the various fluid flow passages and components of

ES 2 625 850 T3 peripheral monitoring 633.

As shown in Figures 19A-20A, with the top 614 removed and the front panel 616 open, an operator can easily access many of the components of the disposable 634 and multipurpose modules 650. For example, the The operator can install, remove and view the nutrient 116 and preservative 118 supply levels of the nutritional subsystem 115. The operator can also control the operation of the nutrient 116 and preservative 118 infusion pump. The operator can also cannulate an organ, such as heart 102, into organ chamber assembly 104. As described in detail below with reference to Figures 21A-21C, this configuration also provides the operator with sufficient access to install and / or removing the single-use module 634 in / from the multi-use module 650.

Figure 20A shows a front perspective view of the multipurpose module 650 with the single-use module 634 removed. As shown, multipurpose module 650 includes: cart 604; lower section 602b of housing 602, along with all components mounted externally thereto, along with all contents therein (described in more detail below, with reference to Figures 21A-21C and 23A-23C); upper section 602a of housing 602 and all components externally mounted therein, including top cover 614, handles 610, 612a, and 612b, and front panel 616; operator interface module 146; and the perfusion fluid pump motor assembly 106. As described in more detail below with reference to Figures 21A-21C, the multi-use module 650 also includes a bracket assembly 638 to receive and lock the single-use module 534 in place.

As shown in Figure 20A and described in more detail below with reference to Figures 22A-22C, the multipurpose module 650 also includes a user endpoint interface circuit board 636 for interfacing with a user endpoint. user endpoint circuit board (shown in Figure 24D at 637) of the 634 disposable module. Also as described in detail with reference to Figures 22A-22C, the power and pulse signal connections between the multipurpose module 650 and the disposable module 634 are established by means of corresponding electromechanical connectors 640 and 647 on the nameplate. front end interface circuits 636 and front end circuit board 637, respectively. By way of example, front end circuit board 637 receives power for disposable module 634 from front end interface circuit board 636 through electromechanical connectors 640 and 647. Front end circuit board 637 also receives pulse signals for various components (eg, heater assembly 110, and oxygenator 114) from controller 150 via front end interface circuit board 636 and electromechanical connectors 640. and 647. Front end circuit board 637 and front end interface circuit board 636 exchange control signals and data (for example between controller 150 and disposable module 134) via optical connectors (shown in Figure 22b at 648). As described in more detail with reference to Figures 22A-22F, the connector configuration employed between the front-end 637 and front-end interface 636 circuit boards ensures that critical power and data interconnections between the modules Single-use and multiple-use 634 and 650, respectively, continue to operate even during transportation over difficult terrain, such as may be experienced during organ transportation.

As shown in Figure 20A, according to another feature, upper section 602a of housing 602 includes a fluid-tight basin 652 which is configured to capture any perfusion fluid 108 and / or nutritional solution 116 and / or preservative 118 that may inadvertently leak. Basin 652 also prevents any leaking fluid 108 or solution 116/118 from flowing into lower section 602b of housing 602. In this manner, basin 652 protects the electronic components of system 100 from any leaking fluid 108 or 116/118 solutions. Protected components include, for example, power board 720 shown in and described in more detail below with reference to Figures 23C and 23D. Basin 652 includes a section 658, which extends over and protects perfusion fluid pump 106 from any inadvertently leaking fluid. In accordance with another feature, basin 652 is sized to accommodate the entire volume of perfusion fluid 108 (including maintenance solutions 116/118) contained within system 100 at any particular time.

Referring also to FIG. 20B, in accordance with a further feature of the illustrative example, an outer side 659 of the portion covering the pump 658 of the basin 652 includes a slot 660. As described in more detail below with reference Referring to Figures 21A21C and 24A, slot 660 mates with a projection 662 on single-use module 634 during installation of single-use module 634 in multipurpose module 650.

Turning now to the installation of the single-use module 634 in the multipurpose module 650, Figure 21A

ES 2 625 850 T3 shows a detailed view of the aforementioned bracket assembly 638 located on the multipurpose module 650 to receive and lock in place the single-use module 634. Figure 21B shows a side perspective view of the single-use module 634 being installed on the bracket assembly 638 and in the multipurpose module 650 and Figure 21C shows a side view of the single-use module 634 installed. inside the multipurpose module 650. Referring to Figures 21A and 21B, bracket assembly 638 includes two mounting brackets 642a and 642b, which are mounted to an inner side of a rear panel 654 of the upper section of housing 602a via mounting holes 644a- 644d and 646a-646d, respectively. A cross member 641 extends between and is rotatably attached to mounting brackets 642a and 642b. Locking arms 643 and 645 are spaced apart along and radially extending from cross member 641. Each locking arm 643 and 645 includes a respective downwardly extending locking projection 643a and 645b. A lever 639 joins to and extends radially upward from the cross member 641. Actuation of the lever 639 in the direction of arrow 651 rotates the locking arms 643 and 645 toward the rear 606b of the housing 602. Operating lever 639 in the direction of arrow 653 rotates locking arms 643 and 645 toward front 606a of housing 602.

As described above with respect to FIG. 10, the infusion pump interface assembly 300 includes four protruding heat bonding points 321a-321d. As shown in Figure 24A, during assembly, projections 321a-321d are aligned with corresponding openings 657a-657d and heat bonded through openings 657a-657d on projections 321a-321d to rigidly mount the side. exterior 304 of the pump interface assembly 300 onto the C-bracket 656 of the frame of the single-use module 635.

With reference to Figures 10, 20B, 21A, 21B, and 24A, during installation, in a first stage, the single-use module 634 is lowered towards the multi-use module 650 while the module is tilted. single use 634 forward (shown in Figure 21B). This process slides the projection 662 of Figure 24A into the slot 660 of Figure 20B. As shown in Figure 10, it also positions the flange 328 of the pump interface assembly 300 within the mating hole 342 of the perfusion pump assembly 106, and the tapered projections 323a and 323b of the pump interface assembly 300 at the clockwise side of the corresponding features 344a and 344b of the 346 pump assembly bracket. In a second stage, the single-use module 634 is rotated back until the recesses of the locking arms 672 and 674 of the frame of the single-use module 635 engage the projections 643 and 645 of the locking arm. spring loaded 638, forcing projections 643 and 645 to rotate upward (direction 651) until locking projections 643a and 645a exceed the height of locking arm niches 672 and 674, point at which springs cause locking arm 638 to rotate downward (direction 653), allowing locking projections 643 and 645a to releasably lock with locking arm niches 672 and 674 of the disposable module frame 635. This movement causes the curved surface 668 of the disposable module frame projection 662 of Figure 24A to rotate and engage a flat side 670 of the slot of the socket 660 of Figure 20B. Lever 639 can be used to rotate locking arm 638 upward (direction 651) to release single-use module 635.

As shown in Figure 10, this movement also causes pump interface assembly 300 to rotate in a counterclockwise direction with respect to pump assembly 106 to slide flange 328 into slot 332 of the coupling hole 342, and at the same time, to slide the tapered projections 323a and 323b under the respective support features 344a and 344b. As the tapered projections 323a and 323b slide under the respective support features 344a and 344b, the inner surfaces of the support features 344a and 344b engage the outer surfaces of the tapered projections 323a and 323b to extract the inner side. 306 from pump interface assembly 300 to pump impeller 334 to form the fluid tight seal between pump interface assembly 300 and pump assembly 106. Lever 639 can be locked in place to keep disposable module 634 secured within multipurpose module 650.

As mentioned above with reference to FIG. 20A, the interlock of the single-use module 374 on the multi-use module 650 forms both electrical and optical interconnections between the front end interface circuit board 636 on the module. 650 multi-purpose circuit board 637 front-end into the 634 single-use module. Electrical and optical connections allow the multipurpose module 650 to power, control, and collect information from the individual module 634. Figure 22A is a conceptual drawing showing various optical couplers and electromechanical connectors on the front end circuit board 637 of the 634 single-use disposable module used to communicate with the corresponding optical couplers and with the electromechanical connectors on the circuit board. front-end interface interface 636 of the multipurpose module 650. Since this correspondence is one-to-one, the various optical couplers and connectors

Electromechanical ES 2 625 850 T3 are described only with reference to front end circuit board 637, rather than also depicting front end circuit board 650.

In accordance with the illustrative example, front end circuit board 637 receives signals from front end interface circuit board 636 through both optical couplers and electromechanical connectors. For example, front end circuit board 637 receives power 358 (also shown in FIG. 14) from front end interface circuit board 636 via electromechanical connectors 712 and 714. The front end circuit board 637 powers the components of the single use module 634, such as the various sensors and transducers of the single use module 634. Optionally, the front end circuit board 637 converts power to appropriate levels before distribution. The front end circuit board 636 also provides the pulse signals from the heater 281a and 281b of Figure 13 to the applicable connections 282a on the heater 246 of Figure 6E via the electromechanical connectors 704 and 706. Similarly, the connectors Electromechanical 708 and 710 couple the pulse signals from heater 283a and 283b of Figure 13 to the applicable connections at 282b of heater 248. The front end circuit board 637 may receive a defibrillation command from the front end interface circuit board 636 via the electromechanical connector 687. In response, the front end circuit board 637 generates the defibrillation signal 143 which has suitable voltage and current levels, and as shown in FIG. 5E, couples signal 143 to organ chamber assembly 104 via electrical interface connections 235a-235b.

In another illustrative example, the defibrillation command may be provided from an external source (not shown), rather than through circuit board 636. As an example, and with reference to Figure 5E and Figure 1, An external defibrillation device can be connected to electrical coupler 613 shown in FIG. 24E, which is connected to electrical interface connections 235a-235b. The external defibrillation device sends a defibrillation signal 143 through coupler 613 and interface connections 235a and 235b to electrodes 142 and 144. Electrodes 142 and 144 then supply signal 143 to heart 102. This alternate example allows the user to provide defibrillation (and pacing) without passing signal 143 through circuit boards 618, 636, and 637. An exemplary external defibrillator device includes the Zoll M Series Portable Defibrillator.

In accordance with the illustrative embodiment, the front end circuit board 637 receives signals from the temperature, pressure, fluid flow rate, oxygenation / hematocrit, and ECG sensors, amplifies the signals, converts the signals into a digital format, and provides them to front end interface circuit board 636 using optical couplers. For example, front end circuit board 637 provides temperature signal 121 from sensor 120 on heater plate 250 (shown in Figures 6A and 13) to front end interface circuit board 636 via coupler. optical 676. Similarly, front end circuit board 637 provides temperature signal 123 from sensor 122 on heater plate 252 (shown in Figures 6a and 13) to front end interface circuit board 636 via the optical coupler 678. Front end circuit board 637 also provides perfusion fluid temperature signals 125 and 127 from thermistor sensor 124 (shown in Figures 6A and 13) to front end interface circuit board 636 via respective optical couplers. 680 and 682. Perfusion fluid pressure signals 129, 131, and 133 are provided from respective pressure transducers 126, 128, and 130 to front end interface circuit board 636 via respective optical couplers 688, 690, and 692. Front end circuit board 637 also provides perfusion fluid flow signals 135, 137 and 139 from respective flow sensors 134, 136 and 138 to front end interface circuit board 636 via respective optical couplers 694, 696 and 698. Additionally, front end circuit board 637 provides oxygen saturation 141 and hematocrit 145 signals from oxygen saturation sensor 104 to front end interface circuit board 636 via respective optical couplers 700 and 702 .

In other illustrative examples, one or more of the above sensors are connected directly to the main system board 718 (described below with reference to Figure 23D) for processing and analysis, thereby bypassing the front end interface circuit board 636. and the front end circuit board 637 together. Such examples may be desirable when the user prefers to reuse one or more of the sensors before disposing of them. In said example, the flow sensors 134, 136 and 138 and the oxygen and hematocrit sensor 140 are electrically coupled directly with the main board of the system 718 through the electrical coupler 611 shown in figure 23C, thus avoiding any connection. with circuit boards 636 and 637.

As previously described with respect to Figures 11-16, the controller 150 uses the signals provided to the front end interface circuit board 636, along with other signals, to transmit data and otherwise control the operation of the system. 100. As described with respect to the figures

ES 2 625 850 T3

17A-17J, the controller 150 also displays sensor information, and may also display the various operator alarms pertaining to the sensor information via the operator interface module 146.

Figure 22B illustrates the operation of a pair of exemplary electromechanical connectors of the type used for electrical interconnections between circuit boards 636 and 637. Similarly, Figure 22C illustrates the operation of a pair of optical couplers of the type used for optically coupled interconnects between circuit boards 636 and 637. An advantage of both the electrical and optical connectors used is that they ensure the integrity of the connection, even when the system 100 is being transported over difficult terrain, for example, when it is being transported across a runway at an airport, or is being transported in an aircraft in bad weather conditions, or being transported in an ambulance over busy roads. Additionally, optical couplers electrically isolate the temperature, pressure, and ECG sensors from the rest of the system 100, preventing a defibrillation signal from damaging the system 100. Power for the front-end circuit board 637 is isolated at one source. DC power supply located on the front end interface circuit board 636.

As shown in Figure 22B, electromechanical connectors, such as connector 704, include a part, such as part 703, located on the front end interface circuit board 636 and a part, such as part 705 , located on the front end circuit board 637. The portion 703 includes an elongated head 703a mounted on a substantially straight and rigid shaft 703b. Head 703 includes a substantially flat outward facing surface 708. Portion 705 includes a rigid, substantially straight pin 705 that includes an end 705a for contacting surface 708 and a spring-loaded end 705b. Pin 705 is axially movable in and out as shown by directional arrow 721 while maintaining electrical contact with surface 708 of elongated head 703a. This feature allows the single-use module 634 to remain in electrical contact with the multi-use mode 650 even when experiencing mechanical disturbances associated with transportation over rough terrain. An advantage of the flat surface 708 is that it allows easy cleaning of the interior surface of the multipurpose module 650. In accordance with the illustrative example, system 100 employs a connector for electrical interconnection between single-use 634 and multipurpose 650 modules. An exemplary connector is part No. 101342 manufactured by Interconnect Devices. However, any suitable connector can be used.

Optical couplers, such as optical couplers 684 and 687 on front end circuit board 637 are used and include corresponding counterparts, such as optical couplers 683 and 685 on front end interface circuit board 636. Transmitters Optics and the optical receiving portions of the optical couplers may be located on either circuit board 636 or 637. For example, in the case of ECG signal 379, optical transmitter 684 is located on circuit board 637 to receive electrical signal 379 and optically couple it to optical receiver 683 on circuit board 636. In the case where the defibrillation signal is transmitted through circuit boards 636 and 637 (instead of directly to main board 718), optical transmitter 685 on circuit board 636 optically couples the signal to the optical receiver. 687 on circuit board 637.

As with the electromechanical connectors employed, the allowable tolerance in optical alignment between the optical transmitters and the corresponding optical receivers allows circuit boards 636 and 637 to remain in optical communication even during transportation over rough terrain. In accordance with the illustrative embodiment, system 101 uses optical couplers manufactured as part # CCFH485P and / or SFH203PFA by Osram. However, any suitable coupler can be used.

Couplers and connectors facilitate data transmission within system 100. Front end interface circuit board 636 and front end circuit board 637 transmit pertinent data to system 100 in the form of pulses. As shown in FIG. 22C, the circuit board 636 transmits to the front end circuit board 637 a clock signal that is synchronized with the clock of the controller 150. Front-end circuit board 637 receives this clock signal and uses it to synchronize its transmission of system data (such as temperatures, pressures, ECG, r-wave detection, or other desired information) with the clock cycle of the controller 150. This data is digitized on a processor on the front-end circuit board 637 in accordance with the clock signal and in a preset sequence of data type and source address (ie, type and location of the sensor providing the data). Front-end interface circuit board 636 receives data from front-end circuit board 637 and transmits the data set to main board 618 for use by controller 150 in evaluating, displaying, and controlling the system. , as previously described with respect to Figures 11, 12 and 14. Additional optical couplers may be added between the multipurpose module and the single-use module for transmission of control data from the multipurpose module to the single-use module, said data including heater control signals or control signals

ES 2 625 850 T3 of the pump.

Having described the mechanical, electrical, and optical interconnections between the single-use module 634 and the multi-use module 650, additional components of the multipurpose module 650 will now be described with respect to Figures 23A-23D, followed by a description of the mechanical arrangement of the components of the single-use module 634 with respect to Figures 24A-28C. As shown in Figures 23A-23D, with the walls of the housing 602 removed, in addition to those previously described components, the multipurpose module 650 includes a built-in gas supply 172 located in the lower section 602b of the housing 602. Gas supply 172 is depicted in Figures 23A-23D as a tank, positioned within tank space 630 by a support structure 712, abutting tank 172. Optionally, the gas supply 172 may be further secured within the gas tank space 630 by a strap and buckle assembly 714 or other suitable mechanism. With particular reference to Figure 23B and as previously described with reference to Figure 1, gas supply 172 provides gas to system 100 through gas regulator 174 and gas flow chamber 176. Gas pressure sensor 132 measures gas pressure in gas supply 172 and gas pressure gauge 178 provides a visual indication of the contents of gas supply 172. Additionally, an electrical connection between controller 150 and chamber Gas flow setting 176 allows controller 150 to automatically regulate the flow of gas into oxygenator 114.

As shown more clearly in FIG. 23C, battery space 628 houses batteries 352a-352c. As noted above with reference to FIG. 14, a locking mechanism is used to prevent more than one of the batteries 352a-352c from being removed from the battery space 628 at any one time while the system 100 is operating.

As described above, system 100 includes a plurality of interconnected circuit boards to facilitate power distribution and data transmission to, from, and within system 100. Particularly, as described above with reference to Figures 22A-22E and as shown in Figure 23C, the multipurpose module 650 includes a front end interface circuit board 636, which is optically coupled and electromechanically to the front end circuit board 637 of the single-use module 650. As also shown in FIG. 23C, the system 100 further includes a main board 718, a power circuit board 720, and a battery interface board 711 located in the multipurpose module 650. The main board 718 is configured to allow the system 100 to be fault tolerant, and that if a malfunction arises in the operation of a given circuit board, (as shown in Figure 23D), the main board 718 saves the pumping and heating parameters in non-volatile memory. When the system 100 restarts, it can recover and continue its operation in accordance with those parameters.

Referring to the conceptual drawing of Figure 23D, wiring 731 brings power (such as AC power 351) from a power source 350 to power circuit board 720 via connectors 744 and 730. Power source 350 converts AC power into DC power and distributes DC power as described above with reference to the power subsystem of Figure 14. Also referring to Figures 14 and 22A, power circuit board 720 couples DC power and a data signal 358 through respective wires 727 and 729 from connectors 726 and 728 to corresponding connectors 713 and 715 on front end interface circuit board 636. Cable 729 carries both power and data signals to front end interface circuit board 636. Cable 727 carries power to heater 110 through front end interface circuit board 636. Connectors 713 and 715 mate with corresponding connectors 712 and 714 (described above with respect to Figure 22A) on the circuit board. front end 637 of the single-use module 634 to provide power to the single-use module 634.

As shown in Figure 23D, power circuit board 720 also provides DC power 358 and a data signal from connectors 732 and 734 respectively, on power circuit board 720 to corresponding connectors 736 and 738 on main circuit board 718 using wires 733 and 735. Also referring to Figures 14 and 19A, cable 737 couples DC power 358 and a data signal from a connector 740 on the main circuit board 718 to the operator interface module 146 via a connector 742 on the module niche. operator interface 623. Power circuit board 720 also provides 358 DC power and a data signal from connectors 745 and 747 through leads 741 and 743 to connectors 749 and 751 on a 711 battery interface circuit board. The cable 741 carries the DC power signal and the 743 cable carries the data signal. The battery interface board 711 distributes DC power and data to batteries 352a, 352b, and 352c. Batteries 352a, 352b, and 352c contain electronic circuits that allow them to communicate with each other to monitor respective charges, as previously described with reference to Figure 14, so that controller 150 can monitor and control charging and discharging of batteries. 352a-352c batteries.

ES 2 625 850 T3

According to some illustrative examples, the controller 150 is located on the main circuit board 718 and performs all the control and processing required by the system 100. However, in other illustrative examples, the controller 150 is distributed, locating some processing functionalities on front end interface circuit board 636, some on power circuit board 720, and / or some on operator interface module 146. Adequate wiring is provided between the various circuit boards, depending on the degree to which controller 150 is distributed within system 100.

As described above with reference to Figures 19A-19C and 23A-23C, the system 100 is mechanically divided into the disposable single-use module 634 and the multipurpose module 650. As also described above, in accordance with the illustrative example, the single-use module 634 includes all or substantially all of the elements / assemblies of the system 100 that come into contact with the perfusion fluid 108, along with various peripheral components, conduits flow controllers, sensors, and supporting electronics to operate components that come into contact with blood. As described above with reference to Figures 22A and 23D in accordance with the illustrative example, the module 634 does not include a processor, depending instead on the controller 150, which may, for example, be distributed across the board. front end interface circuit board 636, power circuit board 720, operator interface module 146 and main circuit board 718, for their control. However, in other illustrative examples, the single-use module 634 may include its own controller / processor, for example, on the front end circuit board 637.

With reference to Figures 24A-28C, the single-use module 634 will now be described in terms of the components it includes. After that, the forward and retrograde flow modes through the described components will be traced by way of example.

Referring first to Figure 24A, disposable module 634 includes a frame 635 having upper 750a and lower 750b sections. The upper section 750a includes a platform 752 to support various components. Lower section 750b supports platform 752 and includes structures for pivotally connecting to multipurpose module 650. More particularly, lower frame section 750b includes C-mount 656 for rigid mounting of perfusion fluid pump interface assembly 300, and projection 662 to slide and snap fit into slot 660. of Figure 20B. The lower frame section 750b also provides structures for mounting the oxygenator 114. As shown in Figures 25A and 25C, the lower section 750b further includes structures for mounting the heater assembly 110. Additionally, the reservoir 160 is mounted on the underside of the platform 725 and extends into the lower frame section. 750b. Various sensors, such as the O2 saturation and hematocrit sensor 140 (shown in Figure 24A and described in detail below with reference to Figures 28A 28C), the flow sensor 136 (shown in Figure 24A), the sensor flow valves 138 (shown in FIG. 25B) are located within and / or mounted on the lower frame section 750b. Flow pressure compliance chamber 188 (shown in Figure 25B) is also located in lower frame section 750b. As shown in Figure 24D, the lower frame section 750b is also mounted on the front end circuit board 637. The conduits located in the lower frame section 750 are described in greater detail below with reference to the trajectories. normal and retrograde flow through the 634 single-use module.

Referring to Figures 24A-25C, and as mentioned above, the upper frame section 750a includes the platform 752. The platform 752 includes the handles 752a and 752b formed therein to aid in the installation and removal of the module. single use 634 from multipurpose module 650. Alternatively, such handles may be located on platform 757 to allow easier accessibility during installation of the single-use module in the multi-use module. As shown most clearly in FIG. 24C, an angle platform 757 is mounted on the platform 752. The organ chamber assembly 104 is mounted on the angle platform 757. According to the illustrative example, with the 634 single-use module installed within the 650 multipurpose module, the 757 platform is angled approximately 10 ° to 80 ° from the horizontal, to provide an optimal operating angle. for the heart 102 when placed within the organ chamber assembly 104. In some illustrative examples, platform 757 is angled at about 20 ° to about 60 °, or about 30 ° to about 50 ° from horizontal. Flow mode selector valve 112, flow sensor 134, and perfusion fluid flow pressure compliance chambers 184 and 186 are also mounted on angle platform 757.

Referring to Figure 24E, several fluid ports are mounted on platform 752. For example, a fluid sampling port 754 allows the operator to sample the flow entering and / or leaving the aorta 158 to

ES 2 625 850 T3 through cannulation interface 162 onto organ chamber assembly 104. A fluid sampling port 755 allows the operator to sample the flow within left atrium 152 via interface 170 on assembly chamber of organs 104. Additionally, a fluid sampling port 758 allows the operator to sample the coronary flow exiting pulmonary artery 164 via pulmonary artery interface 166 onto organ chamber 104. In accordance with the illustrative example, the operator turns on the respective valve 754a, 755a or 758a to obtain the flow from the sampling ports 754, 755 and 758. The flow from the particular selected orifice is provided to a single common outlet 764. According to one characteristic, only the flow from the selected leftmost orifice is provided at the outlet 764. By way of example, if the operator opens both ports 755 and 758, only flow from port 755 is provided at outlet 764. In this manner, system 100 reduces the likelihood that an operator will mix samples from multiple ports.

Single-use module 634 also includes a general injection port 762, operable with valve 762a, to allow the operator to inject medications into perfusion fluid 108, for example, through reservoir 160. Both sampling port 764 like the injection 762 are mounted on the platform 752. Also located on the upper frame section 750a is an infusion port 766, operable with valve 766a, to flow the nutritional fluids 116 and preservative 118 into the perfusion fluid 108. The upper frame section 750a also includes a tube. 744 to load the exsanguinated donor blood into reservoir 160. As shown in Figure 24D, the single-use module 634 also includes non-vented caps 776 to replace vented caps over selected fluid ports used while gas sterilizing through the module. single use 634 during sterilization. Preferably, such sterilization takes place prior to packaging the single-use module 634 for sale.

Upper frame section 750a also includes flow clamp 190 to regulate back pressure applied to left atrium 152 when heart 102 is cannulated and is operating in a normal flow mode in organ chamber assembly 104. Frame 750a further includes a drip valve 768. The drip valve 768 can be opened and closed with the handle 768a to regulate a small fluid flow to the left atrium 152 to wet the left atrium 152 during the retrograde flow mode. Upper frame section 750a also includes ports 770 for infusing additional solutions and 772 for purging oxygenator 114, operable with respective valves 770a and 772a.

As shown most clearly in Figures 24A and 24D, the upper frame section 750 further includes the flow pressure probes 126, 128 and 130. As previously described with reference to Figure 1, the probe 126 measures the pressure of perfusion fluid 108 flowing into / out of aorta 158. Probe 128 measures the pressure of perfusion fluid 108 flowing into left atrium 152 through pulmonary vein 168. Probe 130 measures the pressure of perfusion fluid 108 flowing out of pulmonary artery 164. Each probe includes a respective connector 126a, 128a, and 130a (shown shortened for clarity) to mate with respective signal 129, 131, and 133 to front end circuit board 637.

With particular reference to the cross-sectional side view of Figure 24C of the single-use module 654, the reservoir 160 includes several components. More specifically, reservoir 160 includes four inlets: 782, 784, 786, and 788. Inlet 782 transfers perfusion fluid 108 from drain 201 of organ chamber 194 into reservoir 160. Inlet 184 receives exsanguinated blood from tube 774. Inlet 786 receives oxygenated perfusion fluid 108 from oxygenator 114, and inlet 788 receives perfusion fluid 108 exiting aorta 158 through back pressure clamp 190. Reservoir 160 also has outlet 790, the which provides the perfusion fluid to the one-way inlet valve 191. The reservoir 160 further includes a defoamer 778 and a filter 780. Defoamer 778 removes bubbles from perfusion fluid 180 as it enters reservoir 160. According to the illustrative example, the defoamer is made of porous polyurethane foam with an antifoam coating. Filter 780 is a polyester cloth, which filters debris, blood particles, thrombi, and air bubbles from the perfusion fluid as it enters reservoir 160.

As mentioned earlier in the abstract, the O2 saturation and hematocrit sensor 140 employed in the single-use module 634 includes significant advantages over prior art approaches. Figures 28A-28C depict an illustrative example of the O2 saturation and hematocrit sensor 140 of the invention. As shown in Figure 28A, sensor 140 includes an in-line cuvette section of tube 812 connected to conduit 798, having at least one optically transparent window through which an infrared sensor can provide light. infrared. Exemplary sensors used in the in-line cuvette tube 812 are those manufactured by Datamed, BL0P4. As shown in the cross-sectional view of Figure 28B, cup 812 is a one-piece molded part having connectors 801a and 801b. Connectors 801a and 801b are configured to abut connection receptacles 803a and 803b respectively, of the

ES 2 625 850 T3 ends of conduits 798a and 798b. This interconnection between tub 812 and conduit ends 798a and 798b is configured to provide a substantially constant cross-flow area within conduit 798 and cup 812. The configuration therefore reduces, and in some examples substantially eliminates, discontinuities. at interfaces 814a and 814b between bowl 812 and conduit 798. Reducing / eliminating discontinuities allows blood-based perfusion fluid 108 to flow through the cuvette with reduced red cell lysis and reduced turbulence, allowing a more accurate reading of oxygen levels in the blood flow fluid. perfusion. This also reduces damage to perfusion fluid 108 by system 100, which ultimately reduces damage done to heart 102 during the time it is being perfused by system 100.

In accordance with the illustrative example, cuvette 812 is formed from a light transmitting material, such as any suitable light transmitting crystal or polymer. As shown in FIG. 28A, sensor 140 also includes an optical transceiver 816 for directing light waves to perfusion fluid 108 passing through cuvette 812 and for measuring light transmission and / or reflectance of the light to determine the amount of oxygen in the perfusion fluid 108. As illustrated in Figure 28C, in some examples a light transmitter is located on one side of cuvette 812 and a detector for measuring light transmission through perfusion fluid 108 is located on the opposite side of the cuvette. cuvette 812. FIG. 28C depicts a top cross-sectional view of cuvette 812 and transceiver 816. The transceiver 816 fits around the socket 812 such that the inner flat surfaces of the transceiver 811 and 813 coincide against the flat surfaces of the socket 821 and 823, respectively, while the inner convex surface 815 of the transceiver 816 coincides with the surface convex 819 from bowl 812. In operation, when UV light is transmitted from transceiver 816, it travels from flat surface 811 through fluid 108 into cuvette 812, and is received by flat surface 813. Flat surface 813 may be configured with a detector to measure the transmission of light through the fluid 108.

The fluid flow path through the single-use module 634 in both normal mode and retrograde mode will now be described with reference to Figures 24A-24D and Figure 25A. As described above with reference to Figures 1-4, system 100 can maintain heart 102 in two modes of operation; a normal flow mode shown in Figure 3 and a retrograde flow mode shown in Figure 4. As mentioned above with respect to Figure 1, to switch between normal and retrograde flow modes, system 100 provides flow mode selector valve 112, shown in detail in Figures 26A and 26B. To operate in normal flow mode, the operator places the handle 112e of the flow mode selector valve in the position indicated in FIG. 24A. This has the effect of aligning the flow paths through selector valve 112 as shown in FIG. 26A. Specifically, in normal flow mode, fluid can flow into orifice 112b, through flow channel 112f, and out of orifice 112c. Additionally, fluid can flow into orifice 112d, through flow channel 112g, and out of orifice 112a. To operate in retrograde flow mode, the operator places the handle 112e of the flow mode selector valve in the position indicated in FIG. 24B. This has the effect of aligning the flow paths through selector valve 112 as shown in FIG. 26B. Specifically, in retrograde flow mode, fluid can flow into orifice 112b, through flow channel 112h, and out of orifice 112d.

Referring to Figure 24A, in normal flow mode, reservoir 160 provides perfusion fluid 108 to one-way inlet valve 191 of perfusion pump interface assembly 300. Referring to Figure 25A, the pump Perfusion pump 106 pumps perfusion fluid 108 out of outlet valve 310. Referring to Figure 25C, perfusion fluid 108 then flows through conduit 792 and compliance chamber 188 and into inlet 110a of heater assembly 110. Heater assembly 110 heats perfusion fluid 108 and then it. flows out of the heater outlet 110b. Referring to FIG. 24A, heated perfusion fluid 108 flows from the outlet of heater 110b in lower frame section 750b through frame plate 752 and into port 112b of mode selection valve 112 through duct 794. Referring also to Figure 24D, perfusion fluid 108 flows out of port 112c of the mode valve, through compliance chamber 186, conduit 796, and pressure sensor 128 at the vein cannulation interface. Pulmonary 170 over organ chamber assembly 104.

Referring to FIG. 24A, in normal flow mode, heart 102 pumps perfusion fluid 108 out of pulmonary artery 164 through pulmonary artery interface 166 and pressure sensor 130. Conduit 796 flows. then perfusion fluid 108 from pulmonary artery interface 166 through plate 752 and through O2 saturation and hematocrit sensor 140. Referring also to Figures 25A and 25C, conduit 798 then flows perfusion fluid 108 from sensor 140 through flow sensor 136 into oxygenator 114. Conduit 800 flows perfusion fluid 108 from oxygenator 114 back to reservoir 160 via inlet of reservoir 786.

ES 2 625 850 T3

Referring to Figures 24A, 24D, and 24E, in normal flow mode, heart 102 also pumps perfusion fluid 108 out of aorta 158 through aorta interface 162 and pressure sensor 126. The conduit 802 flows perfusion fluid 108 from pressure sensor 126 through flow sensor 134 and back to port 112d in flow mode selector valve 112. A clamp 804 holds conduit 802 in place. A conduit 806 flows perfusion fluid 108 out of port 112a from flow mode selector valve 112 through compliance chamber 184 and back pressure adjusting clip 190. As mentioned above, clamp 190 can be adjusted to restrict flow through conduit 806 in order to adjust the back pressure experienced by aorta 158 during normal flow mode to more realistically simulate normal physiological conditions. Compliance chamber 184, which can expand and contract as perfusion fluid 108 is pumped in and out of it, interoperates with clamp 190 to dampen flow pressure peaks to improve simulation of nearby physiological conditions. to normal. The afterload clamp 190 is configured to closely emulate the systemic vascular resistance of the human body that affects aortic pressure, left atrial pressure, and coronary flow. A conduit 808 returns perfusion fluid 108 into reservoir 160 via inlet to reservoir 788.

In retrograde flow mode, flow mode selector valve 112 is positioned as shown in FIG. 24B. Referring to Figure 24B, reservoir 160 provides perfusion fluid 108 to inlet valve 191. As shown in Figure 25A, perfusion pump 106 pumps perfusion fluid 108 out of outlet valve 310. As shown in Figure 25C, perfusion fluid 108 then flows through conduit 792 and compliance chamber 188 and into inlet 110a of heater assembly 110. Heater assembly 110 heats perfusion fluid 108 and then it flows out of the heater outlet 110b. Referring to Figure 24B, the heated perfusion fluid 108 flows from the outlet of the heater 110b in the lower frame section 750b through the frame plate 752 and into the inlet 112b of the mode selection valve 112 through duct 794. Also referring to Figure 24D, perfusion fluid 108 flows out of mode valve outlet 112d, into conduit 802, through flow sensor 134, pressure sensor 126, and into the aorta. 158 through aortic interface 162. Perfusion fluid 108 then flows through coronary sinus 155 and the remainder of the coronary vasculature.

Referring to Figure 24B, in retrograde flow mode, heart 102 pumps perfusion fluid 108 out of pulmonary artery 164 through pulmonary artery interface 166 and pressure sensor 130. Conduit 796 flows then perfusion fluid from pulmonary artery interface 166 through plate 752 and into O2 saturation and hematocrit sensor 140. Referring also to Figures 25A and 25C, conduit 798 then flows perfusion fluid 108 from sensor 140 through flow sensor 136 into oxygenator 114. Conduit 800 flows perfusion fluid 108 from oxygenator 114 back to reservoir 160 via inlet of reservoir 786. In retrograde flow mode, substantially no perfusion fluid is pumped into or out of the left atrium 152 through pulmonary vein 168 and pulmonary vein interface 170, with the exception of a small amount of perfusion fluid diverted by drip valve 768 of conduit 794 around flow mode selector valve 112 into compliance chamber 186. As mentioned above, drip flow provides sufficient perfusion fluid 108 to keep left atrium 152 moisturized during retrograde flow.

As described above, the illustrative configuration of system 100 has one or more sensors or probes to measure fluid flow and pressure. Probes and / or sensors can be obtained from standard commercial sources. Flow sensors 134, 136, and 138 are conventional, ultrasonic flow sensors, such as those available from Transonic Systems Inc., Ithaca, NY. Fluid pressure probes 126, 128 and 130 may be conventional strain gauge pressure sensors available from MSI or GE Thermometrics. Alternatively, a precalibrated transducer chip can be embedded in the organ chamber connectors and connected to a data collection site such as front end plate 637.

Having described the electrical and mechanical components and functionality of illustrative configurations of system 100 and certain modes of operation thereof, system 100 will now be described with reference to the illustrative organ harvesting and transplantation procedures of Figures 29A and 29B. More particularly, FIG. 29A is a flow chart 900 depicting exemplary methodologies for removal of donor heart 102 and cannulation within system 100 at a donor location. Figure 29B depicts particular points of care for handling heart 102 in preparation for cannulation, and Figure 30 is a flow chart 902 of exemplary methodologies for removing donor organ 102 from system 100 and transplanting it into a patient. at the recipient's site.

ES 2 625 850 T3

As shown in Figure 29A, the process of obtaining and preparing the heart 102 for cannulation and transport begins with providing a suitable organ donor 904. The organ donor is brought to a donor location, where the process of receiving and Preparing the donor heart 102 for cannulation and transport run through two intersecting routes 906 and 908. Route 906 primarily involves preparing donor heart 102 for transplantation, while route 908 primarily involves preparing system 100 to receive donor heart 102 and then transporting heart 102 through system 100 to the recipient site.

With particular reference to Figure 29A, first route 906 includes exsanguinating donor 910, arresting donor heart 914, explanting heart 916, and preparing heart 102 for cannulation 918 in system 100. In particular, at the stage of exsanguination 910, the donor blood is withdrawn and set aside so that it can be used to perfuse the heart 102 during storage in the system 100. This stage is accomplished by inserting a catheter into the donor's arterial or venous vasculature to allow donor blood to flow out of the donor and be collected in a blood collection bag. Donor blood is allowed to flow until the required amount of blood has been collected, typically 1.0-2.5 liters, after which the catheter is removed. Blood drawn through exsanguination is then filtered and added to a fluid reservoir 160 of system 100 in preparation for use with system 100. Alternatively, blood can be exsanguinated from the donor and filtered to remove leukocytes and platelets in a simple step using an apparatus having a filter integrated with the blood collection cannula and bag. An example of such a filter is a Pall BC2B filter. After donor blood is exsanguinated, donor heart 102 is injected at step 914 with a cardioplegic solution to temporarily stop beating in preparation for removal of heart 102.

After the heart 102 has been stopped, the heart 102 is explanted 916 from the donor and prepared 918 for loading into the system 100. In general, the steps of explanting the heart 916 and preparing it for loading 918 involve severing the connections between the heart vasculature 102 and the donor's inner thoracic cavity, suturing several of the severed connections, and then removing the heart 102 from the thoracic cavity.

More particularly, as shown in FIG. 29B, the right and left pulmonary arteries 164a and 164b are sectioned, and the right pulmonary artery 164a is tied off by surgical suture 901a or other suitable mechanism. This bundle prevents fluid from flowing through the severed end 903a of the left pulmonary artery 164a. As previously described with reference to Figures 24A-24B, the left pulmonary artery 164b remains without suture to allow organ chamber assembly 104 to be cannulated, thereby allowing perfusion fluid 108 to flow through the left pulmonary artery 164b, through pulmonary artery cannulation interface 170, and back to reservoir 160. The left pulmonary veins 168b and 169b and the right pulmonary veins 168a and 169a are also sectioned, and all but a single pulmonary vein 169b are tied with surgical thread 901b, 901c and 901d, respectively. This prevents fluid from flowing through the severed ends 903b and 903c of the right pulmonary veins 168a and 169b, or through the severed end 903d of the left pulmonary vein 168b, but allows the untied pulmonary vein to be cannulated to the set of organ chamber 104 through pulmonary vein interface 170. As previously described with reference to Figures 24A-24B, this arrangement allows perfusion fluid 108 to flow through right pulmonary artery 164b, through pulmonary artery interface 166, and back to oxygenator 114. Alternatively, blood can be expelled from the right ventricle through cannulation of the pulmonary artery trunk. The pulmonary arterial trunk is not shown but includes the segment of pulmonary artery 164 between branches 164a and 164b of pulmonary artery 164 and the right ventricle 159. The superior vena cava 161 is also sectioned and, once the heart is connected to the system 100 and begins to beat, it is tied with thread 901e to prevent fluid from flowing through its end 903e. The inferior vena cava 163 is sectioned in the same way and tied with thread 901f or overstitched to prevent fluid from flowing through its end 903f. The aorta 158 is also sectioned (in the illustrated embodiment at a point downstream of the coronary sinus 155) but is not tethered, allowing it to be cannulated to the organ chamber assembly 104. In one embodiment, the aorta 158 is cannulated to a connector aortic, which can be easily connected to the aortic interface 170.

Continuing with reference to the flow chart of FIG. 29A, after the heart vasculature is sectioned and properly tied, the heart 102 is then loaded into the system 100 by inserting it into the organ chamber assembly 104 and cannulating the aorta 158. , the left pulmonary artery 164b and a pulmonary vein 169b to the appropriate points in the organ chamber assembly 104.

Frequently, hearts obtained from donors who have also donated their lungs lack part or all of the left atrium 152. In this situation, the heart 102 can still be instrumented and perfused in the retrograde mode by cannulating the aorta 158 and either the artery. right pulmonary 164a or a pulmonary artery trunk

ES 2 625 850 T3 (not shown, but described above), and allowing any remaining part of the left atrium 152 to remain open during the retention period.

Continuing with reference to Figure 29A, during preparation of route 906 through the heart, system 100 is primed through the stages of route 908 so that it is primed and waits to receive heart 102 for cannulation and transport. as soon as the heart 102 is ready. By rapidly transferring the donor heart 102 to the system 100, and subsequently perfusing the heart 102 with the perfusion fluid 108, a medical operator can minimize the amount of time the heart 102 is deprived of oxygen and other nutrients, and thus reduce the ischemia and other ill effects that can arise during current organ care techniques. In certain embodiments, the amount of time between infusion of heart 102 with cardioplegic solution and the beginning of flow of perfusion fluid 108 through heart 102 via system 100 is less than about 15 minutes. In other illustrative examples, the elapsed time is less than about half an hour, less than about 1 hour, less than about 2 hours, or even less than about 3 hours. Similarly, the time between transplantation of the heart to an organ care system 100 and bringing the heart 102 to a temperature close to physiological (e.g., between about 34 ° C and about 37 ° C, occurs within a brief period of time, so that ischemia within the cardiac tissues is reduced. In some illustrative examples, the time period is less than about 5 minutes, while in other applications it may be less than about half an hour, less than about 1 hour, less than about 2 hours, or even less than about 3 hours. According to some illustrative examples, the heart can be transferred directly from the donor to the system 100, without the use of cardioplegia, and in such applications the time to start the flow of warm perfusion fluid 108 and / or the time for the heart reaches a temperature close to physiological is, similarly, less than about 5 minutes, less than about half an hour, less than about 1 hour, less than about 2 hours, or even less than about 3 hours. In one implementation, the donor heart is not stopped prior to removal from the donor, and is instrumented on the system 100 while the heart 102 is still beating.

As shown in Figure 29A, system 100 is primed in route 908 through a series of steps, including preparing single-use module 634 (step 922), priming system 100 with priming solution. (step 924), filter donor blood and add it to reservoir 160 of system 100 (step 912), and connect heart 102 to system 100 (step 904). In particular, the step 922 of preparing the single-use module 634 includes assembling the disposable single-use module 634. Suitable assemblies are shown, for example, in Figures 24A-24D, Figures 25Aa-25C and Figure 26. After the 634 module is assembled, or provided in the appropriate assembly, it is then inserted into the uses module. multiples 650 through the process described above with reference to Figures 21A-21C.

In step 924, the system 100 loaded into priming with priming solution, as described in more particular detail below with reference to Table 1. According to one feature, to aid priming, the system 100 provides a conduit organ bypass 810 shown and installed in organ chamber assembly 104 in FIG. 27A. As shown, the diverter conduit includes three segments 810a-810c. Segment 810a connects to pulmonary artery cannulation interface 170. Segment 810B connects to aorta cannulation interface 810b, and segment 819c connects to pulmonary vein cannulation interface 166. Using bypass conduit 810 thus connected / cannulated to organ chamber assembly 104, an operator can cause system 100 to circulate perfusion fluid 108 through all routes used during actual operation. This allows system 100 to be thoroughly tested and primed prior to cannulating heart 102 in place.

In the next step 912, the donor blood is filtered and added to reservoir 160. The filtration process helps reduce the inflammatory process through the complete or partial removal of leukocytes and platelets. Additionally, donor blood is mixed with one or more nutritional solutions 116 and / or preservative 118 to form perfusion fluid 108. In step 926, system 100 is primed with perfusion fluid 108 by pumping it through system 100 in the retrograde flow mode, as previously described with reference to FIG. 24B, and with bypass line 810 in its place. place. As perfusion fluid 108 circulates through system 100 in priming stage 926, it is heated to the desired temperature as it passes through heater assembly 110. The desired temperature range and heating applications have been described above with reference to Figures 6A through 6E, and with reference to Figure 13. At step 920, after system 100 is primed with perfusion fluid 108 , bypass conduit 810 is removed, and heart 102 is instrumented, as previously described and shown in FIG. 27B, on system 100.

ES 2 625 850 T3

After heart 102 is instrumented on system 100, pump 104 is activated and flow mode valve 112 is positioned in retrograde flow mode (described above with reference to Figures 1 and 4) to pump the perfusion fluid 108 in retrograde flow mode through the aorta into the heart vasculature 102. The pumping of the warm perfusion fluid 108, enriched with oxygen and nutrients through the heart 102 allows the heart 102 to function ex vivo in a near normal physiological state. In particular, the warm perfusion fluid 108 heats the heart 102 as it perfuses therethrough, which can cause the heart 102 to restart beating in its natural way. In some cases, it is desirable to assist the heart 102 to restart its beat, which can be done by providing a manual massage or defibrillation signal 143 (shown in Figure 22E) to the heart 102. This can be done as described above with reference to the organ chamber assembly of Figures 5A-5F and the operator interface 146 of Figures 17A-17J.

After the heart is instrumented in system 100 in step 920, subsequent steps 928 and 930 allow the operator to test heart 102 and system 100, and evaluate their respective states. Illustratively, step 928 involves evaluating ECG signals 379 and 381 from sensors 142 and 144 (positioned as shown in Figure 27A), respectively, as well as the hematocrit 145 and oxygen saturation 141 levels of the perfusion fluid 108 from sensor 140. As further described with reference to FIG. 12 and FIGS. 17A-17I, the operator can also monitor the fluid flows, pressures, and temperatures of the system 100 while the heart 102 is cannulated. As described above with reference to Figures 5E and 5F, test step 928 may also include the operator touching / examining the heart 102 by lifting an outer lid 196 of the organ chamber 104 and indirectly touching / examining the heart 102. through flexible membrane 198b. During the evaluation step 930, based on the data and other information obtained during the tests 928, the operator determines if and how to adjust the properties of the system 100 (for example, fluid flows, pressures and temperature) and if it should provide additional defibrillation. , or other modes necessary for the treatment of the heart 102. The operator makes any such adjustments in step 932, then repeats steps 928 and 930 to repeat the tests and retest the heart 102 and system 100. In certain examples, the operator may also choose to perform procedures surgical, therapeutic or other in the heart 102 during the adjustment step 932. For example, the operator can carry out an assessment of the physiological state of the heart, such as, for example, carry out an ultrasound test or other imaging test, carry out an echocardiogram or a diagnostic test on the heart, measuring arterial blood gas levels and other evaluative tests.

In another application, during or after step 932 the system 100 allows a medical operator to evaluate the organ for compatibility with a intended recipient after explant but prior to donor implantation. For example the operator can perform a Human Leukocyte Antigen (HLA) concordance test on the organ while the organ is cannulated in system 100. Such tests can take 12 hours or more and are carried out to ensure compatibility of the organ with the intended recipient. Preservation of an organ using the system 100 described above may allow preservation times in excess of the time required to complete HLA match, potentially resulting in an improved post-transplant outcome. In the HLA concordance test example, the HLA test can be performed on the heart while a preservation solution is being pumped into the heart.

According to a further illustrative example, after the heart is functioning as determined in step 932, the operator may perform surgery on the heart or provide therapeutic or other treatment, such as immunosuppressive treatments, chemotherapy, tests. and gene therapies, or radiation therapy. Since the system 100 allows the heart 102 to be perfused at a temperature, fluid flow rate, and oxygen saturation levels close to physiological, the heart 102 can be maintained after the adjustment step 932 for a long period of time ( for example, for a period of at least 3 days or more, longer than at least a week, at least three weeks, or a month or more) to allow for repeated evaluation and treatment.

According to the illustrative example, steps of test 928, evaluation 930, and adjustment 932 can be carried out with system 100 operating in retrograde flow mode, or they can be carried out with system 100 operating in normal flow mode. . In normal flow mode, the operator can test the function of the heart 102 in blood flow conditions close to physiological. Based on evaluation 930, the parameters of system 100 can be adjusted in step 932, if necessary, to modify flow, heating and / or other characteristics to stabilize heart 102 in step 934 in preparation for transport to the receptor site in step 936. After heart 102 and system 100 are tested and evaluated to ensure proper performance, system 100 with charged heart 102 is transported to the recipient site in step 936.

ES 2 625 850 T3

Referring now to FIG. 30, the first phase 942 of the transplantation process includes repeating the testing 928 and evaluation 930 steps undertaken just prior to leaving the donor site 936. If the function and characteristics of the heart 102 are not acceptable , the system 100 may be adjusted 942 as appropriate, for example, to provide fluid or nutritional oxygenation levels, or to increase or decrease the appropriate fluid temperature. As indicated above, surgical and / or other therapeutic / repair procedures can be performed on the heart 102, in conjunction with the 928 test and the 930 test. In accordance with the illustrative implementation, the recipient site test can be carried out in retrograde flow mode, normal flow mode, or a combination of both.

In step 946, after the test is completed, the system 100 is placed in a normal / forward flow mode. In certain embodiments, this step 946 is not initiated until the left atrium 152 and pulmonary vein 164 are cannulated, and there is adequate operating volume in the system, the heart exhibits stable electrical activity, the ABG and electrolytes are within ranges. acceptable, SvO2 is> 80%, and the blood temperature is between about 34 ° C and about 36 ° C. Step 946 can be accomplished by slowing and / or stopping retrograde pumping to system 100, and then restarting pumping in direct mode. In certain implementations, before restarting in direct mode, the user opens the aortic sampling port 754a, releases the pressure control clamp 190 by turning it counterclockwise, then increases the flow rate of the pump 106 to approximately 1 , 0 l / minute, sets flow control valve 112 to normal / direct flow, and increase the flow rate of pump 106 to approximately 2.0 L / minute to allow blood 102 to displace air in the perfusate lines (for example 802) of system 100 and pass through the left side of heart 102 and into down to the reservoir return path 808. The user then closes the aortic sampling port 754a.

The flow rate of perfusion fluid 108 delivered from pump 106 is then increased in step 950 to a level chosen by the practitioner (typically between about 1 L / minute and about 5 L / minute) to approximate the physiological flow rate provided by the heart. 102 while operating in normal heartbeat mode. The heart 102 and system 100 are retested at step 952 in a similar manner to that described above with respect to steps 928 and 930. The practitioner may also choose to perform other tests or evaluations on the heart, for example, electrocardiogram, electrolyte measurement, cardiac enzyme measurement, metabolite measurements, intravascular ultrasound evaluation, pressure-volume loop evaluation, and Millar pressure evaluation.

In the third phase 946 at the recipient site, the heart 102 is prepared for implantation in the recipient. This phase includes step 956 of turning off the pump 106 to stop the flow of perfusion fluid 108. Then, in step 958, the heart 102 is stopped, for example by injecting it with cardioplegic solution in a similar way to that done at step 914 at the donor site. At step 960, heart 102 is decannulated and removed from organ chamber assembly 106. At step 962, heart 102 is transplanted into the recipient patient by first removing sutures 901a-901f, then inserting heart 102 into the thoracic cavity of the recipient, and suturing the various heart vesicles (eg, 158, 164a, 164b, 168a, 168b, 169a, 169b, and 903a-903f) to their corresponding mating vesicles within the recipient.

Although external devices and procedures have been described for defibrillating the heart, delivering pacing signals to the heart, and performing blood chemistry analyzes on samples taken from the perfusion fluid, it may also be beneficial to integrate these features into the portable system. Such features include defibrillation, pacing, diagnostic ECG detection, and blood chemistry analysis.

As described above, the system 100 employs a priming solution, and also employs a perfusion fluid 108 that combines a nutritional supplement solution 116 and a preservative solution 118 with a blood product or synthetic blood product to form the delivery fluid. infusion 108. The priming, supplement 116, and preservative 118 solutions are described below.

According to certain examples, solutions with particular solutes and concentrations are selected and provided to the organ to function under physiological or near physiological conditions. For example, such conditions include maintaining organ function at or near a physiological temperature and / or maintaining an organ in a state that allows normal cellular metabolism, such as protein synthesis. Exemplary solutions for perfusing a heart are disclosed in US Provisional Application Serial No. 60 / 793,472.

Certain experimental data are available to describe certain embodiments of solutions described herein and their use in perfusing a heart and are set forth in Figures 31-33. Figure 31 represents

ES 2 625 850 T3 a graph demonstrating electrolyte stability for a heart that is perfused in direct mode in accordance with one embodiment of system 100. In the embodiment associated with Figure 31, the organ is a heart 102 where perfusion it is carried out in direct mode (as described above) by pumping perfusion fluid 108 containing solution 116/118 into the left atrium 152 and out of the aorta 158. The infusion flow rate is approximately 30 ml / h. As can be seen from Figure 31, the levels of various electrolytes: sodium, potassium, calcium and chlorine ions, as well as dissolved glucose, remain at stable levels throughout the course of the perfusion, from before the organ is cannulated into the perfusion system 100 for up to six hours after cannulation within the system 100.

Figure 32 represents a graph demonstrating electrolyte stability for an organ undergoing retrograde perfusion in accordance with an implementation of system 100. In the example associated with Figure 32, the organ is a heart where perfusion occurs by pumping the perfusion fluid 108 containing solution 116/118 into the aorta 158 and through the coronary sinus 155. The perfusion flow rate is approximately 30 ml / hr. As can be seen from Figure 32, the levels of various electrolytes: sodium, potassium, calcium and chloride ions, as well as dissolved glucose, remain at stable levels throughout the course of the perfusion, from before the organ is cannulated to the 100 perfusion system for up to six hours after cannulation. Figure 32 also demonstrates that electrolyte and glucose levels remain at levels similar to those for the initial normal physiological state (BL) for the organ.

Figure 33 depicts a graph demonstrating the arterial blood gas profile for an organ undergoing perfusion in accordance with another embodiment of the invention. As can be seen from Figure 33, the levels of various blood gases: carbon dioxide and oxygen, and the pH remain at stable levels during the six hour infusion cycle. Figure 33 also demonstrates that the levels of carbon dioxide, oxygen and pH remain at levels similar to those for two initial measurements (BL) for the initial normal physiological state for the organ. Figures 31-33 demonstrate the ability of the present systems and methods to maintain an organ in stable physiological or near physiological conditions.

The systems and procedures described above for use in perfusing a heart ex vivo can also be adapted for the maintenance of one or more lungs in an ex vivo environment. In general, an exemplary system adapted for ex vivo lung maintenance includes a perfusion circuit that can circulate warm blood or other perfusion fluid through the lungs, and one or more gas sources to ventilate and supply oxygen, carbon dioxide and nitrogen needed to the lungs. An exemplary perfusion circuit includes a pump for circulating the perfusion fluid and one or more cannulation or other interfaces for connecting the lungs within the perfusion circuit. Similar to system 100, the lung maintenance system may also include other features such as a gas exchange device (eg, an oxygenator, or a respirator), a fluid heater to allow the user to control the temperature of the perfusion fluid. , and fluid heating and pumping process control systems. Nutritional sources can also be provided to replenish carbohydrates, electrolytes, and other components of the perfusion fluid that are consumed during operation of the system.

An exemplary lung maintenance system will be described below, along with a description of anatomical features of the lung that affect how the lungs are removed and connected to the system. Exemplary techniques for maintaining lungs ex vivo and for evaluating lungs for functionality and sustainability for transplantation are described below. An exemplary system and components thereof are described in more detail below.

In certain implementations, a lung maintenance system is configured in a portable module similar to the heart system described above, with both single-use and multi-use components that allow for optimal production costs and reuse of the system. Figure 34 depicts a schematic diagram of an exemplary portable lung care system 1000. The illustrated system 1000 includes a disposable single-use module 1002, similar to the single-use module 634, and designed to fit within the system 1000 to contain at least one lung during ex vivo maintenance and to regulate gas composition and flow. flow of perfusion fluid 108 (not shown) to and from the removed organ. More particularly, as shown in Figures 41-43, the disposable module 1002 includes a lung chamber assembly 1018, where at least one lung 1004 is instrumented via a pulmonary artery interface 1022, a pulmonary vein interface 1026, and a tracheal interface 1024. The disposable module 1002 also includes a fluid reservoir 160 to contain the circulating perfusion fluid 108, a perfusion pump interface 300, a heater assembly 110, and a plurality of fluid flow conduits and peripheral monitoring components. The single-use module 1002 is described in more operational detail below with reference to Figures 34 and 41-43. System 1000 also includes a perfusion fluid pump 106, a nutritional subsystem 115, a

ES 2 625 850 T3 power subsystem 148, an operator interface 146, a ventilation source 1003 (for example, a respirator or a breathing circuit that includes a bag), a controller 150, and a multipurpose module 650 (no shown), similar to those described above. In addition, the system 1000 includes one or more gas sources connected to the single-use module 1002, each having an ability to control the pressure and flow of the gases. Exemplary system 1000 also includes a gas exchange device, which, in certain embodiments is an oxygenator 114, for receiving and mixing gases from one or more gas sources.

Figure 35A depicts a pair of explanted lungs 1004 that may be connected to system 1000 for extended ex vivo maintenance. The explanted lungs 1004 are removed from a donor along with a portion of the lung circuits from donor 1010, as illustrated in FIG. 36. In particular, the removed lungs 1004 are excised from the donor by cutting through the donor's left atrium 1009, allowing the explant of a plurality of pulmonary veins 1007 that connect respective lungs 1004 to the excised piece of left atrial tissue, known as an atrial cuff. left 1008. Pulmonary veins 1007 are four in number, two from each lung, and include a right lower vein 1007a, a right upper vein 1007b, a left lower vein 1007c, and a left upper vein 1007d. In an alternative implementation, multiple pieces of left atrial tissue are excised from a donor, each connecting one or more pulmonary veins 1007 to a single left atrial cuff aggregation. Excision is also performed on the donor main pulmonary artery 1012, beginning at the base of the donor right ventricle 1014, to which both the donor right pulmonary artery 1005a and left pulmonary artery 1005b are confluently attached. Optionally, the explanted lungs 1004 also include the donor trachea 1006 through which air is transported into both lungs 1004.

Figure 35B presents a close-up view of a single lung 1004 that is explanted for use in system 1000. The depicted left lung 1004b is excised from a donor by cutting through the donor's left atrium 1009, as described above, allowing the explantation of the left superior 1007c and inferior 1007d veins that are joined in the excised left atrial cuff 1008. The explanted lung 1004b may also include the donor left pulmonary artery 1005b and optionally the donor trachea 1006.

Following explantation, lungs 1004 are placed in an ex vivo perfusion system where they are perfused during transport to a donor site, and where they can be evaluated for functionality and sustainability for transplantation.

More particularly, the system 1000 of FIG. 34 is adapted to maintain the explanted lungs 1004 in two modes of operation - a maintenance mode and an evaluation mode. Maintenance mode is used by system 1000 to preserve lungs 1004 ex vivo for an extended period of time. In general, in maintenance mode, system 1000 circulates perfusion fluid 108 into lungs 1004 through pulmonary artery interface 1022 and out of lungs 1004 through pulmonary vein interface 1026. System 1000 also ventilates lungs 1004 through tracheal interface 1024 during perfusion. Ventilation occurs mechanically by supplying a gas through the tracheal interface 1024 in breaths that include periodic inspiration and expiration, in a manner that approximates normal mechanical lung function in-vivo. In an alternative embodiment, periodic inspiration and expiration is obtained in a protective ventilation manner, whereby the breaths are triggered by a critical opening pressure and a critical closing pressure until a PEEP of approximately 8 to approximately 10 cmH2O is achieved and a tidal volume of about 5 to about 7 ml / kg indicating the volume of gas that flows into the lungs with each breath. The respiratory rate of the lung can be selected by the operator. In certain implementations, the System 1000 provides 12 or fewer breaths per minute; in certain implementations the system provides 6 breaths per minute. The number of breaths per minute is determined by the operator through the controller 150, which sends one or more electrical signals to a valve in the tracheal tube, which opens and allows the gas from the gaseous mixture to flow through the interface. tracheal 1024 and into the lung. Ventilation can be done by lung ventilators eg VentiPAC Model 200D or PneuPac.

In addition, system 1000 supplies a flow of a respiratory gas, having a predetermined composition of gaseous components, to lungs 1004 for use in lung respiration 1004 during perfusion. Upon reaching an equilibrium state of the system 1000, the perfusion fluid 108 flowing into the lungs 1004 includes a substantially constant composition of gaseous components, and the perfusion fluid 108 flowing out of the lungs 1004 also includes a substantially constant composition. constant of gaseous components. As used herein, a constant composition of a component in a fluid is achieved in equilibrium that occurs when the amount of the component in the fluid varies along

ES 2 625 850 T3 of time in an amount less than about 5%, less than about 3%, or less than about 1% at a given sampling location within the system. In this regard, the perfusion fluid 108 used to perfuse the lungs 1004 includes equilibrium compositions of gaseous components. This mode of operation provides the amount of gas that is necessary to deliver to the lungs 1004 to sustain their viability over extended periods of ex vivo maintenance and economizes on transporting the explanted lungs 1004 to the donor site. As illustrated in Figures 37 and 38, the maintenance mode can be implemented using two different approaches, both of which provide the steady state condition in the perfusion fluid 108 as described above. In addition, FIG. 39 provides exemplary steady state measurements of gaseous components in perfusion fluid 108 obtained during one of the two maintenance mode approaches.

Maintenance mode is implemented in two exemplary approaches - a tracheal oxygen delivery approach, and an isolated tracheal volume back breathing approach. Figure 37 depicts a flow chart 1300 of the steps involved in the maintenance mode tracheal oxygen delivery approach. At step 1302, the explanted lungs 1004 are instrumented within a perfusion circuit of the system 1000. In step 1304, the explanted lungs 1004 are perfused with a perfusion fluid 108 that is oxygenated to a desired level prior to initiating perfusion of the lungs 1004. Optionally, the perfusion fluid 108 can be brought to an elevated oxygen level. prior to initiating perfusion of the lungs 1004 so that an initial high oxygen level is delivered to the explanted lungs 1004. During perfusion of lungs 1004, oxygenated perfusion fluid 108 flows into explanted lungs 1004 via pulmonary artery interface 1022 and flows out of lungs 1004 via pulmonary vein interface 1026 (steps 1306). The explanted lungs 1004 are ventilated through the tracheal interface 1024 by a gaseous mixture containing a predetermined composition of gaseous components for organ respiration (step 1308).

Ventilation is accomplished in this approach by flowing ventilation / respiratory gas into the tracheal interface 1024 in periodic breaths containing a predetermined volume and gas pressure. Each breath includes a compression phase where gas is delivered into the lung in a desired volume, followed by decompression or relaxation of the lungs 1004 (and allowing the lungs 1004 to expel gas without assistance) so that the lungs 1004 exhale the gas through the tracheal interface 1024 in a volume approximately equal to the compression volume. An outlet valve at tracheal interface 1024 can be used to ensure minimal PEEP is maintained by preventing pressure from dropping below a user-determined value.

In certain embodiments, the respiratory gas mixture includes from about 10% to about 20% oxygen, from about 2% to about 8% carbon dioxide, and the balance is nitrogen. In certain embodiments, the gas mixture includes about 14% oxygen, about 5% carbon dioxide, and the balance is nitrogen. The oxygen component in the ventilation / respiratory gas provided through the tracheal interface 1024 enters the alveoli of the lungs 1004 and is exchanged with carbon dioxide from the perfusion fluid 108 that flows into the lungs 1004. The perfusion fluid 108 entering the lungs 1004 becomes oxygenated as a result of this exchange and then flows into the lung vasculature, where oxygen is consumed and carbon dioxide is produced. The lungs 1004 can consume oxygen in an amount less than the amount of oxygen provided in tracheal breaths. Carbon dioxide produced by the lungs 1004 passes into the perfusion fluid 108, then into the alveoli and is excreted from the lungs 1004 by exhaled breaths through an outlet valve at the tracheal interface 1024. The Outlet valve is provided through tracheal interface 1024 to allow expired breaths to be expelled from System 1000 and is described below with reference to Figure 43.

In the tracheal oxygen delivery approach, the ventilation / respiratory gas composition is predetermined by the operator to establish a balance of gaseous components in the system. In other words, the oxygen delivered to the lungs 1004 through the tracheal interface 1024 is consumed in the lungs 1004 and the resulting carbon dioxide is expelled through the tracheal interface 1024 without altering the gaseous composition in the perfusion fluid 108 that enters or leaves the lung. At equilibrium by this delivery approach, the perfusion fluid 108 flowing into the lungs 1004 and flowing out of the lungs 1004 have substantially the same oxygen and carbon dioxide composition, as indicated in step 1310. In addition, in step 1312, the lungs 1004 are perfused for an extended period of time while maintaining a fluid and gas balance in the lung.

Figure 38 depicts a flow chart 1400 of the steps involved in the second implementation of the mode.

ES 2 625 850 T3 maintenance. Similar to the first mode, in step 1402, the explanted lungs 1004 are instrumented within the lung care system 1000. In step 1404, the instrumented lungs 1004 are perfused with a perfusion fluid 108 flowing to the inside the lungs 1004 via the pulmonary artery interface 1022 and flows out of the lungs 1004 via the pulmonary vein interface 1026. In addition, one or more respiratory gas mixtures, each containing a predetermined composition of gaseous components, are supplied to the perfusion fluid 108 by a gas exchange device (eg, oxygenator) 1042 of system 1000 (step 1406). . More specifically, a first source of gas supplied to oxygenator 1042 includes a gaseous composition of from about 11% to about 14% oxygen and from about 3% to about 7% carbon dioxide, with the balance being nitrogen. In certain aspects, the first gas source includes about 12% oxygen, about 5% carbon dioxide, and the remainder is nitrogen. Other gases can be used, for example nitric oxide (for endothelial vasodilation and protection) and carbon monoxide (to provide anti-apoptotic effects).

At step 1408, the lungs 1004 are also ventilated with an isolated gas volume delivered through the tracheal interface 1024. The isolated gas volume is provided in a configuration that prevents it from communicating or otherwise interfacing with other fluids. except in the alveoli of the lung. In this approach, the gaseous components in the isolated gas volume are capable of achieving a substantially constant composition by exchange with the gaseous components from the perfusion fluid 108 pumped into the lungs 1004 via the pulmonary artery interface 1022 (step 1408 ). This gas exchange takes place through the alveolar membrane of the lungs 1004. The expired carbon dioxide component produced from the exchange is then removed from the lungs 1004 by the circulating perfusion fluid 108. This carbon dioxide component is substantially removed from the perfusion fluid 108 by the gas exchange device 1042.

Upon reaching equilibrium, as indicated in step 1410, the oxygen and carbon dioxide in the perfusion fluid 108 flowing into the lungs 1004 have a substantially constant first composition, and the oxygen and carbon dioxide in perfusion fluid 108 flowing out of lungs 1004 they have a substantially constant second composition. However, unlike the tracheal oxygen delivery mode, in the isolated tracheal volume mode, the first composition of oxygen and carbon dioxide components in the perfusion fluid 108 flowing into the lungs 1004 may differ from the second composition of the gaseous components in the perfusion fluid 108 flowing out of the lungs 1004. In preferred embodiments of this approach, said first and second compositions differ in amounts substantially equivalent to the amount of oxygen consumed by the lungs 1004 and the amount of carbon dioxide produced by the lungs 1004 during metabolism.

In certain embodiments, the oxygen composition in perfusion fluid 108 is maintained during perfusion at a steady-state oxygen saturation or partial pressure that is higher in perfusion fluid 108 flowing into lungs 1004 than in perfusion fluid 108 flowing out of lungs 1004. In certain embodiments, the carbon dioxide component is maintained during perfusion at an equilibrium partial pressure that is lower in the perfusion fluid 108 flowing into the lungs 1004 than in the perfusion fluid 108 flowing out. of the lungs 1004. This maintenance mode implementation approach is also called an isolated tracheal volume re-breathing approach, where oxygen delivered to perfusion fluid 108 through oxygenator 1042 is consumed in lungs 1004 and the resulting carbon dioxide is withdrawn. from the lungs 1004 by perfusion fluid 108 and removed through oxygenator 1042.

Ventilation is performed in the second mode with breaths occurring approximately as frequently as those delivered in the first mode. However, ventilation in the same mode occurs by first compressing the isolated gas volume, thereby causing the gas to flow from the isolated volume and into the tracheal interface 1024, and then allowing the lungs to relax. and exhale the gas, unaided, from the pulmonary alveoli to fill the isolated volume.

In maintenance mode, system 1000 pumps perfusion fluid 108 into lungs 1004 at a flow rate of about 500 to about 5000 ml / min. This mode of operation can help reduce damage to the lungs 1004 during extended periods of ex vivo maintenance. Therefore, in accordance with a feature of the invention, lungs 1004 are transported to a donor site in maintenance mode. Additionally, functional tests performed during assessment mode, described below, can also be performed during maintenance mode to assess various lung capabilities. In certain aspects, the recruitment of the lungs 1004 can be performed in the mode of

ES 2 625 850 T3 maintenance. For example, a suction force may be applied to the lungs 1004 via the tracheal interface 1024 to clear the lungs 1004 of fluid or debris from the alveoli. The folded alveoli in the lungs 1004 can swell causing the lungs 1004 to breathe in breaths that are of variable volume, such as sighing, which causes the lungs 1004 to breathe in a first breath that has a volume that is greater than the volumes of at least two subsequent breaths using, for example, a respirator or a breathing circuit that includes a bag.

Having described the two different approaches to implementing a maintenance mode of operation with respect to Figures 37 and 38, exemplary measurements of gaseous components in perfusion fluid 108 flowing into and out of a pair of lungs are described below. 1004 in equilibrium for a breathing approach again from an isolated tracheal volume. In particular, as shown in Figure 39, the data in column 4000 provides steady-state measurements of gaseous components in perfusion fluid 108 flowing into explanted lungs 1004 through the pulmonary artery interface. 1022. The data in column 4002 provides steady state measurements of gaseous components in perfusion fluid 108 flowing out of explanted lungs 1004 through pulmonary vein interface 1026. Data in Figure 39 were obtained using an analyzer gas sampler, such as the ABL800 FLEX Radiometer, to analyze 108 perfusion fluid samples taken during isolated tracheal volume respiring approach. Referring briefly to the lung maintenance system 1000 of Figures 41-43, a first sample of the perfusion fluid 108 was taken at port 1080 over the arterial fluid flow. This fluid sample was analyzed by the blood gas analyzer to generate the data in column 4000. For the sake of measurement accuracy, the radiometer was recalibrated after each analysis was performed on a fluid sample. A second sample of perfusion fluid 108 was taken at port 1082 and analyzed by the blood gas analyzer to generate the data at column 4002. The two sets of measurements were separated in time due to the requirement of recalibration.

In general, during the maintenance mode, the perfusion fluid 108 flowing into and out of the lungs 1004 is maintained at a relatively similar composition of gaseous components. For example, the 4000th partial pressure of carbon dioxide in arterial fluid flow (43.8 mmHg) is only slightly less than the 4002nd partial pressure of carbon dioxide in venous fluid flow (44.6 mmHg), and the partial pressure 4000b of oxygen in the arterial fluid flow (84.5 mmHg) is only slightly higher than the partial pressure 4002b of oxygen in the venous fluid flow (83.9 mmHg). These differences in partial pressures may be attributable to imprecision in the measurement system, pulmonary metabolism, or interactions with the oxygenator 1042.

In certain embodiments, the composition of gaseous components in perfusion fluid 108 is selected to provide steady state partial pressures of the gaseous components within the circulating fluid in a range between a gaseous composition of physiological arterial blood of the body and a gaseous composition. of physiological venous blood. For example, as shown in FIG. 39, the composition of the oxygen component in the perfusion fluid 108 is at a partial pressure that is greater than a composition of the oxygen component in physiological venous blood and less than a composition of the component. of physiological arterial blood oxygen. More specifically, this partial pressure of the oxygen component in the perfusion fluid 108 can be between about 75 mmHg and about 100 mmHg, between about 80 mmHg and about 90 mmHg, or between about 83 mmHg and about 85 mmHg. Furthermore, as shown in FIG. 40, the composition of the carbon dioxide component in the perfusion fluid 108 is at a partial pressure that is less than a composition of the carbon dioxide component in physiological venous blood and greater than a composition of the carbon dioxide component in physiological arterial blood. More specifically, this partial pressure of the carbon dioxide component in the perfusion fluid 108 can be between about 40 mmHg and about 50 mmHg, or between about 42 mmHg and about 48 mmHg.

Having described the maintenance mode in detail with respect to Figs. 37-39, the evaluation mode is explained below. Techniques for evaluating lungs 1004 to assess their functionality and sustainability for transplantation will also be described.

In particular, FIG. 40 provides a flow chart 1200 illustrating the steps involved in implementing the evaluation mode. As depicted, the system 1000 perfuses the explanted lungs 1004 with a perfusion fluid 108. The perfusion fluid 108 is prepared to be similar in blood gas partial pressures to the physiological venous blood of a body. This venous gaseous composition in perfusion fluid 108 can be achieved by mixing one or more gases, having a combined composition of carbon dioxide and little or no oxygen, with perfusion fluid 108 (step 1204), until

In ES 2 625 850 T3 a desired venous composition (1206) is reached, at which point the supply of the gases to the perfusion fluid 108 can optionally be stopped (step 1208). In one embodiment, the gases include about 5% carbon dioxide and about 95% nitrogen. Perfusion fluid 108 is adapted to flow into lungs 1004 through pulmonary artery interface 1022 and flow out of lungs 1004 through pulmonary vein interface 1026. as indicated in step 1210, The explanted lungs 1004 can be ventilated by an oxygen-containing gas that is flowed into the tracheal interface 1024 from a suitable ventilation source, such as from a respirator. This gas can comprise about 100% oxygen, about less than 100% oxygen, less than about 75% oxygen, less than about 50% oxygen, or less than about 25% oxygen. In certain embodiments, this gas can be of the same composition as ambient air.

The evaluation mode is useful, for example, to perform tests to evaluate the gas transfer capacity of the lungs 1004 by determining the partial pressure or oxygen saturation of the perfusion fluid 108 both before and after it flows through the lungs. 1004. To perform this test in the evaluation mode, as shown in steps 1212 and 1214, The system 1000 monitors the gaseous composition of the blood from the perfusion fluid 108 after ventilation begins by taking sample measurements of oxygen saturation or oxygen partial pressure in the perfusion fluid 108 flowing into the lungs 1004 by means of the pulmonary artery interface 1022 and flowing out of the lungs 1004 via pulmonary vein interface 1026. The resulting pulmonary artery and pulmonary vein oxygen saturation or oxygen partial pressure measurements are then compared to each other to identify a maximum difference that is representative of the gas transfer capacity of the lungs 1004. In a second approach to assessing the gas transfer capacity of the lungs, the oxygen saturation or partial pressure of oxygen in the perfusion fluid flowing into the lungs 1004 is taken before ventilation begins. At a predetermined time after ventilation begins, another oxygen saturation or oxygen partial pressure measurement is taken in the perfusion fluid flowing out of the lungs 1004 and compared with the first measurement to assess the ability to gas transfer from the lungs 1004. The operator determines if this capacity is sufficient and decides to carry out the transplant, or not. In addition, other functional tests may be performed on the lungs 1004, such as diagnostic bronchoscopy, visual evaluation, and biopsy, both before and after transport of the lungs 1004 to a donor site.

Exemplary functional tests performed on lungs 1004 during evaluation mode include tests that assess the gas exchange functionality of lungs 1004, which can be carried out using blood gas analysis of fluid samples taken from both the arterial side (e.g., through port 1080) as well as the venous side (eg, through port 1082) of fluid flow in the perfusion circuit. Tests can be performed to assess pulmonary circulation to perfusion fluid 108 through the lungs. This may involve calculating the pulmonary vascular resistance (PVR) which is a measure of the ability of the lungs 1004 to resist fluid flow. Details regarding the calculation of the PVR value are provided below with respect to Figure 52. Furthermore, alterations in the PVR value can be monitored in response to an infusion of nitric oxide into the perfusion fluid 108 to detect any reversibility of pulmonary hypertension. Pulmonary angiography can also be performed on the lungs 1004. In certain implementations, assessment of the bronchial tree is carried out using bronchoscopy in conjunction with other analytical applications such as inspecting the airways, collecting bronchial lavages for cytological or microbiological studies, or obtaining multiple biopsies. In certain implementations, imaging studies are performed on the lungs 1004 using, for example, x-rays, CT, or nuclear studies such as perfusion or ventilation scans. These imaging devices may be external to or incorporated into the organ care system 1000. In certain aspects, viability studies are carried out in parenchymal or bronchial tissue of the lungs 1004 using techniques such as biopsies or measurements of tissue levels of AMP. , ADP and ATP. Additionally, assessments such as assessing the severity of ischemic reperfusion injury in instrumented lungs 1004 can be performed by measuring the levels of indicator agents, such as conjugated dienes or lactate, in the perfusion fluid 108. In addition, a test for pulmonary patency in the explanted lungs to determine if the lungs are injured or otherwise compromised. This test includes injecting an agent, such as a dye, into the perfusion fluid and, after a period of perfusion time, visually inspecting the lungs. If the agent is visually detectable in the endo-bronchial tree of the lungs or in the alveoli, then the lungs are injured since they are permeable to the injected substance. Additional evaluations include using biomarkers based on proteomic or genomic approaches to predict organ graft rejection or development of bronchiolitis obliterans syndrome (BOS) in a potential organ recipient. In certain aspects, one or more of the aforementioned tests may be performed on lungs 1004 during a maintenance mode of operation.

ES 2 625 850 T3

Having described exemplary processes for implementing maintenance mode and assessment mode, along with techniques for evaluating 1004 lungs to assess their functionality and suitability for transplantation, characteristics of the 1000 lung care system will now be described in more detail with respect to these two modes of operation. In particular, the instrumentation of the lungs 1004 within the system 1000 is described in more detail. A generalized approach to operating the system is described below, followed by a description of specific system features that are custom designed for each mode of operation.

Figures 41-43 illustrate a pair of explanted lungs 1004, such as the explanted lungs 1004 of Figure 35a, cannulated within one embodiment of the disposable single-use module 1002. In particular, the module 1002 includes a chamber assembly of the lung 1018 containing explanted lungs 1004 connected to array 1018 from at least one of pulmonary artery interface 1022, pulmonary vein interface 1026, and tracheal interface 1024. The lungs 1004 can rest prone or supine in the lung chamber assembly 1018. With brief reference to FIG. 35A, the pulmonary artery interface 1022 includes a cannulation of the lungs 1004 in or near the main pulmonary artery 1012. Tracheal interface 1024 may include a cannulation of lungs 1004 in or near trachea 1006. In optional implementations, where the trachea 1006 is not excised with the lungs 1004, the tracheal interface 1024 may include a conduit that is placed directly in a bronchial branch of each lung 1004, and the lungs 1004 are ventilated through that conduit. The pulmonary vein interface 1026 may include cannulation to the lungs 1004 in the excised left atrial cuff 1008 where at least one of the pulmonary veins 1007 from the two lungs 1004 is joined. However, in certain implementations, the excised left atrial cuff 1008 remains uncannulated. Specific details regarding the pulmonary vein interface 1026 are described below in the context of exemplary operating procedures and with reference to Figures 48-51. Module 1002 also includes reservoir 160 to contain perfusion fluid 108 and an oxygenator 1042 that provides at least one appropriate gas mixture to perfusion fluid 108.

Referring again to Figures 34 and 41-43, in an illustrative embodiment of a general operating process, perfusion fluid 108 is prepared for use within module 1002 (and ultimately within system 1000) by being charged in reservoir 160 via nozzle 774 and optionally treated with therapeutic substances via nozzle 762. The charged perfusion fluid 108 is subsequently pumped from reservoir 160 to heater assembly 110 and is heated to a temperature close to physiological. In this illustrated embodiment, this pumping action is provided by an alignment of the interface assembly of the pump 300 with the impeller of the pump 334 of the multipurpose module 650 previously described with reference to FIG. 8C. Pump interface assembly 300 receives a pumping force from pump impeller 334 and transfers the pumping force to perfusion fluid 108, thereby circulating perfusion fluid 108 to lung chamber assembly 1018. However, Any fluid pump can be used to flow perfusion fluid 108 in the perfusion circuit. The heat assembly 110 includes temperature sensors 120 and 122 a dual sensor 124 that provides temperature measurement of the perfusion fluid 108. A plurality of compliance chambers, such as compliance chambers 1086a-c, can be included in the system 1000. There are essentially small inline fluid accumulators with flexible and elastic walls designed to simulate the vascular compliance of the human body helping the System 1000 to more accurately mimic blood flow in the human body. In particular, the compliance chamber 1086a is located at an outlet of the perfusion fluid pump 300, the compliance chamber 1086b is located at an outlet of the heater assembly 110, and the compliance chamber 1086c is located at an outlet of the oxygenator. 1042. Any one of these compliance chambers 1086a-c can be used individually or a plurality of compliance chambers can be used in any combination.

Perfusion fluid 108 from heater assembly 110 is then pumped to gas exchange device 1042. Depending on the selected flow mode, as well as the type of implementation chosen to execute the selected flow mode, one or more mixing gases, each having a predetermined gaseous composition, can be automatically or manually supplied to the perfusion fluid 108 a through the gas exchange device (eg, an oxygenator) 1042. In certain embodiments, the selection of the flow mode type is accomplished using a mode selector switch 1020 located on the system 1000 between the gas supplies and the oxygenator 1042. The mode selector switch 1020 may be actuated manually as well as by the controller 150. In certain embodiments, the order of oxygenator 1042 and heater assembly 110 along the illustrated perfusion circuit is switched.

Depending on the mode switch 1020 selected, the oxygenator 1042 receives one or more mixing gases from respective gas sources through gas regulators 174, 1030a, and 103b and gas flow chambers 172, 1028a, and 1028b. Gas sources can be external to or incorporated into the organ care system

ES 2 625 850 T3

1000. Gas pressure gauges, such as gauges 178, 1036a, and 1036b, provide visual indication of gas level in respective gas supplies 172, 1028a, and 1028b. Transducers 132, 1032a, and 1032b provide similar information to controller 150. The controller is capable of automatically regulating the flow of gas from each gas source into the oxygenator 1042 depending, for example, on the oxygen content of the perfusion fluid measured in the oxygenation / hematocrit sensor 1064, very similar to the sensor 140 previously described. This sensor also provides a signal indicative of a perfusion fluid hematocrit measurement. Subsequent to mixing the selected gases with the perfusion fluid 108, the perfusion fluid 108 is pumped into the lungs 1004 through the pulmonary artery interface 1022. In an exemplary embodiment, a mixing gas supplied to the oxygenator 1042 from A gas flow chamber is premixed to include a desired gaseous composition for infusion into the perfusion fluid 108. One or more additional gas sources containing, for example, a high level of oxygen, carbon dioxide, or hydrogen, may additionally be supplied to the oxygenator 1042 from other gas flow chambers to modulate the composition of the mixing gas in the fluid. perfusion 108. In another embodiment, gases having different compositions are controllably released from the appropriate gas source chambers to the oxygenator 1042 at rates and volumes that allow the desired gas mixture composition to be obtained in the perfusion fluid 108. However, for certain perfusion modes, the oxygenator 1042 does not activate.

In certain practices, a flow sensor 1056, very similar to flow sensor 134, is positioned along the flow of arterial fluid from oxygenator 1042 to pulmonary artery interface 1022 to measure a flow rate of fluid 108. A flow sensor Pressure 1050, very similar to the pressure sensor 126 described above, is also positioned along the arterial fluid flow to measure the pressure of the perfusion fluid 108. This pressure sensor 1050 may be on an edge of the lung chamber assembly 1018 or within the assembly 1018 and as close as possible to a pulmonary artery cannulation site. In certain implementations, a port 1080 is provided to allow an operator to sample the perfusion fluid 108 along the arterial flow for further off-line analysis.

Perfusion fluid 108 is then pumped into lung chamber assembly 1018 and lungs 1004 cannulated therein via pulmonary artery interface 1022. Pulmonary artery interface 1022 includes cannulation to main pulmonary artery 1005 through of an opening 1040a located on the lung chamber assembly 1018. Lungs 1004 may be ventilated with a gas mixture via tracheal interface 1024 that includes cannulation to trachea 1006 (or a substitute conduit not shown) via opening 1040b located in lung chamber assembly 1018. Alternatively, it may be performed cannulation to a portion of an intact trachea 1006 in explanted lungs 1004. Figures 4143 illustrate various approaches to ventilation of lungs 1004 through tracheal interface 1024. These approaches are mode specific to the maintenance mode approaches described above and as described below in more operational detail. In certain embodiments, controller 150 is capable of regulating a composition of gaseous components delivered to lungs 1004 via tracheal interface 1024 based on fractional inspired O2 (FiO2) concentration measurements and fractional expired CO2 concentration measurements obtained on a meter. FiO2 1030 and a FiCO2 1031 meter, respectively. A flow sensor 1067 can also be used to measure the flow rate at which lungs 1004 are ventilated via tracheal interface 1024. A pressure sensor 1068 can be used to measure the pressure of gas delivered to lungs 1004 via tracheal interface 1024. In Certain embodiments, electrode sensors 1060 and 1062 are coupled to lung chamber assembly 1018 to measure weight and elasticity, respectively, of explanted lungs 1004.

Perfusion fluid 108 is pumped out of lung chamber assembly 1018 via pulmonary vein interface 1026 which includes, in certain embodiments, cannulation to pulmonary veins 1007 through an opening 1040c located on lung chamber assembly. 1018. In other implementations, pulmonary veins 1007 remain uncannulated. In general, pulmonary vein interface 1026 establishes a return path of perfusion fluid 108 from pulmonary veins 1007 to reservoir 160 for continued circulation through the perfusion circuit. In addition, a fluid passage 1084 is provided that connects the lung chamber assembly to reservoir 160. Along a fluid flow path from pulmonary vein interface 1026 to reservoir 160, one or more sensors may be positioned to provide measurements such as fluid flow via flow sensor 1058, fluid pressure via sensor pressure 1052, and oxygenation and hematocrit of the fluid through the sensor 1066. Pressure sensor 1052 may be on an edge of lung chamber assembly 1018 or within assembly 1018 and as close as possible to the pulmonary vein cannulation site. In certain configurations, a port 1082 is provided to allow an operator to sample the perfusion fluid 108 along the venous flow. In certain implementations, a flow clamp 1090, very similar to the clamp 190 described above, is positioned along the fluid flow path from the pulmonary vein interface 1026 to the reservoir 160 to regulate a back pressure.

ES 2 625 850 T3 applied to pulmonary veins 1007 when lungs 1004 are provided with instruments in lung chamber assembly 1018.

Having described a generalized process for operating system 1000, system 1000 is now described in more detail with reference to individual modes. These modes include the assessment mode and the maintenance mode, the latter of which can be implemented using either the tracheal oxygen delivery approach or the isolated tracheal volume again breathing approach, as described above with reference to the Figures 37 and 38.

Figures 41 and 42 illustrate various examples of the single-use module 1002 configured for use with the isolated tracheal re-breathing approach. In particular, the first gas source, which includes a gaseous composition of from about 3% to about 7% carbon dioxide, from about 11% to about 14% oxygen, and the balance being nitrogen, is supplied to the gas exchange device (i.e., an oxygenator) 1042 for circulation through the perfusion system 1000. During perfusion, perfusion fluid 108 is pumped into lungs 1004 through pulmonary artery interface 1022 and is pumped out of lungs 1004 through pulmonary vein interface 1026. In addition, a volume of gas The isolate is delivered to lungs 1004 during perfusion via tracheal interface 1024 to ventilate lungs 1004, as previously described in FIG. 38. In one embodiment depicted in Figure 41, the isolated gas volume is provided by a flexible bag 1069 that can contract and expand with each lung breath 1004 during ex vivo care. In one embodiment depicted in Figure 42, the constant gas volume is provided by a hose 1050 connected to a source of gas 1052 such as a gas tank or a respirator. Hose 1050 is appropriately configured to allow lungs 1004 to breathe in a constant volume of gas during perfusion. In yet another embodiment, a specialized respirator may be used to deliver the constant gas volume to the lungs 1004.

Figure 43 illustrates one embodiment of the single-use module 1002 configured for use with the tracheal oxygen delivery approach described above with reference to Figure 37. The perfusion fluid 108 is oxygenated to a desired gaseous component level prior to perfusing. lungs 1004. This can be accomplished by circulating perfusion fluid 108 through system 1000 prior to instrumenting the lung and supplying fluid 108 with an appropriate gas mixture through, for example, oxygenator 1042. After perfusion fluid 108 reaches a desired level of gaseous components, the oxygenator 1042 is deactivated to stop the supply of respiratory gas to the perfusion fluid 108. The oxygenated perfusion fluid 108 is subsequently stored in reservoir 160 before perfusion of the organ begins.

During perfusion, perfusion fluid 108 is pumped from reservoir 160 to heater assembly 110 and heated to near physiological temperature before being delivered to lungs 1004 in lung chamber assembly via pulmonary artery interface. 1022. In the embodiment of FIG. 43, the lungs 1004 are ventilated with a continuous supply of a gas mixture from an external gas source through an inlet valve 1060 of the tracheal interface 1024. As described above, in One implementation the gas mixture includes a composition of about 14% oxygen, about 5% carbon dioxide, and the balance is nitrogen. The gas source may be a 1062 gas chamber, such as the gas chambers 172, 1028a, and 1028b of Figure 34, housed external to or incorporated into the system 1000. A 1064 gas pressure gauge, such as the gauges 178, 1036a, and 1036b of FIG. 34 provide visual indication of gas pressure in chamber 1062. During perfusion, the oxygen component in the gas mixture inspired by the lungs 1004 through the inlet valve 1060 is exchanged with the carbon dioxide component in the perfusion fluid 108 through the alveoli of the lungs 1004 , and the carbon dioxide component is subsequently expelled from the alveoli on an exhaled breath through an outlet valve 1066 at tracheal interface 1024. Both inlet 1060 and outlet 1066 valves are configured to prevent substantial mixing of gaseous components between the gas mixture flowing through each valve. Perfusion fluid 108 flows out of lung chamber assembly 1018 via pulmonary vein interface 1026.

Having described the system 1000 in relation to the maintenance mode, the system 1000 is described below in relation to the evaluation mode. As mentioned above, the perfusion fluid 108 in reservoir 160 is allowed to reach a predetermined gaseous composition before tests are performed on lungs 1004 to assess, for example, its gas transfer capacity. The predetermined gaseous composition may be, for example, a physiological venous blood gaseous composition. This gaseous composition of venous blood in perfusion fluid 108 can be achieved by applying a low-oxygen or oxygen-free gas mixture to perfusion fluid 108 through oxygenator 1042 after the

ES 2 625 850 T3 perfusion fluid 108 flows out of reservoir 160. Exemplary oxygen-free or low-oxygen gas mixtures include a mixture having from about 4% to about 11% carbon dioxide, from about 0% to about 8% oxygen, and the balance is nitrogen, a mixture that has about 5% carbon dioxide, about 0% oxygen and the rest is nitrogen, and a mixture that has about 5% carbon dioxide, about 5% oxygen, and the rest is nitrogen . The resulting perfusion fluid 108 is optionally passed through heater assembly 110, pumped into lungs 1004 via pulmonary artery interface 1022, and flows out of lungs 1004 via pulmonary vein interface 1026, then back to the tank 160 for a later return through the circuit. In this way, the perfusion fluid 108 is circulated in the system 1000 until a gaseous composition of venous blood is reached in the perfusion fluid 108 that flows into and out of the lungs 1004. After the fluid When perfusion 108 reaches the desired venous gaseous composition, the oxygenator 1042 can be deactivated to stop the flow of the low-oxygen or oxygen-free gas mixture to the perfusion fluid 108. The lungs 1004 are then ventilated with an oxygen-containing gas from an external source via the tracheal interface 1024. The gas transfer capacity of the lungs 1004 can therefore be determined by monitoring the oxygen saturation or the partial pressure. of oxygen in the venous and arterial flows of the perfusion fluid 108 after ventilation begins.

Heretofore, an exemplary system 1000 for lung maintenance has been described, along with a description of anatomical features of the lung that affect how lungs 1004 are removed and connected to system 1000. In addition, exemplary techniques for maintaining lungs have been described. 1004 ex vivo during a maintenance mode of operation. Exemplary techniques for evaluating lungs 1004 have also been described to assess their functionality and suitability for transplantation during the evaluation mode. In addition, exemplary features of the system 1000 have been described in detail in relation to the various modes. Additional exemplary features of the system 1000 are described below, including the lung chamber assembly 1018, the pulmonary vein interface 1026, system controls, and data acquisition and display modules. An exemplary transplantation procedure is described below, along with a description of exemplary solutions used in the 1004 lung care perfusion circuit.

Various examples of the lung chamber assembly 1018 are described with reference to Figures 44-47. As depicted, lung chamber assembly 1018 may be rectangular in shape to accommodate a pair of explanted lungs 1004. Alternatively, lung chamber assembly 1018 may be triangular in shape to accommodate a single explanted lung 1004. With brief reference to Figures 41-43, lung chamber assembly 1018 includes openings 1040a-1040c adapted to receive pulmonary artery interface 1022, tracheal interface 1024, and pulmonary vein interface 1026. In general, the structure and material composition of lung chamber assembly 1018 closely resembles the organ chamber assembly 104 for the containment of a heart described above and depicted in Figures 5A-5F, but expanded to a size sufficient to house a pair of lungs 1004. Particularly, the explanted lungs 1004 may be contained in a soft or hard shell casing in the lung chamber assembly 1018. In certain implementations, the assembly 1018 lies flat. In other embodiments, assembly 1018 is tilted at an adjustable angle so that explanted lungs 1004 rest at the same angle within it.

The sheath cover of the lung chamber assembly 1018 may include a suspension mechanism to provide support and stability to the lungs 1004. Exemplary suspension mechanisms are depicted in Figures 44-47. In an illustrative configuration of the lung chamber assembly 1018 shown in FIG. 44, a flexible membrane (eg, mesh, cloth, cloth, or other suitably flexible material) is used to suspend the explanted lungs 1004 in the chamber assembly of the lung. lung 1018 to minimize contact between a surface of the lungs 1004 and one or more internal walls of the lung chamber assembly 1018. The membrane contacts a large portion of the surface of the lung to support the weight of the lung in a manner that distributes weight across the membrane, thereby reducing pressure on any particular region of the lungs 1004 and avoiding alveolar damage. The flexible membrane 1070 in the depicted embodiment is a mesh structure. Mesh structure 1070 can be mesh or porous and can substantially prevent alveoli in at least a portion of lungs 1004 from collapsing while being contained in assembly 1018 for ex vivo maintenance. In an alternative configuration of the lung chamber assembly 1018 as illustrated in FIG. 45, the lungs 1004 may be additionally or alternatively contained in a second mesh 1072 that suspends the lungs 1004 from a top cover or other structures within the assembly. 1018. This second mesh 1072 simulates the effects that a rib cage has on the lungs 1004 by preventing the lungs 1004 from over-expanding during respiration while maintaining their physiological shape. The second mesh 1072 may be constructed from the same material as the first mesh 1070 or it may be constructed from a substantially different material.

ES 2 625 850 T3

In certain configurations, there is a support structure for the lungs that simulates the interior of the chest cavity, supporting the lungs on the anterior and posterior sides, and helping the lungs maintain their physiological shape. For example, in an illustrative example of lung chamber assembly 1018 as shown in FIG. 46, a rib cage-shaped housing 1074 is used to secure explanted lungs 1004 in lung chamber assembly 1018. Constructed of flexible material, this 1074 rib cage shell simulates the shape and movement of a real rib cage. In certain implementations as depicted in Figure 47, a body diaphragm-like feature 1076 is coupled to the rib cage housing 1074 (refer to the cutaway rib cage in Figure 47 for a better view) extending across a lower part of the housing 1074. This diaphragm 1076 can also be constructed of a flexible material so that it can contract and relax with each breath of the lungs 1004.

Having described specific features of the lung chamber assembly 1018, exemplary features of the pulmonary vein interface 1026 are described below with reference to Figures 48-51. More specifically, Figures 48-51 illustrate various ways of connecting pulmonary veins 1007 in system 1000 at pulmonary vein interface 1026 as illustrated above with reference to Figures 4143. In certain embodiments veins 1007 are cannulated at interface 1026. However, pulmonary veins 1007 can remain uncannulated so that fluid flowing out of pulmonary veins 1007 drains freely into lung chamber assembly 1018 and returns to reservoir 160 through passage 1084, as depicted in the system of Figures 41-43.

Figures 48Aa and 48B depict an exemplary apparatus for cannulation at the pulmonary vein interface 1026 of Figures 41-43. As illustrated, cannulation device 1001 includes a funnel-shaped cannula 1100 having proximal 1168a and distal 1168b ends and a connecting device 1102 having legs 1102a and 1102b. Using the connector device 1102, an operator pairs the cannula 1100 with the excised left atrial cuff 1008 from the donor having all of the donor's pulmonary veins 1007 confluently joined. Since donor pulmonary veins 1007 also join donor lungs 1004, pairing cannula 1100 with sleeve 1008 secures sleeve 1008, veins 1007, and lungs 1004 within system 1000.

As illustrated in Figure 48B, connector device 1102 includes connecting surfaces 1104 and 1112 that are used to form the mating interface between sleeve 1008 and cannula 1100. As shown, surfaces 1104 and 1112 are configured each as a ring with a hollow center and attached to respective legs 1102a and 1102b. Ring 1104 is larger than a cross section 1164 of distal end 1168b of cannula 1100 but less than a cross section 1162 of proximal end 1168a of cannula 1100 so that ring 1104 can be attached behind funnel portion 1160 of the cannula 1100. Furthermore, ring 1112 is configured to be small enough compared to the size of left ear cuff 1008 so that cuff 1008 cannot be easily pulled out of ring 1112 after cuff 1008 has been pushed through ring 1112. .

When cannulation device 1001 is operated in accordance with the illustrative implementation, ring 1104 is inserted into distal end 1168b of cannula 1100 and slid through the length of cannula 1100 until ring 1104 abuts and optionally tightly surrounds a section of cannula 1100. The excised left atrial cuff 1008 is then pushed through ring 1112, leaving a portion 1170 of cuff 1008 that extends beyond the perimeter of ring 1112. An operator then compresses the handles 1118 of the connector device 1102 until the left atrial cuff 1008 mates with the funnel opening in the proximal end 1168a of the cannula 1100 so that the locking mechanisms 1103a and 1103b engage each other to keep connector device 1102 secured. Cannula 1100 is suitably configured so that funnel portion 1160 of cannula 1100 is capable of receiving and mating with left atrial cuff 1008. In certain implementations, cannula 1100 is malleable to allow it to bend as necessary to secure the lungs. 1004 and fit within system 1000. A cannula 1100 is malleable, in general, if it is capable of bending but maintains a generally uniform cross-sectional diameter regardless of how much it bends. In certain implementations, appropriately sized cannulas and connector devices are provided to accommodate an excised left atrial cuff of various sizes.

After coupling sleeve 1008, legs 1102a and 1102b are locked in place by locking mechanism 1103a and 1103b or other suitable mechanisms to hold connector device 1102 in the compressed position.

Figures 49A and 49B depict another example of the apparatus for cannulation at pulmonary vein interface 1026.

ES 2 625 850 T3

This device is also designed for use with a single piece of excised left atrial cuff that has all four donor pulmonary veins 1007 confluently joined. As shown in FIG. 49A, connector device 1102 includes a first connecting surface 1130 configured as a ring with a first inner peripheral surface 1106 and a first outer O-ring 1108. The first inner peripheral surface 1106 includes threads (not shown) that mesh with the outwardly extending grooves 1110 that project from the outer peripheral surface 1111 of the funnel-shaped cannula. Consequently, cannula 1100 is coaxially coupled to ring 1130. Connector device 1102 also includes a second connecting surface 1112 configured as a ring with a second inner peripheral surface 1114 and a second outer O-ring 1116. In one example as depicted in Figure 49B, projections 1120 are regularly spaced around the circumference of the inner peripheral surface 1114 to firmly engage a portion 1101 of the left atrial cuff 1008 to the ring 1112 when the cuff 1008 is pushed through the ring 1112. Other suitable mechanisms may be used to provide the same tissue fixation function. It is noted that the size of the second O-ring 1116 can be small enough compared to the size of the left atrial cuff 1008 so that the portion 1101 of the cuff 1008 rests securely within the O-ring 1116. In turn, the cannula 1100 and the first O-ring 1108 are configured accordingly so that the first 1108 and the second 1116 O-rings match, a fluid-tight seal is formed around the cannula 1100 and the portion 1101 of the ear cuff. left 1008. In certain implementations, appropriately sized cannulas and connector devices are provided to accommodate a severed left atrial cuff of various sizes.

When cannulation device 1001 is operated, ring 1130 is screwed onto outer peripheral surface 1111 of cannula 1100 via grooves 1110 until tight. A portion 1101 of the excised left atrial cuff 1008 is then pushed through the second inner peripheral surface 1114 of the second ring 1112 until the portion 1101 is firmly seated within the seal 1116. An operator then pushes the handles 1118 of the connector device 1102 together until the first 1108 and second 1116 O-rings mate to provide a seal around the cannula 1100 and the left atrial cuff 1008. The legs 1102a and 1102b are then locked in place. in place by a locking pin (not shown) or other suitable mechanisms such as the locking mechanism 1103a and 1103b of Figure 48. In certain implementations, to break the gasket around the cannula 1100 and the left atrial cuff 1008, the operator releases the locking pin (not shown) followed by separating the handles 1118 from the connector device 1102 until the first 1108 and second 116 O-rings separate.

Figures 50A and 50B depict yet another example of the apparatus for cannulation at the pulmonary vein interface 1026. This apparatus is designed for use with the donor's left atrial cuff 1008 that is attached to the four donor pulmonary veins 1007. As illustrated in Figure 50B, the cannulation device 1001 includes a funnel-shaped cannula 1100 having a proximal end 1168a, a connection surface 1800, a stopper 1804, and legs 1102a and 1102b attached to the cannula 1100 and the surface connection 1800, respectively.

In certain examples, proximal end 1168a of cannula 1100 and connection surface 1800 are configured to form a mating surface when lugs 1118 of cannulation device 1001 are in a compressed position and stop 1804 fits within a central bore 1802 of the connection surface 1800. More specifically, connection surface 1800 is configured as a square structure having a square hole 1802 etched through a central portion of connection surface 1800. Stopper 1804 is adapted to fit within square hole 1802 so that square perforation 1802 is divided into four small square perforations 1802a-d. A cross section of the proximal end 1168a of the cannula 1100 is also square in shape and is similarly dimensioned as a cross section of the connection surface 1800. Furthermore, the size of each of the smaller square perforations 1802a-d is small enough compared to the size of the left atrial cuff 1008 so that the cuff 1008 cannot be easily pulled out of the perforations 1802a-d after sleeve 1008 has been pushed through large bore 1802 and secured in place by stopper 1804.

When the cannulation device 1001 is operated in accordance with the illustrative implementation, the excised left atrial cuff 1008 is pushed through the large central perforation 1802 of the connection surface 1800, allowing a portion of the cuff 1008 to extend beyond of a perimeter of bore 1802. An operator then fits stopper 1804 into center bore 1802 to secure sleeve 1800 to connecting surface 1800. The operator then compresses the handles 1118 of the cannulation device 1001 until the left atrial cuff 1008 mates with the funnel opening in the proximal end 1168a of the cannula 1100. The cannula 1100 is suitably configured so that it is capable of

ES 2 625 850 T3 to receive and engage the entire left atrial cuff 1008 secured to the connection surface 1800. In certain configurations, the cannula 1100 is malleable to allow it to bend as needed to further secure the lungs 1004 and fit within the system 1000.

After the entire left atrial cuff 1008 is attached to the cannula 1100, the legs 1102a and 1102b are locked in place by a locking pin (not shown) or other suitable mechanisms to hold the connector device 1102 in the compressed position.

Referring again to Figures 48-50B, in certain respects; a cross section of a proximal opening 1168a of a cannula 1100 may be larger than a cross section of the left atrial cuff 1008 cannulated to the cannula 1100. This configuration allows a portion of the perfusion fluid 108 to flow through the veins tubes 1007 are drained into lung chamber assembly 1018 instead of flowing into cannula 1100. In certain aspects, the mating interface between cannula 1100 and left atrial cuff 1008 is configured to be semi-sealable such that at least a portion of perfusion fluid 108 flowing from pulmonary veins 1007 to cannula 1100 is capable of leakage. into the lung chamber assembly 1018. In certain aspects, cannula 1100 is located in lung chamber assembly 1018 in a relatively upright position relative to left atrial cuff 1008 so that perfusion fluid 108 flows in an upward direction from left atrial cuff 1008 up to cannula 1100. Due to the semi-sealable mating interface formed between the cannula 1100 and the left atrial cuff 1008, a portion of the perfusion fluid 108 is adapted to leak out of the mating interface and drain into the lung chamber assembly 1018. Subsequently a Back pressure is created by perfusion fluid 108 in cannula 1100. In one example, this back pressure is created by a column of perfusion fluid 108 in cannula 1100 that is between about 1 cm and about 3 cm in height.

Figure 51A illustrates another example of connection (eg, by cannulation) at pulmonary vein interface 1026. An excised left atrial cuff 1008, having one or more pulmonary veins 1007 attached to it, is folded over and sealed in a 1900 seam to form a 1902 pocket interface. In particular, left atrial cuff 1008 is folded such that pulmonary veins 1007 are fluidly connected to an empty interior region defined by pocket interface 1902. In addition, a proximal end 1168a of a cannula 1100 is sealed within the pocket 1902 so that proximal opening 1168a of cannula 1100 is also fluidly connected to the empty region of pocket interface 1902. This two-way connection between pulmonary veins 1007 and cannula 1100 via pocket interface 1902 is adapted to conduct perfusion fluid 108 out of lungs 1004 during perfusion. Pocket interface 1902 can be surgically sewn or stapled to itself. In certain implementations, pocket interface 1902 is relatively leak proof such that nearly all of the fluid 108 flowing through pulmonary veins 1007 is conducted to proximal opening 1168a of cannula 1100. In certain implementations, the interface pocket 1902 is designed to allow some amount of fluid 108 to drain into lung chamber assembly 1018 instead of flowing into cannula 1100. This filtered fluid 108 can be returned to reservoir 160 via passage 1084 that connects lung chamber assembly 1018 to reservoir 160.

Figure 51B illustrates yet another example of connection (eg, by cannulation) at pulmonary vein interface 1026. An excised left atrial cuff 1008 is lowered into a cup-shaped interface 4202 from an upper opening 4210 (not shown) of the cup-shaped interface 4202 that is located within the lung chamber assembly 1018. In an exemplary implementation, a size of the upper opening 4210 is smaller than the size of the explanted lungs 1004, but is small enough to allow the left atrial cuff 1008 to be comfortably lowered into the interface 4202. Cup-shaped interface 4202 also includes openings 4203a-c located at varying heights along a side wall of interface 4202 and in fluid communication with a selector valve 4206 via conduits 4204a-c, respectively. Selector valve 4206 is further coupled to an outlet conduit 4208 that is adapted to conduct perfusion fluid 108 out of lung chamber assembly 1018 and into reservoir 160. In certain aspects, selector valve 4206 is manually or electromechanically controlled by controller 150 and / or user interface 146 to perform selective and controlled dispensing of perfusion fluid 108 from cup interface 4202 through a selected of the openings 4203a-c and into the outlet conduit 4208. Therefore, selector valve 4206 can be used to maintain a desired level of perfusion fluid 108 at cup-shaped interface 4202. In operation, as perfusion fluid 108 exits pulmonary veins 1007 via atrial cuff left hand 1008, is collected at cup-shaped interface 4204 until the height of perfusion fluid 108 within interface 4202 reaches one of the openings 4203a-c as adjusted by selector valve 4206. Fluid 108 then exits cup-shaped interface 4202 through the selected opening, flows through the corresponding conduit, enters selector valve 4206, and is carried out of lung chamber assembly 1018 via outlet conduit.

ES 2 625 850 T3

4208. Therefore, the perfusion fluid 108 is capable of filling the cup-shaped interface 4202 to a height where the selected one of the openings 4203a-c is located, in order to create a desired level of back pressure on the pulmonary veins. .

Having described specific features of the lung chamber assembly 1018 and exemplary processes for cannulation at the pulmonary vein interface 1026, details regarding system 1000 data acquisition and display modules are described below.

In one aspect, the illustrative control system schematic depicted in the block diagram of Fig. 11 is used to operate system 1000 for the care of explanted lungs 1004. Each subsystem depicted in the functional blocks of Fig. 11 is particularly configured to maintain the lungs 1004 in an optimally viable state at or near physiological conditions. More specifically, the data acquisition subsystem 147, as illustrated in the block diagram of Figure 12, is modified to include sensors to obtain information pertinent to the function of the system 1000 and the lungs 1004, and to communicate the information. to controller 150 for processing and use by system 1000. As described above with reference to Figures 41-43, the sensors used in the system 1000 include pressure sensors 1050, 1052 and 1068, flow sensors 1056, 1058 and 1067, oxygen / hematocrit sensors 1064 and 1066, 1030 and 1031 FiO2 and FiCO2 concentration meters, 1060 weight sensor and 1062 elasticity sensor. Some of the sensors used by System 100 can also be used by System 1000. These sensors include the temperature sensors 120, 122 and 124, the Hall sensor assembly 388 and the encoder sensor axis 390 of the perfusion pump assembly 106, the battery sensors 352a-352c, the external power available sensors 354 and the battery sensor of the operator interface module 370.

Information obtained by the various sensors in data acquisition subsystem 147 is transmitted to controller 150 and displayed by operator interface subsystem 146. Operator interface subsystem 146 includes a display screen 3100, as shown in Figure 52, which shows a series of numerical and graphical indications regarding the care of the lungs 1004. In particular, the display screen 3100 includes a display area 3140 that displays a representation of the pulmonary arterial pressure (PAP) waveform 3148. Display area 3140 also includes a numeric display 3152 of a PAP reading, as measured by pressure sensor 1050. The display area 3142 of the display screen 3100 shows a representation of the waveform 3150 of the left atrial to pulmonary venous pressure (LAP) and a reading 3154 of the LAP, as measured by the pressure sensor 1052. The Display area 3144 includes a waveform representation 3156 of the breath-ventilation pressure through the tracheal interface 1024 (RESP) and a reading 3158 of the RESP, as measured by the pressure sensor 1068. In certain embodiments, the displayed PAP, LAP, and RESP values ​​are snapshot readings. In certain respects, the PAP and LAP values ​​are displayed as an average, a mean, or a minimum of instantaneous readings collected over a period of time that is less than 30 seconds, less than 20 seconds, or less than 10 seconds. In certain aspects, the RESP value is displayed as an average or minimum of instantaneous readings collected over a period of time that is less than 30 seconds, less than 20 seconds, or less than 10 seconds. Additionally, waveforms 3148, 3150, and 3156 are displayed in real time or periodically with each batch of data collected.

The display screen 3100 further includes a number of additional display areas 3102, 3104, 3106, 3108, 3110, 3112, 3114 and 3116. The display area 3102 displays a numerical reading 3160 of the pulmonary flow (PF) of the perfusion fluid. 108 into lungs 1004 via pulmonary artery interface 1022, as measured by flow sensor 1056. Display area 3104 shows a numerical value 3162 representative of pulmonary vascular resistance (PVR). The value of PVR 3162 indicates the amount of resistance that the lungs 1004 exert on a flow of perfusion fluid 108 and is calculated by subtracting a value of LAP, such as the reading of LAP 3154, from a value of PAP, such as the reading PAP 3152, divided by a PF value, such as the PF 3160 reading and applying a unit conversion factor. In general, a lower PVR value 3162 is preferable as it indicates less restricted flow of perfusion fluid 108 through the vasculature of the lungs 1004. In certain certain implementations, favorable PVR values ​​are in a range between about 0.002 N and about 0.004N (about 200 dynes to about 400 dynes). The display area 3106 shows the venous oxygen saturation (SvO2) 3164 of the perfusion fluid 108, as measured from the oxygen / hematocrit sensor 1066. Similarly, the display area 3108 shows the arterial oxygen saturation ( SvO2) 3166 from perfusion fluid 108, as measured from oxygen / hematocrit sensor 1064. In certain configurations, display areas 3106 and 3108 further include an SvO2 alarm and a Sa O2 alarm, respectively, to indicate to the operator if each oxygen saturation value falls below a threshold preset by the operator. Such an alarm can

ES 2 625 850 T3 be implemented for any parameter measured, calculated or displayed. The display area 3110 includes a numerical reading 3168 of the hematocrit (HCT) of the perfusion fluid 108, and, optionally, an HCT alarm indicator to indicate to the operator if the HCT 3168 falls below a threshold preset by the operator. The display area 3112 indicates the temperature (Temp) 3170 of the perfusion fluid 108 as it flows out of the heater assembly 110. The display area 3112 may also include a Temp alarm indicator, which sends a signal in response to the Temp 3170 falling outside of an operator preset range. An operator selected temperature set point 3172 is also shown in display area 3112. The display area 3114 shows a numerical reading 3174 of the ventilation flow rate measured as breaths per minute (BPM) of a gas delivered to the lungs 1004 via the tracheal interface 1024. A BPM reading from a flow sensor can be assessed, communicated to from a respirator, or obtained from a pressure sensor, such as pressure sensor 1068. The value of BPM 3174 can be measured at flow sensor 1067. In addition, the display area 3114 includes a BPM alarm indicator 3176 that indicates if the BPM 3174 value is outside of an operator preset range. The display area 3116 includes a numerical display 3178 of the tidal volume (TDLV) of a gas flow into the lungs 1004 with each lung breath 1004 and a TDLV alarm indicator 3180 that indicates whether the TDLV value 3178 is outside of a range preset by the operator.

The display screen 3100 further includes a circulatory pump indicator 3118 that displays a status of the system's circulatory pump, a perfusion fluid heater indicator 3120 that displays a status of the perfusion fluid heater assembly 110, and an indicator of 3124 SD card showing if an SD card is used to store data collected during organ perfusion. A display area 3126 is provided that includes a gas tank image 3182 that graphically indicates a volume of gas remaining in a gas supply connected to system 1000. Display area 3126 also includes one or more numerical displays 3184 that indicate a flow rate of the gas in the gas supply along with the remaining time during which the gas is delivered to the lungs 1004 during perfusion. This remaining time can be calculated based on the remaining gas volume and the gas flow rate. Display area 3122 displays an organ type indicator 3186 that indicates which organ is being perfused and an organ mode indicator 3188 that indicates which mode of operation is being used to perfuse the organ. For example, an R is used to indicate a maintenance mode of operation. The display area 3190 shows a graphical representation 3128 of the degree to which the batteries 352a-352c of the multipurpose module 650 are charged. The battery status symbol 3130 indicates that batteries 352a-352c, whose states are represented by graph 3128, are used to power the multipurpose module 650. The display area 3146 may also provide a numerical indication of the amount of time remaining during which the batteries 352a-352c can continue to operate the system 1000 in the current operating mode. The display area 3192 shows a graphical representation 3132 of the degree to which the user interface battery 368 is charged and a numerical indication 3194 of the amount of time remaining during which the user interface battery 368 can continue to operate the device. user interface module 146. The battery status symbol 3134 indicates that the user interface battery 368, the status of which is represented by graphical representation 3132, is used to power the user interface 146. The display area 3136 identifies whether the operator interface module 146 is operating wirelessly 3196, along with a graphical representation 3198 of the quality of the wireless connection between the operator interface module 146 and the rest of the system 1000. Display screen 3100 also includes an alarm image 3101 that indicates whether any system 1000 parameter is outside of an operator-set threshold for that parameter (alarm 3101 is shown as off in figure 52) or communicates a message. alarm related to the system. The display screen 3100 further includes a display area 3146 that displayed a date and time of system operation and a display area 3138 that displays the amount of time that has elapsed since the infusion began.

In other configurations, the 3100 display screen also displays FiO2 and FiCO2 concentrations, which are fractional concentrations of oxygen and carbon dioxide, respectively, measured by 1030 and 1031 sensors through the 1024 tracheal interface. In addition, the display screen 3100 can additionally display weight and elasticity readings of the lungs 1004, PH of the perfusion fluid 108 flowing through the lungs 1004, partial pressures of gaseous components in the perfusion fluid, and positive pressures to the end-expiration (PEEP) of the lungs 1004 indicating the pressure in the lungs 1004 at the end of the expired breath.

Having described specific features of the lung chamber assembly 1018 and exemplary processes for cannulation at the pulmonary vein interface 1026, and the system 1000 data acquisition and display modules, an exemplary lung transplantation procedure is described below with reference to Figures 53 and 54.

ES 2 625 850 T3

The process of obtaining and preparing lungs 1004 for cannulation and transport, as shown in FIG. 53 is similar to the steps shown in FIG. 29A for caring for a heart. This process begins by providing a suitable organ donor at stage 2000. The organ donor is taken to a donor location, where the process of receiving and preparing donor 1004's lungs for cannulation and transport takes place through two intersecting routes. The routes primarily involve preparing system 1000 to receive the lungs from donor 1004 and then transporting lungs 1004 via system 1000 to a recipient site. In particular, route 2002 includes exsanguination of the donor, arresting the donor heart, and preparing the lungs 1004 for cannulation in system 1000. In particular, in the exsanguination stage 2006, the donor's blood is withdrawn and set aside so that may be used to perfuse lungs 1004 during their maintenance in system 1000. The steps involved in withdrawing blood from the exsanguinated patient have been described above with respect to FIG. 29A. After the donor blood is exsanguinated, the donor heart is injected at stage 2008 with a cardioplegic solution to temporarily stop its beating in preparation for the removal of the lungs 1004.

After the donor heart has stopped, a pneumoplegic solution is administered to the lungs at stage 2009 before 1004 lungs are explanted from the donor at stage 2010 and prepared for loading into system 1000 at stage 2012. The processes involved in explanting a single lung or a pair of lungs 1004 have been previously explained with respect to Figures 35 and 36.

Continuing with reference to Figure 53, after lungs 1004 are explanted from the donor body, they are instrumented on system 1000 at step 2021 by insertion into lung chamber assembly 1018 and cannulation into the Appropriate interfaces as described above with respect to Figures 34 and 48-51.

In accordance with other illustrative implementations, lungs 1004 can be transferred directly from donor to system 1000 without the use of cardioplegia. In a particular implementation, the lungs of donor 1004 are removed without the donor heart being stopped and subsequently instrumented in system 1000 for maintenance.

During the preparation of lungs 1004, via route 2002, system 1000 is prepared through the stages of route 2004 so that it is primed and expects to receive lungs 1004 for cannulation and transport as soon as lungs 1004 are ready . In particular, system 1000 is prepared on route 2004 through a series of stages, including providing single-use module 1002 (stage 2014), priming system 1000 with a primary solution (stage 2016), filtering the donor blood and add it to reservoir 160 (step 2018), and prime system 1000 with a mixture of blood and perfusion fluid 108 (step 2020). In certain embodiments, the perfusion fluid 108 includes whole blood. In certain embodiments, the perfusion fluid 108 is partially or completely depleted of leukocytes. In certain embodiments, the perfusion fluid 108 is partially or completely depleted of platelets. The priming, supplemental and preservative solutions used by the organ care system 100 for the maintenance of a heart can also be used in the system 1000. In certain embodiments, the solutions used with system 100 are used, but new additives including prostaglandin E, prostacyclin, dextran, isuprel, flolan, and nitric oxide donors are added while epinephrine is removed. The additives can generally be selected from antimicrobial, vasodilator and anti-inflammatory drugs. Additives can be supplied to System 1000 through ports 762 and 774 attached to the reservoir. 160 or via the 1024 tracheal interface through a nebulizer or bronchoscope. The various solutions used by the organ care system 1000 will now be described in more detail.

In step 2022, the system 1000 is selected to operate in the maintenance mode. Different maintenance mode implementation approaches have been described above with reference to Figures 37 and 38. In general, explanted lungs 1004 are connected in system 1000. Perfusion fluid 108 is pumped into lungs 1004 through pulmonary artery interface 1022 and is pumped out of lungs 1004 through pulmonary vein interface 1026. A gas supply, such as an isolated volume or A continuous flow is provided to the lungs 1004 via the tracheal interface 1024. A flow of a respiratory gas, having a predetermined composition of gaseous components, is also provided to the lungs 1004 for use in lung respiration 1004 during perfusion. In addition, in an equilibrium state of the system 1000, a composition of gaseous components in the perfusion fluid 108 flowing into the lungs 1004 includes a substantially constant composition of components, and the perfusion fluid 108 flowing out of the lungs 1004 also includes a substantially constant composition of components. In addition, in step 2024, instrumented lungs 1004 can be monitored and evaluated using a plurality of monitoring components coupled to system 1000.

ES 2 625 850 T3

Based on the monitored parameters, in some respects, it is desirable to provide recruitment to the lungs 1004 during maintenance mode (step 2026). For example, lungs 1004 can be treated with antimicrobials or suctioned to remove fluid and alveoli debris in trachea 1006. The folded alveoli in the lungs 1004 can be swollen using sigh breathing, causing the lungs 1004 to breathe in breaths that are of variable volume, such as causing the lungs 1004 to breathe in a first breath that has a volume that is greater than the volumes of at least two next breaths. In some aspects, an operator can perform surgery on the lungs 1004 or provide a therapeutic substance or other treatment, such as immunosuppressive treatments, chemotherapy, genetic testing, or radiation therapy. Additional assessments of lungs 1004 have been described above with respect to Figures 37-40.

Figure 54 provides an exemplary process for conducting additional tests on lungs 1004 while system 1000 is at the recipient site (step 3000). In particular, at step 3002, the system 1000 is set to operate in the evaluation mode to provide a perfusion state that is suitable for evaluating the lungs 1004 to determine their gas transfer capacity. Additional recruitment may be performed during the assessment mode at step 3003 based on the assessment of the lungs 1004 performed at step 3005. Steps involved in the implementation of the assessment mode have been described in detail above with reference to FIG. 39. After the tests are completed at the recipient site, the lungs 1004 are prepared for implantation into the recipient. This includes configuring system 1000 for lung removal by cutting off power to pump 106 to stop the flow of perfusion fluid 108 (step 3004) and optionally administering a pneumoplegic solution to lungs 1004. Next, step 3008 , lungs 1004 are decannulated and removed from lung chamber assembly 1018. At step 3018, lungs 1004 are transplanted into the recipient patient by inserting them into the recipient's chest cavity and suturing the various lung connections to their appropriate mating connections within the recipient. In certain implementations, a portion of the recipient's left atrium may be excised and replaced with one or more of the donor's left atrial cuff 1008 to which the donor's pulmonary veins are attached.

As described above, the system 1000 employs a priming solution, and also a perfusion fluid 108 that combines a nutritional supplement solution 116 and a preservative solution 118 with a blood product or synthetic blood product to form the perfusion fluid. 108. Priming, Supplement 116, and Preservative 118 solutions are described below.

According to certain embodiments, solutions with particular solutes and concentrations are selected and provided to perfusion fluid 108 to allow lungs 1004 to function under physiological or near physiological conditions. For example, such conditions include maintaining lung function at or near a physiological temperature and / or maintaining a lung in a state that allows normal cellular metabolism, such as protein synthesis.

In certain examples, solutions are formed from compositions by combining components with a fluid, from solutions more concentrated by dilution, or from solutions more dilute by concentration. In exemplary implementations, suitable solutions include a source of energy and one or more amino acids selected and provided such that the organ continues its cellular metabolism during perfusion. Cellular metabolism includes, for example, carrying out protein synthesis while functioning during infusion. Some illustrative solutions are aqueous based while other illustrative solutions are non-aqueous based, eg, organic solvent base, ionic liquid base, or fatty acid base.

Solutions can include one or more energy-rich components to help the organ carry out its normal physiological function. These components can include energy-rich materials that are metabolizable and / or components of such materials that an organ can use to synthesize energy sources during perfusion. Exemplary sources of energy-rich molecules include, for example, one or more carbohydrates. Examples of carbohydrates include monosaccharides, disaccharides, oligosaccharides, polysaccharides, or combinations thereof, or precursors or metabolites thereof. Although not intended to be limiting, examples of suitable monosaccharides for solutions include octoses; heptose; hexoses such as fructose, allose, altrose, glucose, mannose, gulose, idosa, galactose, and talose; pentoses such as ribose, arabinose, xylose, and lixose; tetrosa such as erythrose and treose; and trioses such as glyceraldehyde. Although not intended to be limiting, examples of suitable disaccharides for solutions include (+) - maltose (4O- (oD-glucopyranosyl) -o-D-glucopyranose), (+) - cellobiose (4-O- (oD-glucopyranosyl) - D-glucopyranose), (+) - lactose- (4-O- (oD-galactopyranosyl) -oD-glucopyranose), sucrose (2-O- (oD-glucopyranosyl) -oD-fructofuranoside). Although it is not intended to be limiting,

ES 2 625 850 T3 examples of suitable polysaccharides for solutions include cellulose, starch, amylose, amylopeptin, sulfomucopolysaccharides (such as dermatan sulfate, chondroitin sulfate, sulodexide, mesoglycans, heparan sulfates, idoxanes, heparins, and heparinoids), and glycogens. . In some embodiments, monosaccharides, disaccharides, and polysaccharides of both aldoses and ketoses or a combination thereof are used. One or more isomers, including enantiomers, diastereomers, and / or tautomers of disaccharide monosaccharides and / or polysaccharides, including those described and those not described herein may be employed in the solutions described herein. In some embodiments, one or more monosaccharides, disaccharides, and / or polysaccharides may have been chemically modified, for example, by derivatizing and / or protecting (with protecting groups) one or more functional groups. In certain embodiments, carbohydrates, such as dextrose or other forms of glucose, are preferred.

Other possible energy sources include adenosine triphosphate (ATP), coenzyme A, pyruvate, flavin adenine dinucleotide (FAD), thiamine chloride pyrophosphate (cocarboxylase), β-nicotinamide adenine dinucleotide (NAD), β nicotinamine adenine dinucleotide ADPH phosphate (NADPH). and phosphate derivatives of nucleosides, eg, nucleotides that include mono, di, and triphosphates (eg, UTP, GTP, GDF, and UDP), coenzymes, or other biomolecules that have similar cellular metabolic functions, and / or metabolites or precursors thereof. For example, phosphate derivatives of adenosine, guanosine, thymidine (5-Me-uridine), cytidine, and uridine, as well as other naturally and chemically modified nucleosides are also contemplated.

In certain implementations, one or more carbohydrates are provided in conjunction with a phosphate source, such as a nucleotide. An exemplary carbohydrate is dextran. The carbohydrate helps the organ produce ATP or other energy sources during the infusion. The phosphate source can be provided directly through ATP, ADP, AMP, or other sources. In other illustrative embodiments, a phosphate is provided through a phosphate salt, such as a glycerophosphate, sodium phosphate, or other phosphate ions. A phosphate can include any form thereof in any ionic state, including protonated forms and forms with one or more counterions.

In some aspects, additional components are provided to assist the lungs 1004 in carrying out their metabolism during infusion. These components include, for example, forms or derivatives of adenine and / or adenosine, which can be used for ATP synthesis, to maintain endothelial function, and / or to attenuate ischemia and / or reperfusion lessons. According to certain implementations, a magnesium ion source is provided with a phosphate, and in certain embodiments with adenosine to further enhance ATP synthesis within perfused lung cells 1004.

The solutions described herein may include one or more amino acids, preferably a plurality of amino acids, to support protein synthesis by organ cells. Suitable amino acids include, for example, any of the naturally occurring amino acids. Amino acids can be, in various enantiomeric or diastereomeric forms. For example, the solutions can use either Do Laminoacids or a combination thereof, ie 48 enantioenriched solutions in more quantity of the Do L-isomeric or racemic solutions. Suitable amino acids can also be non-naturally occurring or modified amino acids such as citrulline, ornithine, homocysteine, homoserine, β-amino acids such as β-alanine, aminocaproic acid, or combinations thereof.

Certain exemplary solutions include some but not all naturally occurring amino acids. In some examples, the solutions include essential amino acids. For example, a solution can be prepared with one or more of the following amino acids:

<td>Wisteria</td>

<td>To the girl</td>

<td>Arginine</td>

<td>Aspartic acid</td>

<td>Glutamic acid</td>

<td>Histidine</td>

<td>Isoleucine</td>

<td>Leucine</td>

<td>Methionine</td>

<td>Phenylalanine</td>

<td>Proline</td>

<td>Serine</td>

<td>Threonine</td>

ES 2 625 850 T3

Tryptophan

Tyrosine

Valine

Lysine acetate

In certain examples, non-essential and / or semi-essential amino acids are not included in the solutions. For example, in some embodiments, asparagine, glutamine, and / or cysteine ​​are not included. In other embodiments, the solution contains one or more non-essential and / or semi-essential amino acids. Accordingly, other examples include asparagine, glutamine, and / or cysteine.

The solutions can also contain electrolytes, particularly calcium ions to facilitate enzymatic reactions and / or coagulation within the organ. Other electrolytes such as sodium, potassium, chlorine, sulfate, magnesium, and other inorganic and organic charged species, or combinations thereof, can be used. It should be noted that any component provided hereinafter, where valence and stability allow, may be provided, in an ionic form, in a protonated or non-protonated form, in a free base or salt form, or as ionic or covalent substituents in combination with other components that hydrolyze and make the component available in aqueous solutions, as appropriate and appropriate.

In certain examples, the solutions contain buffer components. For example, suitable buffer systems include 2-morpholinoethanesulfonic acid monohydrate (MES), cacodylic acid, H2CO3 / NaHCO3 (pKal), citric acid ((pK_to3), bis (2-hydroxyethyl) -imino-tris- (hydroxymethyl) methane (Bis-Tris), Ncarbamoylmethylimidine acetic acid (ADA), 3-bis [tris (hydroxymethyl) methylamino] propane (Bis-Tris propane) (pKal ), piperazine1,4-bis (2-ethanesulfonic acid), (PIPES), N- (2-Acetamido) -2-aminoethanesulfonic acid (AcEs), imidazole, N, Nbis (2-hydroxyethyl) -2-aminoethanesulfonic acid (BES) , 3- (N-morpholino) propanesulfonic acid (MOPS),

NaH2PO4 / Na2HPO4 (pKa2), N-tris- (hydroxymethyl) methyl-2-aminoethanesulfonic acid (TES), N- (2-hydroxyethyl) piperazine-N'-2-ethanesulfonic acid (HEPES), N- (2-hydroxyethyl ) piperazine-N '- (2-hydroxypropanesulfonic acid) (HEPPSO), triethanolamine, N- [tris (hydroxymethyl) methyl] glycine (Tricine), tris hydroxymethylaminoethane (Tris) glycinamide, N, N-bis (2hydroxyethyl) glycine (Bicine ), glycylglycine (pKa2), N-tris (hydroxymethyl) methyl-3-aminopropanesulfonic acid (TAPS), or a combination thereof. In some embodiments, the solutions contain sodium bicarbonate, potassium phosphate, or TRIS buffer.

In another aspect, a blood product is provided with the solution to support the organ during metabolism. Exemplary suitable blood products can include whole blood, and / or one or more components thereof such as blood serum, plasma, albumin, and red blood cells. In embodiments where whole blood is used, the blood can be passed through a filter to remove leukocytes and platelets to reduce pyrogens, antibodies, and / or other elements that can cause inflammation in the organ. Thus, in some embodiments, the solution employs whole blood that has been at least partially depleted of leukocytes and / or whole blood that has been at least partially depleted of platelets.

The solutions are preferably provided at a physiological temperature and are kept approximately the same throughout the perfusion and recirculation. As used herein, "physiological temperature" refers to temperatures between about 25 ° C and about 37 ° C, for example, between about 30 ° C and about 37 ° C, such as between about 34 ° C and about 37 ° C. ° C.

Table 1 presents the components that are used in exemplary aqueous priming solutions. The amounts of the components in Table 1 are relative to each other and to the amount of aqueous solvent employed in the solution (approximately 500 ml, in the exemplary embodiment) and can be scaled as appropriate. In certain implementations, the amount of aqueous solvent varies ± about 10%.

<td colspan="3">Table 1: Exemplary Priming Solution Composition (Approximately 500 ml Aqueous Solution)</td>

<td>Component</td><td>Quantity</td><td>Specification</td>

<td>Dextran</td><td>20g</td><td>± about 50%</td>

<td>Sodium chloride</td><td>4.8 g</td><td>± about 10%</td>

<td>Potassium chloride</td><td>185 mg</td><td>± about 10%</td>

<td>Magnesium sulfate heptahydrate</td><td>185 mg</td><td>± about 10%</td>

<td>Sodium glycerophosphate</td><td>900 mg</td><td>± about 10%</td>

With respect to the nutritional supplement solution 116, in certain implementations, it includes one or more

ES 2 625 850 T3 carbohydrates and may also include a phosphate source. The nutritional supplement solution 116 is normally maintained at a pH of from about 5.0 to about 6.5, for example from about 5.5 to about 6.0.

Table 2 presents components that are used in an exemplary nutritional supplement solution 116. In some examples, the nutritional solution 116 further includes sodium glycerol phosphate. The amount of components in Table 2 is relative to the amount of aqueous solvent used in solution 116 (about 500 ml) and can be scaled as appropriate. In some examples, the amount of aqueous solvent varies ± about 10%.

<td colspan="3">Table 2: Components of Exemplary Nutritional Solution (Approximately 500 ml)</td>

<td>Component</td><td>Quantity</td><td>Specification</td>

<td>Dextrose</td><td>40 g</td><td>± about 10%</td>

In certain examples, the nutritional supplement solution 116 includes one or more carbohydrates and may also include a source of phosphate. Nutritional solution 116 is normally maintained at a pH of from about 5.0 to about 6.5, for example from about 5.5 to about 6.0.

Other components can be added to preservation solution 118, including, for example, adenosine, magnesium, phosphate, calcium, and / or sources thereof. In some aspects, additional components are provided to assist the organ in carrying out its metabolism during infusion. These components include, for example, forms of adenosine, which can be used for ATP synthesis, to maintain endothelial function, and / or to attenuate ischemia and / or reperfusion lessons. The components can also include other nucleosides, such as guanosine, thymidine (5-Me-uridine), cytidine, and uridine, as well as other naturally and chemically modified nucleosides that include nucleotides thereof. According to some implementations, a magnesium ion source is provided with a phosphate, and in certain embodiments with adenosine to further enhance ATP synthesis within cells of the perfused organ. A plurality of amino acids can also be added to aid in the synthesis of proteins by the cells of the heart 102. Applicable amino acids can include, for example, any of the naturally occurring amino acids, as well as those mentioned above.

Table 3 presents the components that can be used in solutions 118 to preserve an organ as described herein. Solution 118 can include one or more of the components described in Table 3.

<td colspan="2">Table 3: Component of Exemplary Composition for Preservative Solution</td>

<td>Component</td><td>Exemplary concentration ranges in preservative solution</td>

<td>To the girl</td><td>about 1 mg / l - about 10 g / l</td>

<td>Arginine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Asparagine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Aspartic acid</td><td>about 1 mg / l - about 10 g / l</td>

<td>Cysteine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Cystine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Glutamic acid</td><td>about 1 mg / l - about 10 g / l</td>

<td>Glutamine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Wisteria</td><td>about 1 mg / l - about 10 g / l</td>

<td>Histidine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Hydroxyproline</td><td>about 1 mg / l - about 10 g / l</td>

<td>Isoleucine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Leucine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Lysine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Methionine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Phenylalanine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Proline</td><td>about 1 mg / l - about 10 g / l</td>

<td>Serine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Threonine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Tryptophan</td><td>about 1 mg / l - about 10 g / l</td>

<td>Tyrosine</td><td>about 1 mg / l - about 10 g / l</td>

ES 2 625 850 T3

<td>Valine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Adenine</td><td>about 1 mg / l - about 10 g / l</td>

<td>ATP</td><td>about 10 ug / l - about 100 g / l</td>

<td>Adenylic acid</td><td>about 10 ug / l - about 100 g / l</td>

<td>ADP</td><td>about 10 ug / l - about 100 g / l</td>

<td>AMP</td><td>about 10 ug / l - about 100 g / l</td>

<td>Ascorbic acid</td><td>about 1 ug / l - about 10 g / l</td>

<td>D-Biotin</td><td>about 1 ug / l - about 10 g / l</td>

<td>Vitamin D-12</td><td>about 1 ug / l - about 10 g / l</td>

<td>Cholesterol</td><td>about 1 ug / l - about 10 g / l</td>

<td>Dextrose (Glucose)</td><td>about 1 g / l - about 150 g / l</td>

<td>Multivitamin Adults</td><td>about 1 mg / l - about 20 mg / l or 1 unit vial</td>

<td>Folic acid</td><td>about 1 ug / l - about 10 g / l</td>

<td>Glutathione</td><td>about 1 ug / l - about 10 g / l</td>

<td>Guanine</td><td>about 1 ug / l - about 10 g / l</td>

<td>Inositol</td><td>about 1 g / l - about 100 g / l</td>

<td>Riboflavin</td><td>about 1 ug / l - about g / l</td>

<td>Ribose</td><td>about 1 ug / l - about 10 g / l</td>

<td>Thiamine</td><td>about 1 mg / l - about 10 g / l</td>

<td>Uracil</td><td>about 1 mg / l - about 10 g / l</td>

<td>Calcium chloride</td><td>about 1 g / l - about 100 g / l</td>

<td>NaHCOa</td><td>about 1 g / l - about 100 g / l</td>

<td>Magnesium sulphate</td><td>about 1 g / l - about 100 g / l</td>

<td>Potassium chloride</td><td>about 1 g / l - about 100 g / l</td>

<td>Glycerophosphate sodium</td><td>about 1 g / l - about 100 g / l</td>

<td>Sodium chloride</td><td>about 1 g / l - about 100 g / l</td>

<td>Sodium phosphate</td><td>about 1 g / l - about 100 g / l</td>

<td>Insulin</td><td>- approximately 1 IU - approximately 150 IU</td>

<td>Serum albumin</td><td>about 1 g / l - about 100 g / l</td>

<td>Pyruvate</td><td>about 1 g / l - about 100 g / l</td>

<td>Coenzyme A</td><td>about 1 ug / l - about 10 g / l</td>

<td>Serum</td><td>about 1 ml / l - about 100 ml / l</td>

<td>Heparin</td><td>about 500 U / l - about 1500 U / l</td>

<td>Solumedrol</td><td>about 200 mg / l - about 500 mg / l</td>

<td>Dexamethasone</td><td>about 1mg / l - about 1g / l</td>

<td>FAD</td><td>about 1 ug / l - about 10 g / l</td>

<td>NADP</td><td>about 1 ug / l - about 10 g / l</td>

<td>adenosine</td><td>about 1 mg / l - about 10 g / l</td>

<td>guanosine</td><td>about 1 mg / l - about 10 g / l</td>

<td>GTP</td><td>about 10 ug / l - about 100 g / l</td>

<td>GDP</td><td>about 10 ug / l - about 100 g / l</td>

<td>GMP</td><td>about 10 ug / l - about 100 g / l</td>

Table 4 presents components that are used in an exemplary preservative solution 118. The amounts provided in Table 4 describe preferred amounts over other components in the table and can be scaled to provide compositions of sufficient amount. In some examples, the amounts listed in Table 4 may vary by ± about 10% and can still be used in the solutions described herein.

<td colspan="2">Table 4: Exemplary Preservative Solution Component</td>

<td>Component</td><td>Quantity</td>

<td>Adenosine</td><td>Approximately 675 mg- Approximately 825 mg</td>

<td>Calcium chloride dihydrate</td><td>Approximately 2,100 mg - Approximately 2,600 mg</td>

<td>Wisteria</td><td>Approximately 315 mg - Approximately 3 85 mg</td>

<td>L-Alanine</td><td>Approximately 150 mg - Approximately 200 mg</td>

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<td>L-Arginine</td><td>Approximately 600 mg - Approximately 800 mg</td>

<td>L-aspartic acid</td><td>Approximately 220 mg- Approximately 270 mg</td>

<td>L-glutamic acid</td><td>Approximately 230 mg - Approximately 290 mg</td>

<td>L-Histidine</td><td>Approximately 200 mg - Approximately 250 mg</td>

<td>L-Isoleucine</td><td>About 100mg About 130mg</td>

<td>L-Leucine</td><td>Approximately 300 mg - Approximately 380 mg</td>

<td>J L-Methionine</td><td>Approximately 50 mg - Approximately 65 mg</td>

<td>L-Phenylalanine</td><td>Approximately 45 mg - Approximately 60 mg</td>

<td>L-Proline</td><td>About 110 mg - About 140 mg</td>

<td>L-Serine</td><td>Approximately 80 mg - Approximately 105 mg</td>

<td>L-Threonine</td><td>Approximately 60 mg - Approximately 80 mg</td>

<td>L-Tryptophan</td><td>Approximately 30 mg - Approximately 40 mg</td>

<td>L-Tyrosine</td><td>Approximately 80 mg - Approximately 110 mg</td>

<td>L-Valine</td><td>Approximately 150 mg - Approximately 190 mg</td>

<td>Lysine acetate</td><td>Approximately 200 mg - Approximately 250 mg</td>

<td>Magnesium sulphate heptahydrate</td><td>Approximately 350 mg - Approximately 450 mg</td>

<td>Potassium chloride</td><td>About 15mg - About 25mg</td>

<td>Sodium chloride</td><td>Approximately 1500 mg - Approximately 2000 mg</td>

<td>Dextrose</td><td>Approximately 25 gm - Approximately 120 gm</td>

<td>Insulin</td><td>Approximately 75 Units - Approximately 150 Units</td>

<td>MVI-Adults</td><td>1 unit vial</td>

<td>SoluMedrol</td><td>about 200mg - 500mg</td>

<td>Sodium bicarbonate</td><td>Approximately 10-25 mEq</td>

In the exemplary embodiment of solution 118, the components in Table 4 are combined in the relative amounts listed therein per approximately 1 L of aqueous fluid to form solution 118. In some examples, the components in Table 4 are combined in the relative amounts listed there for about 500 ml of aqueous fluid and then combined with solution 116, also about 500 ml to provide a 116/118 maintenance solution of about 1 l of aqueous fluid. In some embodiments the amount of aqueous fluid in solutions 116, 118 and / or 116/118 can vary ± about 10%. The pH of solution 118 can be adjusted between about 7.0 and about 8.0, for example about 7.3 and about 7.6. Solution 118 can be sterilized, for example by autoclaving, to provide improved purity.

Table 5 presents another exemplary preservative solution 118, comprising a tissue culture medium having the components identified in Table 5 and combined with an aqueous fluid, which can be used in perfusion fluid 108 as described in present document. The amounts of the components listed in Table 5 are relative to each other and to the amount of aqueous solution used. In some aspects, about 500 ml of aqueous fluid is used. In other examples, about 1 L of aqueous fluid is used. For example, combining approximately 500 ml of preservative solution 118 with 500 ml of nutritional solution 116 produces a maintenance solution 116/118 of approximately 1 L. In some implementations, the amount of aqueous solution can vary ± approximately 10%. The amounts of components and the amount of aqueous solution can be scaled as appropriate for use. The pH of preservative solution 118 in this example can be adjusted between about 7.0 and about 8.0, for example about 7.3 and about 7.6.

<td colspan="3">Table 5: Composition of another exemplary preservative solution (approximately 500 ml aqueous solution)</td>

<td>Tissue culture component</td><td>Quantity</td><td>Specification</td>

<td>Adenosine</td><td>750 mg</td><td>± about 10%</td>

<td>Calcium chloride dihydrate</td><td>2400 mg</td><td>± about 10%</td>

<td>Wisteria</td><td>350 mg</td><td>± about 10%</td>

<td>L-Alanine</td><td>174 mg</td><td>± about 10%</td>

<td>L-Arginine</td><td>700 mg</td><td>± about 10%</td>

<td>L-aspartic acid</td><td>245 mg</td><td>± about 10%</td>

<td>L-glutamic acid</td><td>258 mg</td><td>± about 10%</td>

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<td>L-Histidine</td><td>225 mg</td><td>± about 10%</td>

<td>L-Isoleucine</td><td>115.5 mg</td><td>± about 10%</td>

<td>L-Leucine</td><td>343 mg</td><td>± about 10%</td>

<td>L-Methionine</td><td>59 mg</td><td>± about 10%</td>

<td>L-Phenylalanine</td><td>52 mg</td><td>± about 10%</td>

<td>L-Proline</td><td>126 mg</td><td>± about 10%</td>

<td>L-Serine</td><td>93 mg</td><td>± about 10%</td>

<td>L-Threonine</td><td>70 mg</td><td>± about 10%</td>

<td>L-Tryptophan</td><td>35 mg</td><td>± about 10%</td>

<td>L-Tyrosine</td><td>92 mg</td><td>± about 10%</td>

<td>L-Valine</td><td>171.5 mg</td><td>± about 10%</td>

<td>Lysine acetate</td><td>225 mg</td><td>± about 10%</td>

<td>Magnesium sulfate heptahydrate</td><td>400 mg</td><td>± about 10%</td>

<td>Potassium chloride</td><td>20 mg</td><td>± about 10%</td>

<td>Sodium chloride</td><td>1750 mg</td><td>± about 10%</td>

Since amino acids are the building blocks of proteins, the unique characteristics of each amino acid impart certain important properties to a protein such as the ability to provide structure and catalyze biochemical reactions. The selection and concentrations of the amino acids provided in the preservative solutions provide support for normal physiological functions such as the metabolism of sugars to provide energy, regulation of protein metabolism, mineral transport, nucleic acid synthesis (DNA and RNA), regulation of glycemia and support of electrical activity, in addition to providing protein structure. Additionally, the concentrations of the specific amino acids found in preservative solutions can be used to predictably stabilize the pH of maintenance solution 116/118 and perfusion fluid 108.

In one aspect, a maintenance solution 116/118 is prepared from the combination of preservative solution 118, which includes one or more amino acids, and nutritional solution 116, which includes one or more carbohydrates, such as glucose or dextrose. Maintenance solution 116/118 may also have additives, such as those described herein, administered at the point of use just prior to infusion into the organ's perfusion system. For example, additional additives that may be included with the solution or added at the point of use by the user include hormones and steroids, such as dexamethasone and insulin, prostacyclin, and other members of the prostaglandin family, beta-1-agonists (e.g. eg albuterol, isopreternaol), vitamins, such as an adult multivitamin, for example adult multivitamins for infusion, such as MVI-adults. Additional small molecules and large biomolecules may also be included with the solution or added at the point of use by the user in port 762, for example, therapeutic substances and / or components normally associated with blood or blood plasma, such as albumin.

The solutions may include therapeutic components to help maintain the lungs 1004 and protect them against ischemia, reperfusion injury, and other damaging effects during infusion, to help mitigate edema, or provide general endothelial tissue support for the lungs 1004. In certain exemplary embodiments, these components may include hormones (eg, insulin), vitamins (eg, an adult multivitamin, such as MVI-adult multivitamins), and / or steroids (eg, dexamethasone and SoluMedrol). In some embodiments, therapeutics that are included in organ maintenance compositions and solutions to help mitigate edema, provide endothelial support, and otherwise provide preventive or prophylactic treatment to the lungs 1004. In certain embodiments, the systems described herein include hormones, such as thyroid hormones, for example thyroid hormones T3 and / or T4 added to nutritional solution 116, preservative solution 118 and / or maintenance solutions 116/118 and to either before or during the perfusion of the organ. Additional exemplary therapeutic agents include isuprel, Flolan, prostacyclin or other prostaglandin, beta-1-agonists, beta-2-antagonists, bronchodilators, isoproterenol, pentoxifylline, and nitric oxide donors (eg, L-arginine, nitroglycerin, nitroprusside) . The above therapeutic substances can also be added directly to the system, for example, to perfusion fluid 108, before or during perfusion of the organ. In certain embodiments, colloids are added, such as dextran, albumin, hydroxyethyl starches, or gelatins. Other components that can be added include antimicrobial agents, antifungal agents, antiviral agents, vasodilators, surfactants adapted to resist the withdrawal of alveoli within the lung, and anti-inflammatory drugs.

In particular, the addition of dextran offers numerous benefits, including improving the deformability of the

ES 2 625 850 T3 erythrocytes, prevention of erythrocyte aggregation, induction of dissolution of already aggregated cells, improvement of pulmonary circulation and preservation of the endothelial-epithelial membrane. Dextran also has anti-thrombotic effects by being able to coat endothelial surfaces and platelets. The addition of prostaglandins in various solutions induces effects such as vasodilation of the pulmonary vascular bed, inhibition of platelet aggregation, bronchodilation, reducing endothelial permeability and reduction of neutrophil adhesion. In addition, nitric oxide is used to treat ischemia-reperfusion injury of the lungs 1004, as it can improve ventilation-perfusion incoordination and lower pulmonary arterial pressure. Isoproterenol, as a therapeutic agent, acts as a non-selective beta-adrenergic agonist. It is adapted to relax almost all varieties of smooth muscles, thus preventing or alleviating bronchoconstriction and the production of pulmonary vasodilation. On the other hand, therapeutic agents such as surfactants prevent the folding of the alveoli in the lungs 1004 during the respiration cycle, as well as protect the lungs 1004 from injury and infection caused by foreign organisms and pathogens. Pentoxifylline, as a therapeutic agent, alleviates ischemia-reperfusion injury, for example, by inhibiting leukocyte sequestration in the lungs 1004, thus preventing the release of free radicals and cytokine.

The one or more therapeutic substances or other additives can be delivered to the lung through the tracheal interface 1024 via a nebulizer, or added to the infusion fluid 108 through the maintenance solution, or added by injection directly into the fluid reservoir. infusion at the point of use. In certain embodiments, therapeutic agents such as nitric oxide are indirectly delivered to the explanted lungs 1004 through the administration of an upstream precursor molecule, such as Larginine or through the infusion of a nitric oxide donor, such as nitroglycerin. or nitroprusside. In certain embodiments, therapeutic agents such as bronchodilators are delivered to the lungs 1004 in an injectable form in the perfusion fluid 108 or through the tracheal interface 1024 in a nebulized form. In certain embodiments, exogenous surfactants are delivered to lungs 1004 through tracheal interface 1024 or delivered to different sections of lungs 1004 using bronchoscopy. In certain embodiments, pentoxifylline is added to infusion fluid 108 in an injectable form.

With further reference to Table 4, certain components used in exemplary preservative solution 118 are molecules, such as small organic molecules, or large biomolecules, that would be inactivated, for example, through decomposition or denaturation, if passed through sterilization. According to system 100, the inactivatable components of solution 118 can be prepared separately from the remaining components of solution 118. Separate preparation involves separately purifying each component through known techniques. The remaining components of solution 118 are sterilized, for example through an autoclave, then combined with the biological components.

Table 6 lists certain biological components that can be separately purified and added to the solutions described herein after sterilization, according to this two-step process. These additional or supplemental components can be added to solutions 118, 116, 116/118, the priming solution or a combination thereof individually, in various combinations, all at once as a composition, or as a combined solution. For example, in certain examples, epinephrine, insulin, and IVM-Adults, listed in Table 6, are added to Maintenance Solution 116/118. In another example, the SoluMedrol and sodium bicarbonate, listed in Table 6, are added to the priming solution. The additional components can also be combined in one or more combinations or all together and placed in solution before adding them to solutions 116, 118, 116/118, and / or the priming solution. In some embodiments, additional components are added directly to perfusion fluid 108 through port 762. The component amounts listed in Table 6 are relative to each other and / or to the component amounts listed in one or more of Tables 1-5 as well as the amount of aqueous solution used in preparing solutions 116, 118, 116/118, and / or the priming solution and can be scaled as appropriate for the amount of solution required.

<td colspan="4">Table 6: Exemplary Biological Components Added Before Use</td>

<td>Component</td><td>Quantity</td><td>Kind</td><td>Specification</td>

<td>Insulin</td><td>about 100 Units</td><td>Hormone</td><td>± about 10%</td>

<td>MVI-Adults</td><td>1 ml unit vial</td><td>Vitamin</td><td>± about 10%</td>

<td>SoluMedrol</td><td>Approximately 250 mg</td><td>Steroid</td><td>± about 10%</td>

<td>Bicarbonate of</td><td>Approximately 20 mEq</td><td>Tampon</td><td>± approximately one</td>

ES 2 625 850 T3 sodium 10%

In one aspect, a 116/118 maintenance solution use composition is provided to comprise one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids that do not include asparagine, glutamine, or cysteine. The composition can also include other substances, such as those used in solutions described herein.

In another aspect, there is provided a system for perfusing an organ, such as a heart, comprising an organ and a substantially cell-free composition, comprising one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids that they do not include asparagine, glutamine, or cysteine. Substantially cell-free systems include systems that are substantially free of cellular material; in particular, systems that are not derived from cells. For example, "substantially cell-free" includes compositions and solutions prepared from non-cellular sources.

In another aspect, solutions 116 and 118 may be provided in the form of a kit that includes one or more organ maintenance solutions. An exemplary maintenance solution may include components identified above in one or more fluid solutions for use in an organ perfusion fluid 108. In certain aspects, the maintenance solution 116/118 can include multiple solutions, such as a maintenance solution 118 and a nutritional solution 116 and / or a composition or supplement solution, or it can include dry components that can be regenerated in a fluid. to form one or more solutions 116/118. The kit may also comprise components of solutions 116 and / or 118 in one or more concentrated solutions which, in dilution, provide a preservative, nutritional and / or supplemental solution as described herein. The kit can also include a priming solution. In an exemplary example, the maintenance solution includes a preservation solution 118 and a nutritional solution 116 such as those described above, and a priming solution such as that described above.

In certain implementations, the kit is provided in an individual package, where the kit includes one or more solutions (or components necessary to formulate the one or more solutions by mixing with an appropriate fluid), and instructions for sterilization, flow control, and temperature during perfusion and use and other information necessary or appropriate to apply the kit to perfusion of the organ. In certain implementations, a kit is provided with only a single solution 116, 118 and / or 116/118 (or a set of dry components for use in a solution by mixing with an appropriate fluid), and the single solution 116, 118 and / or 116/118 (or a set of dry components) is provided along with a set of instructions and other information or materials necessary or useful to handle solution 116, 118 and / or 116/118 in system 100.

In another aspect the systems, solutions and procedures can be used to deliver therapeutic substances to an organ during perfusion. For example, one or more of the solutions and / or systems described above may include one or more drugs, biological agents, gene therapy vectors, or other therapeutic substances that are delivered to the organ during perfusion. Exemplary therapeutic substances can include drugs, biological agents, or both. Suitable drugs may include, for example, antifungals, antimicrobials or antibiotics, anti-inflammatory, antiproliferative, antiviral, steroids, retinoids, NSAIDs, vitamin D3 and vitamin D3 analogues, calcium channel blockers, complement neutralizers, ACE inhibitors, immunosuppressants and other drugs. Suitable biological agents can include proteins; suitable biological agents can also include vectors loaded with one or more genes for the application of gene therapy.

For example, suitable steroids include but are not limited to androgen and estrogenic steroid hormones, androgen receptor antagonists and 5-α-reductase inhibitors, and corticosteroids. Specific examples include but are not limited to alclomethasone, clobetasol, fluosinolone, fluocortolone, diflucortolone, fluticasone, halsinonide, mometasone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone and dexamethasone esters and acetaminophen and various esters of the same.

Suitable retinoids include but are not limited to retinol, retinal, isotretinoin, acitethrin, adapalene, tasarotene, and bexarotene.

Suitable NSAIDs include but are not limited to naproxen, suprofen, ketoprofen, ibuprofen, flubirprofen, diclofenac, indomethasin, celecoxib, and rofecoxib.

Suitable vitamin D3 analogs include but are not limited to adoxercalciferol, seocalcitol, calcipotriene, tacalcitol, calcitriol, ergocalciferol, and calcifediol.

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Suitable antiviral agents include but are not limited to trifluridine, cidofovir, acyclovir, pensiclovir, famciclovir, valciclovir, ganciclovir, and docosanol.

Suitable human carbonic anhydrase inhibitors include but are not limited to metazoliamide, acetazolamide, and dorzolamide.

Suitable antiproliferative agents include but are not limited to 5-FU, taxol, daunorubicin, and mitomycin.

Suitable antibiotic (antimicrobial) agents include, but are not limited to, bacitracin, chlorhexidine, chlorhexidine digluconate, ciprofloxacin, clindamycin, erythromycin, gentamicin, lomefloxacin, metronidazole, minocycline, monifloxacin, mupiroxidine, binoxafycin, tetracycline, rifamycin, polycycline, rifamycin, biphycin Tobramycin, Triclosan, and Vancomycin. The antiviral and antibacterial prodrugs described herein can be used to appropriately treat sensitive systemic infections.

In certain aspects, a solution system for use in a perfusion fluid 108, comprising a first chamber that contains a first solution, such as a preservation solution 118, that includes one or more heart stimulates and a plurality of amino acids that do not include asparagine, glutamine, or cysteine, and a second chamber, which contains a second solution, such as a nutritional solution 116, which includes one or more carbohydrates, such as dextrose. The system can also include a sterilization system to sterilize the first solution and the second solution before using the solutions to infuse a heart. In some examples, one or more of solutions 118 and 116 include one or more therapeutic substances. In some examples, the solution system includes a third chamber comprising a priming solution, as described above, which may have one or more carbohydrates. In certain examples, the first solution 118 includes adenosine, insulin, one or more immunosuppressants, a multivitamin, and / or one or more electrolytes.

It should be understood that, although the invention has been described in conjunction with the various illustrative embodiments, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. For example, various systems and / or procedures can be implemented based on the disclosure. Other aspects, advantages and modifications are within the scope of the following claims.