Systems and methods for ex-vivo organ care

<u style="single">Reference of related application</u> The title of this application is a system and method for organ management. US Provisional Patent Application No. 60 / 616,835 filed October 7, 2004; US Provisional Patent Application 60 / 694,971 filed June 28, 2005; and US Provisional Patent Application filed October 6, 2005. It claims priority based on a patent application. The full text of each of the above specifications shall be incorporated herein by reference.

<u style="single">Field of invention</u> The present invention generally relates to systems, methods and devices for ex-vivo organ management. More specifically, in various embodiments, the present invention relates to ex-vivo management of organs in physiological or near-physiological conditions.

<u style="single">Background of the invention</u> Current organ preservation techniques typically involve cryopreserving organs in a chemical perfusion solution on ice. In the case of the heart, it is typically stationary and is in a cold, non-functional state cooled with a conserved / cardiac paralytic solution. These techniques utilize a variety of cardiac paralytic solutions, none of which adequately protect the heart from myocardial damage caused by ischemia. Such damage is not preferred if an organ such as the heart is intended to be transplanted from the donor to the recipient. In addition to myocardial damage caused by ischemia, reperfusion of the heart can exacerbate myocardial damage, cause damage to the coronary endothelium and smooth muscles, and cause coronary vasomotor dysfunction. It may be connected.

Using conventional approaches, such damage increases as a function of the length of time it takes to keep an organ ex-vivo. In the case of the heart, for example, it is typically left in ex-vivo for only an hour or two and becomes unusable for transplantation. Such a fairly short time limits the number of recipients that can be reached from a donor's location, resulting in a limited pool of recipients for the collected heart. .. Even within this one or two hour time limit, the heart can be severely damaged. The big problem is that there may be no apparent damage. This can lead to suboptimal organ transplantation, leading to post-transplant organ dysfunction or other damage. Thus, it would be preferable to develop a technique that can extend the time that organs can be stored ex-vivo in a healthy state. Such techniques would reduce the risk of transplant failure and increase the pool of potential donors and recipients.

Effective preservation of ex-vivo organs will also provide a number of other benefits. For example, if it can be stored ex-vivo for a long time, more careful observation and functional examination of the collected organs will be possible. This, in turn, will allow for earlier detection of defects in the collected organs and, if possible, repair, which will further reduce the chance of transplant failure. Furthermore, the ability to perform simple repairs on organs has made it possible to use a large number of organs with small defects that would have to be discarded with current transplantation techniques.

In addition, more effective matching between organs and specific recipients can be achieved, further reducing the likelihood of final organ damage. Current transplantation techniques rely primarily on matching the blood types of donors and recipients, which in and of itself is not a very reliable indicator of whether an organ will be rejected by the recipient. .. A more preferred test for organ compatibility is the human leukocyte antigen (HLA) compatibility test, but current cryoischemic organ preservation methods often require 12 hours or more to complete the use of this test. It's a hindrance.

Ex-vivo Organ management for a long time and with high reliability would be beneficial outside of organ transplantation. For example, a patient's entire body can typically tolerate much lower levels of chemical, biological, and radiation therapy than many specific organs. The ex-vivo organ management system will allow organs to be collected from the body and processed independently, reducing the risk of damage to other parts of the body.

In view of the above, there is a need for excellent systems, methods and devices for ex-vivo management of organs.

<u style="single">Outline of the invention</u> The present invention provides excellent systems, methods and devices for mobile ex-vivo organ management that address defects in prior art in a variety of embodiments. More specifically, in various aspects, the invention provides systems, methods and devices for mobile ex-vivo cardiac management. One advance is that the cardiac management system of the present invention keeps the heart in a pulsatile state under normal physiological conditions or conditions close to normal physiological conditions. To this end, the system delivers oxygenated, nutritious perfusate at or at physiological temperature, pressure and flow rate, or at a temperature, pressure or flow rate close to physiological temperature, pressure or flow rate. Circulate to. In certain embodiments, the system utilizes a blood product-based perfusate to more accurately mimic normal physiological conditions. In an alternative embodiment, the invention uses a synthetic blood substitute solution, but in other embodiments, the solution may contain a blood product in combination with a blood substitute.

As another advance, the system of the present invention refers to the collected heart as normal aortic flow mode (also referred to as "normal flow mode") and retrograde aortic flow mode (also referred to as "retrograde flow mode"). It can be maintained in two operating modes. In general, in normal flow mode, the system circulates perfusate to the heart in the same manner that blood circulates in the human body. More specifically, this perfusate enters the heart through the left atrium and flows out of the heart through the right and left ventricles. In normal flow mode, the system pumps perfusate into the heart at a rate between about 1 liter / minute and about 5 liters / minute. This mode is useful, for example, for performing functional tests to confirm that the heart is free of defects, both before and after transplantation to the donor location. Conversely, in retrograde mode, the system pumps perfusate into the heart through the aorta, through the coronary sinus, and then exhales from this heart through the right ventricle. In this mode of operation, the system slows the flow rate of the perfusate between about 300 ml / min and about 1 liter / min. We have found that retrograde channels, combined with reduced flow velocity, reduce damage to the heart during prolonged ex-vivo management. Therefore, one of the features of the present invention is that the heart is transported to the donor's location in retrograde mode.

In various aspects, the systems and / or devices of the invention include one or more of the following, and / or the methods of the invention utilize one or more of the following: ex-vivo management. Organ chamber assembly for containing the heart in; a reservoir for containing a volume of perfusate and selectively defoaming and / or filtering; pumping perfusate into the collected heart / Perfusate pump for circulation; heater assembly for maintaining perfusate temperature at or near physiological temperature; fluid flow mode selection valve for switching between normal and retrograde modes; perfusate An oxygen adder for reoxygenating it after it has been exhaled from the heart; as well as replenishing nutrients to the perfusion fluid as it is metabolized by the heart, as well as cardiac ischemia and / or other reperfusion-related injuries, etc. Nutrient subsystems for providing preservatives to the perfusate to reduce; observe the perfusate temperature, pressure, flow velocity, and / or oxygenation, and / or observe electrical signals from the heart, Alternatively, a sensor subsystem for observing electrical signals from various components used to maintain suitable fluid flow conditions towards and from the heart; observing system operation and / or heart condition. An operator interface that assists the operator and / or allows the operator to set various operating parameters; a power subsystem that provides fault tolerance to the organ management system; and the organ management system. A control subsystem for controlling the operation of the heart.

On the working side, in one embodiment, the heart is taken from the donor and secured to the organ chamber assembly by a cannulation process. The perfusate pump draws perfusate out of the reservoir and pumps it into the heater assembly. The heater assembly heats the perfusate to or near normal physiological temperature. In one embodiment, the heater assembly heats the perfusate from about 32 ° C to about 37 ° C. The perfusate flows from the heater assembly to the flow mode selection valve. Initially, this fluid flow mode selection valve is located in retrograde mode, directing perfusate from the heater assembly to the first interface on the organ chamber assembly. The first interface, also referred to herein as the aortic interface or the left ventricular interface, is cannulated into the vascular tissue of the left ventricle (eg, aortic stub) through a conduit located within the organ chamber assembly. The heart thus expels the perfusate from the heart through the second interface on the organ chamber assembly from the right ventricle. The second interface, also referred to herein as the pulmonary artery interface or the right ventricular interface, is cannulated into the vascular tissue of the right ventricle (eg, the pulmonary artery stub) through a conduit located within the organ chamber assembly. In retrograde mode, the perfusate is neither delivered to the left side of the heart nor exhaled, except in the form of a small stream of perfusate delivered to moisten the left atrium. It directs perfusate to the left atrium of the heart through the third interface of the organ chamber assembly in response to a fluid flow mode selection valve in the normal flow mode position. This third interface, also referred to as the pulmonary vein interface or the left atrial interface, is cannulated into the vascular tissue of the left atrium (eg, the pulmonary vein stub) through a conduit located within the organ chamber assembly. The heart thus exhales perfusate through the left ventricle through the aortic interface and through the right ventricle through the pulmonary interface.

In both modes of operation, perfusate flows from the pulmonary artery interface into the oxygen adductor. The oxygen adder receives oxygen from an external or on-board gas source and adds a gas (eg, oxygen) to it before the perfusate returns to the reservoir. The system may include one or more oxygen saturation sensors to measure the oxygen saturation level of the perfusate to ensure that the perfusate is maintained at physiological oxygen levels. In embodiments where the perfusate is a blood-based product, it contains red blood cells (ie, oxygen-carrying cells). Optionally, the oxygen saturation sensor may be one that makes a hematocrit measurement of the red blood cell concentration in the perfusate.

In both normal and retrograde modes, the nutrient subsystem provides the perfusate with a feed maintenance solution when the perfusate flows through the system and, in some embodiments, in the reservoir. Inhale. In one feature, the maintenance solution contains nutrients such as glucose. Another feature is that the maintenance solution is a supply of therapeutic and / or preservatives (eg, cardiac stimulants, insulin, amino acids, etc.) to reduce ischemia and / or other reperfusion damage to the heart. )including.

In another embodiment, the perfusate comprises blood collected from a donor through a phlebotomy process during the collection of the heart. Initially, this blood from the donor is stored in the reservoir, bypassing the cannula position in the organ chamber assembly through a bypass conduit, allowing a normal flow mode of perfusate through the system, not through the heart. There is. Prior to cannulating the collected heart, the system may be primed by circulating phlebotomized donor blood through the system and heating, oxygenating and / or filtering it. Nutrients, preservatives, and / or other therapeutic agents may also be provided through the inhalation pump of the nutrient subsystem during priming. Various parameters may be initialized through the operator interface during priming and calibrated during priming. After priming and working properly, reduce the flow of the pump or remove it from the cycle, remove the bypass duct from the organ chamber assembly and cannulate it from the heart into this organ chamber assembly. Then, as the case may be, the flow of the pump is restored or increased. As a feature, the operator interface may be connected to the system by wire, or may be disconnected and used for wireless communication with the system of the present invention.

In one feature, the system includes multiple extensibility chambers. This extensibility chamber is basically a small in-series fluid accumulator with flexible and elastic walls, such as providing fluid back pressure and / or hydraulic pressure due to changes in flow velocity or the like. It mimics the vascular extensibility of the human body by helping the system more accurately mimic blood flow in the human body, such as by filtering / reducing spikes. In some configurations, the extensibility chamber is located on either side of the fluid flow mode selection valve and on the output side of the perfusate pump. In one feature, the extensible champer is located next to a clamp used to regulate back pressure on the aorta when operating in normal flow mode.

In certain embodiments, the sensor subsystem includes an electrocardiogram (ECG) sensor that observes electrical signals from the heart. In some embodiments, the control subsystem synchronizes the pumping of the perfusate with the ECD signal. In one feature, the ECG signal contains an r-wave, which the control subsystem uses to synchronize perfusate pumping with diastole of the heart. Another feature is that the control subsystem regulates pump stroke volume and / or pump speed depending on the ECG signal. For example, in one embodiment, the control subsystem reduces the amount of pump stroke as the speed of the heart increases in order to maintain blood flow. In another embodiment, the system reduces the amount of pump stroke in response to the detection of irregular heart velocity. In either case, the result is to reduce the amount of perfusate delivered to the heart, which in turn reduces the potential for damage to the heart. In various embodiments, the sensor includes a perfusate flow velocity and / or flow pressure sensor, which provides feedback for controlling a perfusate pump. In some embodiments, the pump of the system is a pulsatile pump in order to more accurately stimulate normal circulation through the body.

In some aspects of the invention, the organ chamber assembly comprises several improved features. More specifically, in some configurations, the organ chamber assembly of the present invention includes a housing, an outer lid and an intermediate lid. The housing includes a bottom surface and one or more walls to accommodate the organs. The intermediate lid covers the opening of the housing to substantially enclose the organs in the housing and includes a frame and a flexible membrane suspended within the frame. The flexible membrane is preferably transparent, but may be opaque, translucent, or substantially transparent. In one feature, the flexible membrane contains sufficient extra membrane material to contact the organs contained within the chamber. This feature allows medical operators to indirectly touch / examine organs through this membrane while maintaining the sterility of the system and organs. The outer lid opens and closes above the middle lid, separate from the middle lid. Preferably, the outer lid is rigid enough to protect the organ from indirect or direct contact.

In some embodiments, the intermediate lid is hinged to the enclosure. The intermediate lid may also include a latch to secure the intermediate lid closed above the opening of the organ chamber. The outer lid may be hinged and latched as well. In some configurations, to form a fluid seal between the intermediate lid frame and one or more organ chamber walls, and / or around the outer lid and with the intermediate lid frame. A gasket is provided to form a fluid seal between them.

Optionally, the organ chamber assembly includes a pad or sack assembly sized and shaped to fit the bottom of the housing. Preferably, the pad assembly comprises a pad made of a material that is elastic enough to buffer the organ from mechanical vibrations and shocks in transit. When the organ chamber assembly is configured to accommodate the heart, one feature is that the pads of the invention include a mechanism for receiving at least one electrode. The mechanism may include, but is not limited to, one or more slots, recesses, protrusions, through holes, partially penetrated holes, hooks, fasteners, snaps, adhesive patches, and the like. One advantage is that the mechanism allows the at least one of the electrodes to be adjustablely arranged on or within the pad to accommodate hearts of various sizes and shapes. In certain embodiments, the pad comprises a through hole through which the electrical leads of at least one of the electrodes can pass.

In certain embodiments, the pad assembly comprises at least one electrode that is adjustablely placed on or within the pad in a manner that facilitates contact with the heart placed on the pad, such as an organ chamber assembly. Including. In some configurations, at least one of the electrodes rests on the surface of the pad and is anchored in place by the weight of the heart. In another configuration, the at least one electrode is glued to the surface of the pad. The at least one electrode said includes one or more sensors for observing one or more electrical signals from the heart. Further, it may include one or more cardioversion devices to provide an electrical signal to the heart. One of the advantages of the pad / electrode configuration of the present invention is that it is not necessary to permanently or temporarily sew or mechanically connect at least one of the electrodes to the heart. Conversely, electrical connectivity is achieved by placing the heart on one or more of the electrodes described above. In some configurations, at least one of the electrodes is an integral sensor that allows the user to observe electrical signals from the heart and provide electrical signals to the heart through a common electrical interface connection to the organ chamber assembly. Includes electrodefibrillation contacts. As another feature, the common electrical interface described above organs one or more electrical ports for transporting electrical signals between at least one electrode in the chamber and a device located outside the enclosure. Included on the chamber assembly. As an example, this port may provide ECG signals to an external processor and / or display and / or provide power for an electrodefibrillator to the electrodes.

Optionally, the chamber housing further includes a base for angling the housing for optimal cardiac function. In one feature, the pedestal maintains the heart housed in the organ chamber at an angle of about 30 ° C to about 60 ° C with respect to the horizon.

In another aspect, the perfusate heater assembly of the present invention includes several excellent features relating to a small solid state mechanism for heating the perfusate. Some features of the heater assembly make it particularly suitable for heating the perfusate of the blood-based embodiment. In certain embodiments, the heater assembly of the present invention includes a suction port, a discharge port, a flow path, first and second flow path plates, and a first heater. The flow path is formed between the first and second flow path plates. The suction port allows the perfusate to flow into the flow path, and the discharge port discharges the perfusate from the heater. The first and second channel plates have a substantially bioactive perfusate contact surface to provide direct contact with the perfusate flowing through the channel. The perfusate contact surface can be formed, for example, by treating the substrate or forming a film on the substrate, or may be the substrate surface itself. The first heater is thermally connected to the first flow path plate to heat the first flow path plate. In some configurations, the first heater is located on the non-perfusate contact side of the first flow path plate. In a further embodiment, the heater assembly of the present invention also includes a second heater thermally connected to the second flow path plate in order to heat the second flow path plate and provide a more uniform temperature distribution in the flow path. Further included.

In some configurations, the heater assembly has a first heater plate placed between the first heater and the first channel plate to thermally connect the heat from the first heater to the first channel plate. Including. In one feature, the first heater plate is formed from a material that conducts and disperses heat from the heater relatively uniformly, such as aluminum. The heat of the heater plate thus uniformly dispersed is connected to the first flow path plate, which is preferably sufficient when placed in direct contact with the heater, such as titanium. It may be formed from a bioinert material that does not necessarily provide uniform heat dispersion. The heater assembly also includes a second heater plate located between the second heater and the second flow plate to connect the heat from the second heater to the second flow plate. Good.

In certain embodiments, the first and / or second heaters of the present invention are resistance heaters. In some configurations, each of these includes a resistant heating element formed on a polyimide substrate. In a further configuration, the resistance heating element has a resistance of about 5 ohms. In other configurations, the resistance of the heating element is in the range of about 3 ohms to about 10 ohms.

Optionally, the heater assembly of the present invention includes one or more temperature sensors. For example, the heater assembly may include a temperature sensor at its outlet to report the temperature of the perfusate exiting the heater to the control subsystem. The signal from this sensor may be used in a feedback loop to control the temperature of the heater plate by controlling the drive signals to the first and second heaters. In addition, first and / or second heating to the heater assembly and to the control subsystem to ensure that the perfusate contact surface of the heater plate does not exceed temperatures that could damage the perfusate. A temperature sensor that reports the temperature of the vessel may be included. In addition, signals from these sensors may be used in a feedback loop to further control the drive signals to the first and / or second heaters to limit the maximum temperature of the heater plate. In a variant of this embodiment, the heater assembly may include a temperature sensor that reports the temperature of the first and / or second heater to the control subsystem.

Provides excellent contact between the first and / or second heaters and their respective heater plates, and further between the first and / or second heater plates and their respective flow path plates. In order to do so, the heater assembly also has a first heater in contact with the first heater plate and a second heater in contact with the second heater plate in response to compressive forces. First and second elastic pads placed on each heater may be included to maintain. This compressive force may be provided, for example, to one or more heater assembly housing components. In one feature, the heater assembly comprises a housing component that is made of polycarbonate and weighs less than about 5 lbs, and in other embodiments, the heater assembly is less than about 4 lbs, less than about 3 lbs, It may weigh less than about 2 pounds, or even less than about 1 pound. Another feature is that the heater assemblies are all about 6.75 inches long, about 2.75 inches wide, and about 2.5 inches thick, except for the inlet and outlet and temperature sensor assemblies. Another feature is that the heater assembly is a disposable assembly.

In some embodiments, the heater assembly uses about 1 watt to about 200 watts of power during operation. In a further embodiment, the heater assembly of the present invention draws about 2.5 liters of perfusate through a channel at a rate of about 300 ml / min to about 5 L / min, from temperatures below about 30 ° C to about 37 ° C. In less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, or even less than about 10 minutes, it causes substantial hemolysis of blood cells or is contained in the perfusate. It is sized and shaped so that it can be transferred without causing denaturation of any of the wax proteins.

In a further embodiment, the power subsystem of the present invention provides a fault tolerant battery configuration. More specifically, multiple batteries, all of which are mutually locked so that they cannot be removed from the system at any time while the system is operating to maintain an organ. In one feature, the power subsystem can switch between external power and on-board battery backup without interrupting system operation. As another feature, the power subsystem automatically distributes the externally provided power between the power supply of the system, the battery power supply, and the internal battery power supply of the operator interface wirelessly.

In another aspect, the present invention divides the various subsystems and components of a portable organ management system into two modules: a portable multiplex module and a single-use disposable module. In one segmentation, the system of the invention allocates parts that come into contact with the perfusate (thus contacting the blood product in embodiments with blood product perfusate) into a disposable module and does not contact the perfusate. Mostly allocate things (thus parts that do not come into contact with blood products) to the multi-use module. However, the disposable unit may also include parts that do not come into contact with blood. One feature is that the part in contact with the perfusate is coated with heparin or other anticoagulant or biocompatible material to reduce the inflammatory response that may occur when the perfusate comes into contact with the surface of the part. Alternatively, it may be adhered. Heparin may be added to the maintenance solution to circulate within the system.

In some embodiments, the portable multiplex module comprises a morphological enclosure built on a portable chassis, and the single-use disposable module comprises a disposable chassis. In some configurations, the chassis of the idle module is made of molded plastic such as polycarbonate to reduce weight, and the chassis of the multi-use module is made of molded material such as polycarbonate or carbon fiber composite. One feature is that the useless chassis weighs less than about 12 lbs when no parts are attached, and the useless module weighs less than about 18 lbs when attached. Another feature is that the multi-use enclosure and chassis, when no parts are mounted, weigh less than about 50 lbs and combine the multi-use module, batteries, gas, maintenance solution, perfusate and heart together. It costs less than about 85 pounds. As another advantage, the systems of the invention, including both single-use and multi-use modules, weigh less than about 65 lbs without any perfusate, nutrients, preservatives or other fluids, batteries and oxygen supplies. That's right.

The single-use disposable chassis is of a size and shape that interlocks with the portable chassis of the multi-use module and the interaction of the multi-use module with electrical, mechanical, gas and fluid. One feature is that the multi-use and reusing modules communicate with each other through an optical interface, which automatically opticals when the reusing disposable module is installed inside the portable multi-use module. Aligned with. Another feature is that the portable multi-use module provides power to the single-use module via a spring-loaded connection, which also has the single-use module installed inside the portable multiple-use module. Connects automatically when you do. One feature is that the optical interface and spring-loaded connections ensure that the connection between the unreserved and multi-modules is not lost due to collisions, such as during transportation on bumpy roads.

In various embodiments, the organ chamber assembly and the pump interface assembly are both mounted on a disposable chassis. The pump interface assembly is aligned to receive pumping force from the pump drive of the perfusate pump, thus the interface assembly translates this pumping force towards the perfusate to bring the perfusate to the organ. Circulate to the chamber assembly. In some embodiments, the perfusate pump is a pulsatile pump, the pump interface assembly comprising a housing, a first deformable membrane, a fluid inlet, and a fluid outlet. The housing of the pump interface assembly includes inner and outer sides. The first deformable membrane is mounted in a fluid-tightly interconnected state with the inner side surface of the housing so that the chamber is between the inner side surface of the first deformable membrane and the inner side surface of the housing. To form. The fluid inlet is first deformable by receiving the perfusate from a reservoir or the like in response to a pump drive moving away from the inner side of the housing and providing this fluid into the chamber. Deform the membrane in the same direction. The discharge port discharges the perfusate from the chamber and sends it to a heater assembly or the like in response to a pump drive moving in a direction toward the inner side surface of the housing.

In some configurations, the pump interface assembly fits around the first deformable membrane to form a fluid seal between the inner side of this deformable membrane and the circumference of the inner side of the housing. Includes brackets. In a further configuration, the pump interface assembly includes a gasket that provides a fluid seal between the pump drive of the perfusate and the pump interface housing.

In some embodiments, the system further includes a flow valve located on the suction side of the fluid into the inlet. The fluid flow valve opens in response to a pump drive that moves away from the inner side of the enclosure to allow perfusate to pass through the chamber through a bidirectional fluid inlet and the enclosure. Includes a ball valve assembly that closes in response to a pump drive moving in the direction of the medial side and is oriented to stop the perfusate passing into the chamber through the fluid inlet. In a further embodiment, the fluid discharge port also closes in response to a pump drive moving away from the inner surface of the housing and in response to a pump drive moving toward the inner side surface of the housing. Includes a ball valve assembly that opens and discharges the perfusate of the organ through the fluid outlet.

Optionally, the perfusate pump is fixedly mounted on a portable multi-use chassis, the pump interface assembly is fixedly mounted on a disposable chassis, and the system is a perfusion pump drive and pump. It comprises the feature of automatically forming a fluid seal between the interface assembly in response to the useless disposable module mating with the portable multi-use module. More specifically, the pump interface assembly is one of the portable multi-use modules to force / attract the inner side of the housing of the pump interface assembly towards the pump drive of the perfusion pump. The outer side surface of the interface assembly housing may include one or more protrusions of a size and shape that engage and abut the above surface.

In one feature, the pump interface assembly was mounted adjacent to the first deformable membrane to provide a fault-tolerant seal if the first deformable membrane was avoided. Includes a deformable membrane. As another feature, the pump interface assembly is at least partially formed from polycarbonate or other molded plastic material to reduce the weight of the disposable module.

In one embodiment, the perfusate reservoir is mounted on a disposable chassis that fluidly communicates with the organ chamber. In a further embodiment, the liquid flow mode selection valve is mounted on a disposable chassis. In another embodiment, the solid state perfusion heater of the present invention is mounted on a disposable chassis. The oxygen adder is preferably provided with a multi-use module, but in some embodiments it may be part of a disposable module instead. The oxygen supply source to the oxygen adder may be included in the portable multiplex chassis, part of the multiplex module, or external to the system.

In some configurations, the various sensors associated with the heater assembly, oxygen addition device and / or perfusate pump are included in the disposable module. However, this does not apply to the case of a sensor that does not come into contact with the perfusate. In one embodiment, the disposable module measures the optical properties of an in-line cuvette through which the perfusate passes, a light source that directs light to the perfusate through the cuvette, and the perfusate through the cuvette. An oxygen sensor including an optical sensor is used. Preferably, the in-line cuvette adheres seamlessly or substantially seamlessly to the perfusate flow conduit in order to reduce the perfusate vortex and provide one or more accurate measurements. .. This seamless or substantially seamless configuration also reduces damage to any blood-based component in the perfusate.

In a further configuration, the single-use disposable module is located, for example, at the outlet of the perfusate pump, and on either side between the organ chamber and the mode selection valve, the multiple in-line extensions described above. Includes sex chamber. In a further embodiment, the disposable module comprises a plurality of ports for sampling fluid from the organ chamber assembly, wherein the port is from the first of the plurality of ports. When there is fluid sampling, they are mutually locked so that fluids from the second port of the plurality are prohibited from being sampled at the same time. This safety feature reduces the chance of fluid samples mixing and accidentally opening ports. In some embodiments, the organ chamber assembly comprises a port for fluid communication of one or more of the pulmonary artery, aorta and left atrium interface.

In another aspect, the invention relates to a method of preserving the heart ex-vivo. The method comprises placing the heart in a protective chamber of a portable organ management system and pumping the perfusate into the heart, with the perfusate between about 25 ° C and about 37 ° C. Ex vivo the heart, which is the temperature, a volume between about 200 ml / min and about 5 L / min, and the step of observing one or more of its physiological features while the heart is beating in a protective chamber. It comprises adjusting the pumping characteristics based on at least the electrical characteristics for storage in vivo.

In another aspect, the invention relates to a method of storing the heart ex vivo, wherein the method comprises placing the heart on one or more electrodes in a protective chamber of a portable organ management system, and the perfusate. A step of pumping into the heart, wherein the perfusate has a temperature between about 25 ° C and about 37 ° C and a volume between about 200 ml / min and about 5 L / min. Includes the step of observing electrical signals from the electrodes while pumping the perfusate into the heart for ex vivo storage.

In a further aspect, the present invention relates to a method of transporting the heart ex vivo, the method comprising placing the transporting heart in a protective chamber of a portable organ management system and applying perfusate to the heart to the heart's aorta. A step of pumping through the heart and a step of providing a flow of perfusate away from the heart through the right ventricle of the heart, and while pumping the perfusate into the heart through the aorta and to the right of the heart. It involves transporting the heart into a portable organ management system from the donor's location to the recipient's location while providing a flow of perfusate through the ventricles away from the heart.

In a further aspect, the present invention relates to a method of assessing a transport heart, the method comprising placing the heart in a protective chamber of a portable organ management system and applying perfusate to the heart in the left ventricle of the heart. A step of pumping through the heart, a step of providing a flow of perfusate away from the heart through the right ventricle of the heart, and a step of pumping the heart from donor position to recipient position via a portable organ management system. The step of pumping perfusate into the heart through the left ventricle and the step of providing a flow of perfusate with respect to the right ventricle away from the heart; before transplanting the heart into the recipient. Manipulating the fluid flow control outside the protective chamber, the perfusate is pumped into the heart through the left atrium of the heart and out of the heart through the right and left ventricles of the heart. Includes steps to alter flow; steps to assess the heart. In some embodiments, the assessment comprises performing an HLA test on the heart during inhalation of perfusate.

In another aspect, the invention relates to a method of treating the heart. The method involves placing the heart in a protective chamber of a portable organ management system, pumping perfusate into the heart through the left ventricle of the heart, and from the heart via the right ventricle of the heart. Manipulating the steps that provide the flow of perfusate in the distant direction and the fluid flow control outside the protection chamber, the perfusate is pumped into the heart through the left atrium of this heart and from the heart to this heart. It includes changing the flow of perfusate to flow through the right and left ventricles; and performing therapeutic treatment on the heart. The treatment may include, for example, applying one or more of immunosuppressive treatment, chemotherapy, gene therapy and radiation therapy to the heart.

In another aspect, the invention relates to a method of implanting a heart. The method includes a step of stopping the donor's heart, a step of exoplanting the heart from this donor, a step of transferring the heart to an organ management system, and (to reduce the time of ectopic low temperature ischemia of the heart). The step of pumping the perfusate into the heart less than 30 after explanting the heart from the donor, wherein the perfusate is at a temperature between about 32 ° C and about 37 ° C. Including. In some embodiments, the heart is transferred to an organ management system and then brought to a temperature of less than 10 between about 35 ° C and about 37 ° C.

These and other features and advantages of the present invention will be further described below with reference to exemplary embodiments of the present invention.

<u style="single">Illustrative commentary</u> As mentioned above in the overview, the present invention generally provides an excellent approach for organ management ex-vivo. More specifically, in various embodiments, the present invention relates to superior systems, methods and devices relating to maintaining an organ in an ex-vivo portable environment. In one improvement, the organ preservation system of the present invention keeps the heart in a beating state under normal physiological conditions or conditions close to normal physiological conditions. For this purpose, the system circulates an oxygenated, nutrient-rich perfusate through the heart at temperatures, pressures and flow rates close to physiological temperatures, pressures and flow rates. In one example, the system uses a perfusate solution that more closely mimics normal physiological conditions. In some embodiments, the perfusate is blood product based. In an alternative embodiment, the solution is synthetic blood substitute based. In other embodiments, the solution may contain a blood product in combination with a blood substitute product.

In various exemplary embodiments, the improvements of the invention ex vivo the organs such as the heart for extended periods of time, eg 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, It can be maintained for 22, 24 or more hours. This long ex-vivo maintenance time can expand the pool of potential recipients for donor organs, reducing the importance of the geographical distance between donors and recipients. Further to be a long time to maintain time in the ex-vivo as in the present invention more, because the time required to adapt the gene and HLA between donor organs and organ recipients are provided, good It is more likely to produce results. Furthermore, the ability to maintain organs under conditions close to physiological functional conditions allows clinicians to evaluate organ function ex-vivo, further increasing the chances of successful transplantation. In some cases, the increased maintenance time allows the medical operator to perform repairs on small defective donor organs. Another advantage is that the ex-vivo organ maintenance time can be extended in the present invention, so that organs can be collected from a patient, treated in an ex-vivo isolated state, and then returned to the patient's body. Such procedures may include, but are not limited to, surgical procedures, chemical, biological, genetic and / or radiation therapy.

Exemplary systems, methods and devices of the present invention are described below in the following order. First, the parts of the organ management system 100 as an example will be explained. Second, we discuss the operation of System 100 as an example. Third, some of the components of System 100 will be described in more detail. Fourth, a control system example and a method example of the system 100 will be discussed. Fifth, an example of a user interface will be described. Sixth, the mechanical features of System 100 will be discussed in more detail with respect to the examples. Seventh, examples of methods using System 100 during organ collection, transport, and transplantation methods will be described. Eighth, examples of perfusion solutions, nutrient solutions and preservative solutions suitable for use in System 100 are introduced.

With reference to Examples, FIG. 1 shows a schematic diagram of a portable organ management system 100 according to an example of the present invention. FIG. 2 shows a conceptual diagram of the heart 102 that may be preserved / maintained ex-vivo by the organ management system 100 of the present invention. Referring to FIGS. 1 and 2, an exemplary system 100 includes an organ chamber assembly 104 that houses the heart 102 during ex-vivo maintenance, a reservoir 160 that holds, defoams, and filters perfusate 108, and perfusion. A portal 774 that fills the reservoir 160 with fluid 108, a portal 762 that adds a therapeutic agent to the perfusate 108 contained in the reservoir 160, and a pump inhalation / circulation of the perfusate 108 back and forth to the collected heart 102. With the perfusate pump 106; with the collected heart 102; with the heater assembly 110 that maintains the temperature of the perfusate 108 at or near the physiological temperature; normal and retrograde aortic flow modes (respectively). A fluid flow mode selection valve 112 that switches between "normal fluid flow mode" and "retrograde fluid flow mode"); oxygen that reoxygenates the perfusate 108 after it has been expelled from the heart 102. With the adder 114; the nutrient 116 in the perfusate 108 is replenished as it is metabolized by the heart 102, and the perfusate is provided with an additional preservative 118 for ischemia and / or other recurrence of the heart 102. Includes nutrient subsystem 115 to reduce perfusion-related damage and the like. The illustrated system 100 further includes, but is not limited to: temperature sensors 120, 122 and 124; pressure sensors 126, 128, 130 and 132; perfusion flow velocity sensors 134, 136 and 138; perfusion oxygen addition sensors 140; and sensor electrodes 142. Includes multiple sensors, including 144 and 144, as well as defibrillation source 143. System 100 is also a versatile component used to maintain suitable anterior-posterior fluid flow conditions for the heart 102;

Also with reference to FIGS. 3 and 4, in the illustrated embodiment, the system 100 can maintain the heart 102 in two modes of operation: the normal flow mode shown in FIG. 3 and the retrograde flow mode shown in FIG. In general, in the normal flow mode of FIG. 3, system 100 circulates perfusate 108 to the heart 102 in the same manner that blood circulates in the human body. More specifically, referring to Figure 1-3, perfusate enters the left atrium 152 of the heart 102 via the pulmonary vein 168. Perfusate 108 flows from the right ventricle 154 through the pulmonary artery 164 and from the left ventricle 156 through the aorta 158. In normal flow mode, System 100 pumps perfusate into the heart 102 at a rate close to the physiological rate of about 1 liter / min to about 5 liters / min. This mode is useful, for example, to perform functional tests to check for defects in the heart 102 both before and after transport to the donor location.

Conversely, in the retrograde flow mode shown in FIG. 4, system 100 flushes perfusate 108 to the heart 102 via the aorta 158, through the coronary sinus 155 and the other coronary vasculature of the heart, and the right ventricle of the heart 102. It flows out from 154 through the pulmonary artery 164. As further detailed below with respect to FIGS. 24A and 24B, System 100 provides a trickle 769 to the left atrium 152 via a trickle valve 768. This trickle is provided in sufficient quantity to moisten the left atrium 152 and left ventricle 156. In some applications, the granules are less than about 5 ml / min, less than about 1 ml / min, or less than about 0.1 ml / min. In this mode of operation, the system 100 reduces the flow rate of the perfusate 108 from about 300 ml / min to about 1 liter / min. The present inventor has found that the retrograde flow path of FIG. 4, combined with this decrease in flow velocity, reduces damage to the heart 102 during prolonged ex-vivo maintenance. Therefore, one of the features of the present invention is that the heart 102 is transported to the donor position in retrograde mode.

Now that the normal flow and retrograde flow modes have been briefly explained, the operation of this system 100 will be explained in more detail. With reference to Figure 1-4 again, in one embodiment, the heart 102 is harvested from the donor and cannulated into the organ chamber assembly 104. Perfusate 108 is prepared for use within System 100 by filling Reservoir 160 via Portal 774 and optionally treating with therapeutic agent via Portal 762. The pump 106 pumps the filled perfusate 108 from the reservoir 160 into the heater assembly 110. The heater assembly 110 heats the perfusate 108 to or near physiological temperature. In one embodiment, the heater assembly 110 heats the perfusate to about 32 ° C to about 37 ° C. The heater assembly 110 has an inner liquid flow channel with a cross-sectional flow area approximately equal to the inner cross-sectional area of the fluid conduit that carries the perfusate 108 back and forth with respect to the heater assembly 110 to suppress the fluid flow vortex. .. Perfusion fluid 108 flows from the heater assembly 110 to the fluid flow mode selection valve 112.

Initially, the fluid flow mode selection valve 112 is placed in retrograde mode to direct the perfusate 108 from the heater assembly 110 to the organ chamber assembly 104 via the first interface 162. This first interface 162, also referred to as the aortic interface or the left ventricular interface, is cannulated into the vascular tissue of the left ventricle through an opening 228b located on the organ chamber assembly 104 (as shown in Figure 5A-5B). including. When the heart 102 warms up, it begins to beat, which causes the heart 102 to expel perfusate 108 through the coronary vasculature 155, from the heart 102, through the right ventricle 154, and through the second interface 166. The second interface 166, also referred to as the pulmonary artery interface or the right ventricular interface, includes the insertion of a cannula into the vascular tissue of the right ventricle through the opening 228c located on the organ chamber assembly 104 (as shown in Figure 5A-5B). .. As mentioned above, in retrograde mode, fluid is not actively pumped or aspirated from the left side of the heart, with the exception of the relatively thin trickle 769 of the perfusate, described below with reference to Figure 24A-24E. As such, it is delivered to moisten the left atrium 152 and the left ventricle 156.

In response to the fluid flow mode selection valve 112 being placed in the normal flow mode position, perfusate 108 is directed to the left atrium 152 of the heart 102 via the third interface 170. This third interface 170, also referred to as the pulmonary vein interface or the left atrium interface, cannulas the left atrium 152 to vascular tissue through an opening 228a located on the organ chamber assembly 104 (as shown in Figure 5A-5B). Including insertion. The heart 102 thus discharges the perfusate 108 through the left ventricle 156 through the aortic interface 162 and through the right ventricle 154 through the pulmonary interface 166.

Each of these interfaces can also be cannulated into the heart 102 by pulling vascular tissue (eg, aortic stub) over the respective ends of interfaces 162, 166 and 170 and then tying or anchoring this tissue to that interface. Good. The vascular tissue is preferably a short portion of a blood vessel (eg, aortic stub 158) that remains connected to the heart 102 even after the heart 102 has been cut and explanted from the donor. For example, the aorta interface 162 is cannulated into a small portion of the amputated aorta 158 formed by cutting the aorta 158 downstream from the coronary sinus 155. In some applications, this short vessel portion may be about 5 to about 10 inches long, or even longer. This portion may be shorter than about 5 inches. This portion may be about 2 to about 4 inches long, or about 1 to about 2 inches long. For other uses, this portion may be less than about half an inch, or less than about a quarter.

Alternatively, it may be preferred in applications such as preparing the heart 102 for explantation by cutting the entire blood vessel without leaving any stub portion of the vessel connected to the heart 102, but an interface. Cannula insertion may be performed by directly anchoring the to the appropriate atria or ventricles. For example, an interface 170 can be inserted directly into the left atrium 152 and clamped in place to form a cannula insertion of the left atrium 152 without having to tie it to any pulmonary vein 168 tissue.

Continuing with reference to FIG. 1, in both fluid flow modes, perfusate 108 flows from the pulmonary artery interface 166 to the oxygen adder 114. The oxygen accumulator 114 receives gas from an external or on-board source 172 through the gas regulator 174 and the gas flow chamber 176, which is a pulse width regulating solenoid valve that controls the gas flow. Alternatively, it may be another gas control device that enables precise control of the gas flow rate. The gas pressure gauge 178 provides a visual indicator of how sufficient the gas supply 172 is. The converter 132 provides similar information to the controller 150. The controller 150 can automatically adjust the gas flow to the oxygen adder 114 according to, for example, the oxygen content of the perfusate measured by the sensor 140. In various exemplary embodiments, the oxygen adder 114 is a Liliput manufactured by Dideco, a division of Sorin Biomedical. 2 or MINIMAX manufactured by Medtronic PLUS^TMIs a standard membrane oxygen adder such as. In an exemplary embodiment, the gas comprises a mixture of oxygen and carbon dioxide. An example of the composition of such a mixture is about 85% O₂, About 1% CO₂, Remaining N₂Is contained. Following reoxygenation, the oxygen adder 114 returns the perfusate 108 to the reservoir 160. In an exemplary embodiment, the sensor 140 measures the amount of light absorbed or reflected by the perfusate 108 when applied at multiple wavelengths and produces an oxygen saturation measurement based on the light. In some embodiments, the perfusate 108 is blood product based and may contain red blood cells (ie, oxygen-carrying cells). Therefore, sensor 140 also provides signal 145, which indicates a hematocrit measurement of perfusate 108. In an alternative embodiment, the solution 108 is formed from a synthetic blood substitute, and in other embodiments, the solution 108 may contain the blood product in combination with the blood substitute product.

In addition, in both fluid flow modes, the nutrient subsystem 115, including the supply of maintenance solution 116/118 and the inhalation pump 182, is when perfusate 108 flows through system 100, and in some embodiments it is. When in Reservoir 160, inhale nutrients 116 such as glucose into perfusate 108. Maintenance solution 116/118 also includes the supply of therapeutic agents and preservatives 118 to reduce ischemia and other reperfusion-related injuries of the heart 102.

Both normal and retrograde modes will be described in more detail below with reference to FIGS. 24A-26B.

In an exemplary embodiment, the system 100 is primed prior to introducing the organ into the organ chamber assembly 104. During priming, a priming solution (discussed below) is inserted into the organ chamber 160 and pumped through system 100. In some application examples, this priming is performed for a time of about 5 to about 20 minutes. Bypassing interfaces 162, 166 and 170 for cannulation in the organ chamber assembly 104, perfusate 108 flows through the system 100 in normal flow mode without the donor heart 102. The reservoir 160 is then filled with blood (or a synthetic blood substitute). This blood may be blood exsanguinated from a donor for concentration of the heart 102, or blood obtained from stored blood with a blood type-matched and cross-matched. The system 100 thus circulates through the blood (or blood substitute) system 100 to heat, oxygenate, and filter it. Nutrients, preservatives and / or other therapeutic agents are provided through the inhalation pump 182 of the nutrient subsystem 115. Various parameters may be initialized and calibrated through the operator interface 146 during priming. If the system 100 is working properly, the pump speed can be reduced or reduced to zero and the heart 102 can be cannulated into the organ chamber assembly 104. After that, the pump speed can be increased. The priming of the system 100 will be further described below with reference to the flowchart of FIG. 29A.

As shown in FIG. 1, the system 100 further includes a plurality of extensible chambers 184, 186 and 188. Extensible chambers 184, 186 and 188 are basically small series fluid accumulators with flexible and elastic walls, such as by providing liquid flow back pressure and / or flow velocity changes and / or. By filtering / reducing hydraulic spikes caused by pump inhalation of pump 106, etc., this system helps to more accurately imitate blood flow in the human body, thereby imitating the vascular extensibility of the human body. It is designed to. In an exemplary embodiment, the extensibility chamber 184 is located between the output side 112a of the fluid flow mode selection valve 112 and the reservoir 160, in cooperation with the adjustable clamp 190 during normal flow mode. By providing back pressure to the aorta 158, the perfusate flows into the coronary sinus 155 and supplies it to the heart 102. In an embodiment of this example, the back pressure of the fluid provided to the aorta 158 is from about 55 mmHg to about 55 mmHg, which is near the average aortic blood pressure acceptable physiological range (typically between about 80 mmHg and about 100 mmHg). It is between 85 mmHg. This back pressure on the aorta 158 helps System 100 to mimic normal physiological conditions. The extensible chamber 186 is located between the output side 112b of the fluid flow mode selection valve 112 and the interface 170 for pulmonary vein cannula insertion in the organ chamber assembly 104. The main function of this extensible chamber 186 results from the pumping action of the perfusator pump 106, which provides back pressure to the left atrium 154 and delivers blood to the heart without causing substantial fluid pressure spikes. To smooth the pressure / flow spikes. In an exemplary embodiment, the fluid back pressure provided to the left atrium 152 is from about 0 mmHg to about 14 mmHg, which is about the same as the left atrium pressure under normal physiological conditions. The extensible chamber 188 is located between the output side of the one-way valve 310 and the suction port 110a of the heater assembly 110. The main function of this extensibility chamber 188 is also the perfusate pon It is to smooth the spikes of pressure / fluid flow caused by the pumping action of the pump 106 and to provide fluid back pressure to the pulmonary artery 164. In an exemplary embodiment, the fluid back pressure provided to the pulmonary artery 164 is from about 0 mmHg to about 25 mmH, which is within the acceptable physiological range of mean arterial blood pressure (from about 0 mmHg to about 12 mmHg).

Extensible chambers 184, 186 and 188 offer the advantages described above through their size and shape and the materials used in their design. Extensible chambers 184, 186 and 188 are sized to accommodate approximately 20 ml to approximately 100 ml of perfusate 108, which receive perfusate 108 and expand to attenuate pressure spikes and relative to heart 102. It is molded into an elliptical shape that can provide back pressure. In some applications, the materials used in the extensibility chambers 184, 186 and 188 are Shore A durametric with chambers of about 10 (high flexibility) to about 60 (small flexibility). Includes at least one flexible membrane selected to have hardness (ASTM D2240 00), and in some preferred embodiments, the chamber is about 30 (± about 8) to about 50 (± about 8). Has a hardness of. In this exemplary embodiment, the extensible chamber 184 has a Shore A hardness of about 50 (± about 8) and the extensible chamber 186 has a Shore A hardness of about 30 (± about 8). Has hardness. In an exemplary embodiment, the extensibility chamber 188 has a double layer construction, the inner chamber has a Shore A hardness of about 50 (± about 8), and the outer sleeve has about 30 (± about 8). Shore A has hardness. Alternatively, this 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). Can be done.

Now that the operational overview of the system 100 has been introduced, the organ chamber assembly 104, the perfusate heater assembly 110, and the pump head interface assembly 192 that interfaces with the pump 106 will be further described in more detail. Figures 5A-5F show a variety of diagrams of the exemplary organ chamber assembly 104 of Figure 1. As most clearly visible in Figure 5A-5D, the organ chamber assembly 104 includes a housing 194, an outer lid 196 and an intermediate lid 198. The housing includes a bottom surface 194e to accommodate the heart 102 and one or more wall surfaces 194a-194d. The intermediate lid 198 covers the opening 200 of the housing 194 and substantially encapsulates the heart 102 within the housing 194. As most clearly shown in FIGS. 5E and 5F, the intermediate lid 198 includes a frame 198a and a flexible membrane 198b suspended within this frame 198a. The flexible membrane 198b is preferably transparent, but may be opaque, translucent, or substantially transparent. In one feature, this flexible membrane contains sufficient extra membrane material to contact the heart 102 housed within the housing 195. This feature allows the medical operator to indirectly touch / examine the heart 102 through the membrane 198b, or ultrasound through the membrane 198b through the heart 102 while maintaining the sterility of the housing 195. A probe can be applied. Membrane 198b could be made from any suitable flexible polymer plastic, such as polyurethane. Further, the membrane 198b may have integrated conductive pads / contacts 199a and 199b, through which the electrical activity of the heart is transmitted through electrodes such as electrodes 142 and 144. It may be detected and / or the defibrillation or pacing signal may be delivered through the pads / contacts 199a and 199b as further detailed below. Alternatively, contacts 199a and 199b are electrodes. Electrodes may include all or part of the functions 142 and 144. As shown in FIG. 5C, the outer lid 196 opens and closes on the middle lid 198 independently of the middle lid 198. Preferably, the outer lid 196 is rigid enough to protect the heart 102 from indirect or indirect physical contact. The outer lid 196 and chamber 194 could also be made from any suitable polymer plastic, such as polycarbonate.

In one embodiment, the housing 194 comprises two hinge portions 202a and 202b, and the frame 198a of the intermediate lid comprises two corresponding pairing hinge portions 204a and 204b, respectively. The hinge portions 202a and 202b on the housing 194 are fitted with the hinge portions 204a and 204b on the frame 198a of the intermediate lid so that the intermediate lid 198 can be opened and closed with respect to the opening 200 of the housing. As most clearly seen in FIGS. 5D and 5F, the organ chamber assembly 104 also includes two latches 206a and 206b that secure the intermediate lid 198 closed over the opening 200. As shown in FIGS. 5E and 5F, the latches 206a and 206b rotatably and elastically fit into one latch hinge portion 208a and 208b attached to the wall surface 194c on the housing 194, respectively. As shown in FIGS. 5A and 5E, the intermediate lid frame 198a also includes the hinge portion 210. Since the hinge portion 210 rotatably and elastically fits with the mating hinge portion 212 on the outer lid 196, the outer lid 196 can be opened without opening the intermediate lid 198. As best shown in FIGS. 5B, 5D and 5F, the outer lid 196 further includes two cutouts 214a and 214b so that the latches 206a and 206b can grip the end 216 of the frame 198a of the intermediate lid. .. As shown in FIGS. 5B, 5D and 5F, the organ chamber assembly 104 further includes a latch 218 that rotatably and elastically fits into the hinge portion 220 attached to the wall surface 194c of the housing 194. Upon action, the latch 218 engages a tab 221 on the end 225 of the outer lid 196 to secure the outer lid 196 closed onto the intermediate lid 198.

As most clearly shown in Figures 5E and 5F, the middle lid also includes two gaskets 198c and 198d. When the outer lid 196 is closed, the gasket 198d fits between the periphery of the frame 198a of the intermediate lid and the periphery of the outer lid 196, thereby causing fluid between the intermediate lid 198 and the outer lid 196. Form a seal. When the intermediate lid 198 is closed, the gasket 198c fits between the outer edge 194f of the housing 194 and the frame 198a of the intermediate lid, thereby between the intermediate lid 198 and the peripheral portion 194f of the housing 194. To form a fluid seal.

Optionally, the organ chamber assembly 104 includes a pad 222 or sack assembly sized and shaped to fit on the inner bottom surface 194 g of the housing 194. Preferably, the pad 222 is formed from a material that is elastic enough to buffer the heart 102 from mechanical vibrations and shocks in transit, such as closed cell foam. In one feature, the pad 222 includes a mechanism for adjustable placement of the pair of electrodes, such as the electrodes 142 and 144 of FIG. In an exemplary embodiment, the mechanism includes through holes 224a and 224b that allow electrical leads to pass from underneath the pad 222 to the corresponding electrodes 142 and 144 on the cardiac contact surface of the pad. By passing electrical leads from the pad 222 to the electrodes 142 and 144, the electrodes 142 and 144 can be adjustablely arranged within the pad 222 for hearts of various sizes. In other embodiments, the mechanism is limited to, but not limited to, one or more variously oriented slots, recesses, protrusions, through holes, partially through holes, hooks, fasteners, snaps, adhesives. Patches and the like may be included. In some embodiments, the pad 222 is configured with one or more sleeve-like structures to allow the electrode to be inserted into the pad 222 so that the membrane-like surface of the pad 222 is between the electrode and the heart 102. May be arranged.

In some exemplary embodiments, the pad 222 is configured as a pad assembly, in which one or more, such as electrodes 142 and 144, are tunably placed in or on the pad 222. Include electrodes. One advantage is that the pad / electrode configuration of the present invention allows the electrodes to be placed on the electrodes and pads 222 without having to temporarily or permanently sew or mechanically connect the electrodes to the heart 102. Contact with the heart 102 can be facilitated. The weight of the heart 102 itself also helps stabilize the electrodes during transport. In an exemplary embodiment, electrodes 142 and 144 include one or more sensors that observe one or more electrical signals from the heart and / or a defibrillator that provides an electrical signal to the heart. .. As shown in FIGS. 1 and 5C, the organ chamber assembly 104 includes electrical interface connections 235a-235b that are attached to openings 234a-234b within the wall surface 194b of the housing 194, respectively. A cover 226 is provided to protect this electrical interface connection 235a-235b when not in use.

As further detailed below with reference to FIG. 15, interface connections 235a and 235b send electrical signals, such as ECG signals from electrodes 142 and 144, out of the housing 194, eg, controllers 194 and / Alternatively, connect to the operator interface 146 or the like. The interface connections 235a and 235b may be further connected to a defibrillation source, the defibrillation source may provide an external device, or as described in more detail below with reference to FIG. 22A. Although it may be in the circuit of system 100, this defibrillation source is capable of delivering defibrillation or pacing signals 143 to the heart 102 through electrodes 142 and 144.

As most clearly shown in FIGS. 5E and 5F, the organ chamber assembly 104 includes an openable membrane interface 230 that attaches to interface opening 232. The interface 230 includes a frame 230a and a releasable polymer membrane 230b mounted within the frame 230a. Membrane 230b may be made from silicone or any other suitable polymer. During operation, interface 230 is used to provide pacing leads to heart 102 without the need to open chamber lids 196 and 198, if necessary. Membrane 230b seals around this pacing lead to maintain a sealed environment around the heart 102. Membrane 230b is also resealed in response to removal of pacing leads.

As shown in FIGS. 5A and 5B, the organ chamber assembly 104 has openings 228a-228c for receiving the aortic interface 162, the pulmonary artery interface 166 and the pulmonary vein interface 170, as described above with respect to FIG. 1-4, and in FIG. Includes 24A-28C as described below. As shown in FIG. 5D, the organ chamber assembly 104 further includes a drain 201 for removing the perfusate 108 from the housing and returning it to the reservoir 160, and a module for organ chamber assembly 104 (at 634 in FIG. 19A). Includes mounting sockets 203A-203d for mounting on).

6A-6F show various drawings of the perfusate heater assembly 110 of FIG. As shown in FIGS. 6A and 6B, the heater assembly 110 includes a housing 234 having a suction port 110a and a discharge port 110b. As shown in both the longitudinal cross-sectional view of FIG. 6D and the transverse cross-sectional view of FIG. 6E, the heater assembly 110 includes a flow path 240 extending between the suction port 110a and the discharge port 110b. The heater assembly 110 may be conceptualized as having a symmetrical half portion of the upper 236 and the lower 238. Therefore, only the upper half is shown in the exploded view of FIG. 6F.

With reference to FIG. 6D-6F, the flow path 240 is formed between the first 242 and the second 244 flow path plates. The suction port 110a flows the perfusate into the flow path 240, and the discharge port 110b discharges the perfusate from the heater 110. The first 242 and second 244 channel plates provide direct contact of the perfusate flowing through the channel 240, a substantially bioactive Perfusate 108 contact surface (this surface is several). In embodiments, it may contain blood products). The fluid contact surface may be formed by treating or coating the plate, or may be the plate surface itself. The heater assembly 110 includes first and second electric heaters 246 and 248, respectively. The first heater 246 is located adjacent to the first heater plate 250 to connect heat to this plate. The first heater plate 250 then connects this heat to the first flow path plate 242. Similarly, the second heater 248 is located adjacent to the second heater plate 252 to connect heat to this plate. The second heater plate 252 connects heat to the second flow path plate 244. In an exemplary embodiment, the first 250 and second 252 heater plates are formed from a material, such as aluminum, that conducts and disperses heat from the first 246 and second 248 electric heaters relatively uniformly, respectively. To. The uniform thermal dispersion by the heater plates 250 and 252 allows the channel plate to be formed from a bioinert material such as titanium, reducing concerns about its thermal dispersion properties.

With particular reference to FIGS. 6E and 6F, the heater assembly 110 further includes O-rings 254 and 256 for fluid-sealing the flow path plates 242 and 244 with respect to the housing 234 to form the flow path 240, respectively. ..

The heater assembly 110 further includes first assembly brackets 258 and 260. The assembly bracket 258 is mounted on the upper 236 of the heater assembly 110 and on the periphery of the electric heater 246 to hold the heater 246, the heater plate 250 and the flow path plate 242 together with the assembly bracket 258. It is sandwiched between the body 234 and the body. These bolts 262a-262j are fitted into the corresponding through holes in the bracket 258, electric heater 246, heater plate 250 and flow path plate 242 and screwed into the corresponding nuts 264a-264j. Fix all the parts to the housing 234. The assembly bracket 260 is attached to the bottom surface 238 of the heater assembly 110 in a manner similar to fixing the heater 248, the heater plate 252 and the flow path plate 244 to the housing 234. The elastic pad 268 fits within the perimeter of the bracket 258. Similarly, the elastic pad 270 fits within the perimeter of the bracket 268. Bracket 272 fits on pad 268. The bolts 278a-278f are fitted into the holes 276a-276f of the bracket 272, respectively, and screwed into the nuts 280a-280f to compress the elastic pad 268 towards the heater 246 into the heater plate 250. On the other hand, it provides more efficient heat transfer. The elastic pad 270 is compressed by the bracket 274 towards the heater 248 in a similar manner.

As mentioned with respect to FIG. 1 and as shown in FIG. 6A, the illustrated heater assembly 110 includes temperature sensors 120 and 122 as well as dual sensors 124. The dual sensor 124 actually includes a dual thermistor that provides fault tolerance, measures the temperature of the perfusate 108 coming out of the heater assembly 110, and provides these temperatures to the controller 150. Signals from sensors 120, 122 and 124 are used in a feedback loop to drive signals to the first 246 and / or second 248 heaters, as further detailed below with respect to the heating subsystem 149 of FIG. By controlling, the temperature of the heaters 256 and 248 may be controlled. In addition, the illustrated heater assembly 110 is provided so that the heater plates 250 and 252, and thus the blood contact surfaces 242 and 244 of the heater plates 250 and 252, do not reach temperatures that could damage the perfusate. It further includes temperature sensors / leads 120 and 122 that observe the temperatures of the heaters 246 and 248 and provide these temperatures to the controller 150, respectively. In reality, the sensors attached to the sensors / leads 120 and 122 are RTDs. (Resistance temperature device) Base. As further detailed with respect to FIG. 13, signals from sensors attached to sensors / leads 120 and 122 are used in a feedback loop to further drive signals to the first 246 and / or second 248 heaters. By controlling, the maximum temperature of the heater plates 250 and 252 may be limited. As protection in the event of a failure, each of the heaters 246 and 248 has a sensor so that if one fails, the system can operate at the temperature of the other sensor.

As further detailed below with respect to FIG. 13, the heater 246 of the heater assembly 110 receives drive signals 281a and 281b (collectively 281) from the controller 150 to the corresponding drive leads 282a. Similarly, the heater 248 receives the drive signals 283a and 283b (collectively 283) from the controller 150 to the drive lead 282b. The drive signals 281 and 283 control the current to the heaters 246 and 248 and thus the heat generated by the heaters 246 and 248. More specifically, as shown in FIG. 7, the drive lead 282a includes a high pair and a low pair connected to the resistance element 286 of the heater 246. The greater the current provided through the resistor element 286, the hotter the resistor element 286. The heater 248 operates in the same manner with respect to the drive lead 282b. In the illustrated embodiment, device 286 has a resistance of about 5 ohms. However, in other exemplary embodiments, the device may have a resistance between about 3 ohms and about 10 ohms. Heaters 246 and 248 may be individually controlled by processor 150, as described in more detail below with respect to FIGS. 11 and 13.

In an exemplary embodiment, the heater assembly 110 containing the parts is made of molded plastic such as polycarbonate and weighs less than about 1 lb. More specifically, the housing 234 and the brackets 258, 260, 272 and 274 are all made of molded plastic such as polycarbonate. Another feature is that the heater assembly is a disposable assembly.

During operation, the illustrated heater assembly 110 uses about 1 watt to about 200 watts of power to drive the perfusate 108 flowing through the flow path 240 at a flow rate of about 300 ml / min to about 5 L / min at about 30 ° C. At temperatures below or 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, cells hemolyze or or It is sized and shaped to transfer the protein without denatured or damaging any blood product portion of the perfusate.

In one feature, the heater assembly 110 includes a housing 234 that is made of polycarbonate and weighs less than about 5 lbs and containment parts such as brackets 258, 260, 272 and 274. In other embodiments, the heater assembly may weigh less than about 4 lbs, less than about 3 lbs, less than about 2 lbs, or even less than about 1 lb. In an exemplary embodiment, the heater assembly 110 has a length of about 6.6 inches 288 and a width of about 2.7 inches 290 without including the inlet 110a and the outlet 110b. The heater assembly 110 has a height of about 2.6 inches and a height of 292. The flow path 240 of the heater assembly 110 has a nominal width of about 1.5 inches, a nominal length of about 3.5 inches of length 294, and a nominal height of about 0.070 inches of height 298. The height 298 and width 296 are selected so that the perfusate 108 is uniformly heated as it passes through the flow path 240. The height 298 and width 296 are also such that the cross-sectional area of the flow path 240 is approximately equal to the medial cross-sectional area of the fluid conduit that carries the perfusate 108 into and / or out of the heater assembly 110. , Will be selected. In some configurations, height 298 and width 296 make the cross-sectional area within the flow path 240 approximately equal to the medial cross-sectional area of the suction-side fluid conduit 792 (shown below with reference to FIG. 25C) and / or. It is selected to be substantially equal to the inner cross-sectional area of the discharge side fluid conduit 794 (shown below with reference to FIG. 24E).

The protrusions 257a-257d and 259a-259d are included in the heater assembly 110 and are used to receive the heat-activated adhesive for binding the heater assembly to the multi-use unit 650 (see Figure 20A).

8A-8C show various drawings of the pump interface assembly 300 based on an exemplary embodiment of the invention. FIG. 9 shows a perspective view of the pump-drive side of the perfusate pump assembly 106 of FIG. 1, and FIG. 10 shows the pump of the perfusate pump assembly 106 according to an exemplary embodiment of the invention. -Shows the pump interface assembly 300 paired to the drive side. Referring to FIG. 8A-10, the pump interface assembly 300 includes a housing 302 having an outer side surface 304 and an inner side surface 306. The interface assembly 300 includes a suction port 308 and a discharge port 310. As most clearly shown in the bottom view of Figure 8B and the exploded view of Figure 8C, the pump interface assembly 300 has an O-ring seal on the inside 312 and outside 314, and two deformable membranes 316 and 318. Includes a donut-shaped bracket 320 and halflings 319a and 319b that fit between the O-ring 314 and bracket 320 described above. Halflings 319a and 319b may be made from foam, plastic or other suitable material.

The inner O-ring 312 fits an annular trajectory along the perimeter of the inner side surface 306. The first deformable membrane 316 is attached to the inner O-ring 312 in a fluid-tightly interconnected state with the inner side surface 306 of the housing 302 to form an inner side surface of the first deformable membrane 316. A chamber is formed with the inner side surface 306 of the housing 302. The second deformable membrane 318, by fitting over the first deformable membrane 316, provides fault tolerance in the event that the first deformable membrane 316 is torn or torn. For example, the deformable membranes 316 and 318 are formed from a thin polyurethane film (about 0.002 inch thick). However, any suitable material of any suitable thickness may be used. With reference to FIGS. 8A and 8B, the bracket 320 is mounted on the second deformable membrane 318 and the rings 319a and 319b are secured to the housing 302 along the periphery of the inner side surface 306. The threaded fasteners 322a-322i attach the bracket 320 to the housing 302 through the threaded opening 324a-324i of the bracket 320. As shown in FIG. 8B, the outer O-ring 314 fits into the annular groove of the bracket 320 to provide fluid encapsulation with the pump assembly 106. Prior to inserting the O-ring 314 into the annular groove of this bracket 320, the halflings 319a and 319b are placed in place in the groove. The O-ring 314 is then compressed and placed in the annular groove of the bracket 320. After placement in the annular groove, the O-ring 314 expands in this groove to secure itself and the halflings 319a and 319b in place.

The pump interface assembly 300 further includes heat caulking points 321a-321c projecting from its outer side surface 304. As further detailed below with reference to FIGS. 21A-21C and 24A-24C, this point 321a-321c accepts hot contacts and disposes of the pump interface assembly 300 of the disposable module chassis 635. Heat to C-shaped bracket 656.

As shown in FIG. 8C, the fluid discharge port 310 includes a discharge port housing 310a, a discharge port pipe joint 310b, a liquid flow adjusting ball 310c, and a discharge port port 310d. The ball 310c fits inside the discharge port 310d, but is sized so that it does not pass through the inner opening 326 of the discharge port 310. The fitting 310b is glued to the outlet port 310d (eg, with epoxy or another adhesive) to trap the ball 310c between the inner opening 326 and the fitting 310b. The discharge port housing 310a is also adhered to the pipe joint 310b.

Upon action, the pump interface assembly 300 receives the pumping force from the pump drive 334 of the perfusate pump assembly 106 and translates this pumping force into the perfusate 108 to provide the perfusate 108 to the organ chamber assembly. Aligned to circulate to 104. In this exemplary embodiment, the perfusate pump assembly 106 comprises a pulsatile pump in contact with the membrane 318, having a drive device 334 (more detailed below with reference to FIG. 9). The fluid suction port 308 sucks the perfusate 108 from the reservoir 160 or the like in response to the deformable membrane 316 and the pump drive moving away from the 318, and draws this fluid into the inner membrane 316 and the housing 302. The membranes 316 and 318 are deformed in the same direction by providing to a chamber formed between the inner side surface 306 of the membrane. As the pump drive moves away from the deformable membranes 316 and 318, the pressure head of the fluid 108 in the reservoir 160 causes the perfusate 108 to flow from the reservoir 160 into the pump assembly 106. At this time, the pump assembly 106, the suction port valve 191 and the reservoir 160 are oriented to naturally feed the perfusate 108 to the pump assembly 106. At the same time, the liquid flow adjusting ball 310c is pulled into the opening 326 to prevent the perfusate 108 from being drawn into the chamber through the discharge port 310. Note that the outlet valve 310 and the inlet valve 191 are one-way valves in the illustrated embodiment, but in alternative embodiments these valves 310 and / or 191 are two-way valves. In response to the pump drive 334 moving in the direction towards the deformable membranes 316 and 318, the liquid flow control ball 310c moves towards the fitting 310b to open the inner opening 326, so that the discharge port 310 , Perfusate 108 can be discharged out of the chamber formed between the inner side surface 306 of the housing 302 and the inner side surface of the deformable membrane 316.

In some embodiments, the organ management system 100 is mechanically a single-use disposable unit (634 in FIGS. 19A-19C and 24A-25C), as further detailed below with reference to FIGS. 18A-27B. (Shown) and a non-disposable multi-use unit (shown as 650 in Figure 20A). In such an embodiment, the pump assembly 106 is fixedly attached to the multi-use module 650 and the pump interface assembly 300 is fixedly attached to the single-use disposable module 634. The pump assembly 106 and the pump interface assembly 300 have corresponding interconnect lock connections that, when paired with each other, form a fluid seal between the two assemblies 106 and 30.

More specifically, as shown in the perspective view of FIG. 9, the perfusate pump assembly 106 includes a pump drive housing 338 having a top surface 340 and a pump drive housed in a cylinder 336 of the housing 338. Includes device 334 and. The pump drive housing 338 further includes a coupling port 342 including a slot 332 sized and shaped to face a flange 328 protruding from the pump interface assembly 300. As shown in FIG. 10, the top surface 340 of the pump drive housing 338 is mounted on bracket 346 on a non-disposable multi-use module unit 65. The bracket 346 includes features 344a and 344b that abut the tapered protrusions 323a and 323b of the pump interface assembly 300, respectively. Bracket 346 further includes a coupling port 342 and a notch 330 sized and shaped to align with slot 332 of the pump drive housing 338.

Operationally, the seal between the pump interface assembly 300 and the fluid pump assembly 106 is formed in two steps, as illustrated in FIGS. 9 and 10. In the first step, the flange 328 is placed in the coupling port 342 and the tapered protrusions 323a and 323b are placed on the clockwise sides adjacent to the corresponding features 344a and 344b on the bracket 346. In the second stage, the pump interface assembly 300 and the fluid pump assembly 106 are rotated in opposite directions (eg, the pump interface assembly 300 is counterclockwise, as shown by arrows 345, 347 and 349 in FIG. By holding the pump assembly 106 fixed (for example, while rotating it), the flange 328 slides into slot 332 of the coupling port 342. At the same time, the tapered protrusions 323a and 323b slide under the bracket features 344a and 344b, respectively, to taper the inner surface of the bracket features 344a and 344b to the tapered protrusions 323a and 323b. Engaging with the outer surface, pulls the inner side surface 306 of the pump interface assembly 300 towards the pump drive 334, while connecting the flange 328 to the coupling port 342 and the tapered protrusions 323a and 323b. Mutually lock with bracket features 344a and 344b to form a fluid seal between the two assemblies 300 and 106.

Having described the exemplary organ management system 100 from a systematic, operational and component perspective, the exemplary control systems and methods for achieving system 100 operation are now discussed. More specifically, FIG. 11 shows a block diagram of an exemplary control scheme for System 100. As mentioned above with reference to FIG. 1, the system 100 includes a controller 150 that controls the operation of the system 100. As shown, the controller 150 interconnects with the following six subsystems: assisting the operator in monitoring and controlling the system 100 and in monitoring the condition of the heart 102. Operator interface 146; A data acquisition subsystem that has a variety of sensors to obtain data about the heart 102 and the system 100 and carry the data to the controller 150; a power management sub system that provides fault tolerance to the system 100. System 148; A heating subsystem that provides controlled energy to a heater 110 that warms the perfusate 108; a data management subsystem 151 that stores and maintains data about the operation of the system 100 and the heart 102; and the book. Pump subsystems that control pumping of perfusate 108 through system 100 153. System 100 is conceptually described for a single controller 150, but control of system 100 can be controlled by multiple controllers or Note that it may be distributed across the processors. For example, any or all of the subsystems described may include dedicated processors / controls. Optionally, dedicated processors / controllers of various subsystems may be communicated and relayed to a central controller / processor.

Figure 12-17J shows the interaction of the various subsystems in Figure 11. First referring to the block diagram of FIG. 12, the data acquisition subsystem 147 obtains information on how the system 100 and the heart 102 work, and the controller 150 is directed towards processing and use by the system 100. Includes sensors that communicate that information. As discussed with respect to FIG. 1, the sensors in subsystem 147 are, but are not limited to, temperature sensors 120, 122 and 124; pressure sensors 126, 128, and 130; flow velocity sensors. 134, 136 and 138; oxygen addition / hematocrit sensor 140; and electrodes 142 and 144 are included. The data acquisition subsystem 147 is further: a set of Hall sensors 388 and shaft encoder 390 from the perfusion pump assembly 106; battery sensors 362a-362c to detect if the batteries 352a-352c are fully charged, respectively; external External power available sensor 354 to detect if AC power is available; Operator interface module battery sensor 370 to detect the state of charge of the module battery of the operator interface; and gas flow from the gas flow chamber 176 Includes a gas pressure sensor 132. Heating 149, power management 148, pump injection 153, data management 151, and operator interface 146, respectively, show how the system 100 uses information from the data acquisition subsystem 147 in more detail in Figure 13-17J, respectively. It is explained below with reference to the subsystem.

The heating subsystem 149 is shown in the block diagram of FIG. Further referring to FIG. 1, the heating subsystem 149 controls the temperature of the perfusate 108 in the system 100 through a double feedback loop method. In the first loop 251 (perfusion fluid temperature loop), the perfusate temperature thermistor sensor 124 provides two (fault tolerant) signals 125 and 127 to the controller 150. The signals 125 and 127 indicate the temperature at which the perfusate 108 exits the heater assembly 110. Controller 150 regulates drive signals 285 and 287 to drives 247 and 249, respectively. Drives 247 and 249 heat the corresponding digital level signals 285 and 287 from this controller 150 to the first 246 and second 248 heating to heat the perfusate 108 to a temperature range selected by the operator. Convert to heater drive signals 281 and 283, which have sufficient current levels to drive the vessel, respectively. In response to the controller 150 detecting that the perfusate temperatures 125 and 127 were below the temperature range selected by the operator, it gave drive signals 281 and 283 to the first 246 and second 248 heaters, respectively. , Set the perfusate 108 to a level sufficient to continue heating. Conversely, in response to the controller 150 detecting that the perfusate temperatures 125 and 127 exceed the temperature range selected by the operator, it provides drive signals 281 and 281 to the first 246 and second 248 heaters, respectively. Decrease 283. In response to detecting that the temperature of the perfusate 108 is within the temperature range selected by the operator, the controller 150 maintains the drive signals 281 and 283 at constant or substantially constant levels.

Preferably, the controller 150 modifies the drive signals 281 and 283 in substantially the same manner. However, this may not always be the case. For example, each heater 246 and 248 may respond differently to a drive signal at a particular current or voltage level. In such cases, controller 150 may drive each heater 246 and 248 at slightly different levels to obtain the same temperature from each. In one feature, the heaters 246 and 248 each have an associated calibration factor, which the controller 150 stores and uses in determining the level of a particular drive signal for a particular heater. Offer to try to achieve a particular temperature result. In some configurations, the controller 150 sets one of the thermistors of the dual sensor 124 to the default thermistor and reads the temperature from this default thermistor if the thermistor gives two different readings. Will use the value. In some configurations, if the temperature readings are within a predetermined range, the controller 150 uses the higher of the two readings. The drives 247 and 249 apply the heater drive signals 281 and 283 to the corresponding drive leads 282a and 282b of the heater assembly 110.

In the second loop 253 (heater temperature loop), the heater temperature sensors 120 and 122 provide the controller 150 with signals 121 and 123 indicating the temperatures of the heaters 246 and 248, respectively. In the illustrated embodiment, a temperature ceiling is established in the heaters 246 and 248 (eg, by default or at the operator's choice) where the temperature of the heaters 246 and 248 is not allowed to rise above it. As the temperature of heaters 246 and 248 rises and approaches this temperature ceiling, sensors 121 and 123 indicate this to controller 150, which controls drive signals 281 and 283 to heaters 246 and 248. To reduce or stop the power supply to the heaters 246 and 248. Thus, the cold signal 125 or 127 from the perfusate temperature sensor 124 can increase the power to the heaters 246 and 248 in the controller 150, while the high temperature sensors 120 and 122 are in the heater 246 and 248 ensures that each of those heater plates 250 and 252 is not driven until it is hot enough to damage the perfusate 108. In various exemplary embodiments, the controller 150 is set to maintain the perfusate temperature between about 32 ° C and about 37 ° C, or between about 34 ° C and about 36 ° C. To. In a further embodiment, the controller 150 is set to limit the maximum temperature of the heater plates 250 and 252 to less than about 38 ° C, 39 ° C, 40 ° C, 41 ° C, or 42 ° C. To.

As shown, if necessary, the temperature readings from the temperature sensors 120 and 122 indicating that the heaters 246 and 248 are reaching the maximum permissible temperature are the effects of any cold signal from the perfusate temperature sensor 124. The second loop 253 is configured to override the first loop 251 so that it also overrides. In this regard, subsystem 149 ensures that the temperatures of the heater plates 250 and 252 do not rise above the maximum permissible temperature even if the temperature of the perfusate 108 does not reach the temperature value selected by the operator. It is to ensure that. This override feature is especially important in the event of a failure. For example, if both perfusate temperature sensors 124 fail, a second loop 253 switches control to heater temperature sensors 120 and 122 only and lowers the temperature setting point to a lower value, thereby reducing the heater assembly 110. Do not overheat or damage the perfusate 108. In one feature, controller 150 takes into account two time constants specified for the deviations associated with temperature measurements from heaters 246 and 248 as well as perfusate 108 to optimize the dynamic response of temperature control. Put in.

FIG. 14 shows a block diagram of a power management system 148 that provides fault tolerance to the system 100. As shown, the System 100 has one or three individual power sources of fourexternal AC power sources 351 (eg 60 Hz, 120 VAC in North America, or 50 Hz, 230 VAC in Europe). Power may be supplied from any of the batteries 352a-352c. The controller 150 receives data from the AC line voltage availability sensor 354, which indicates whether the AC voltage 351 is available to the system 100. In response to the controller 150 detecting that the AC voltage 351 is not available, the controller 150 signals the power switching circuit system 356 to provide a system power high 358 from one of the batteries 352a-352c. .. The controller 150 determines from the battery charge sensor 362a-362c which of the available batteries 352a-352c is the most fully charged, and then switches through the switching network 356 to operate the battery.

Conversely, when the controller 150 detects that an external AC voltage 351 is available, this available AC voltage 351 (eg, after rectification) is used to provide system power 358, and the user interface module. The internal battery of the user interface module 146 to power the 146, to charge one or more of the batteries 352a-352c, and / or to have its own internal charger and charge controller. Determine if it should be used to charge the 368. To use the available AC voltage 351 the controller 150 draws the AC voltage 351 into the power source 350 by sending a signal through the switching system 364. When the power supply 350 receives the AC voltage 351, it converts it into a DC current to power the system 100. The power supply 350 is general purpose and can operate any line frequency or voltage commonly used all over the world. In an exemplary embodiment, the controller 150 further directs power to a suitable battery through a switching network 364 and a charging circuit 366 in response to one or more of the battery sensors 362a-362c exhibiting a low battery. Turn. When the controller 150 receives the low battery signal from the sensor 370, in response to this, or additionally, the charging voltage 367 is directed to the user interface battery 368. As another feature, the power management subsystem 148 selects the battery that supplies power to the system 100 in the order of the least charged battery first and the most charged battery later. If the battery currently in use to power system 100 is removed by the user, the power management subsystem 148 automatically powers the next least charged battery to continue powering system 100. Switch to.

As another feature, the power management subsystem 148 utilizes a lockout mechanism to prevent two or more of the batteries 352a-352c from being removed from system 100 at once. Once one battery is removed, the other two are mechanically locked in place within the system 100. In this regard, the system 148 provides a level of fault tolerance that helps ensure that the power supply 358 is always available to the system 100.

The pump injection subsystem 153 of FIG. 11 will be further described below with reference to FIGS. 15 and 16. More specifically, FIG. 15 is a conceptual block diagram showing an exemplary pumping subsystem 153, and FIG. 16 is a heart 102 synchronized with 385 waveforms showing pumping output by subsystem 153. An exemplary ECG414 is shown. ECG414 shown in FIG. 16 has P, Q, R, S, T, and U peaks. The pump injection subsystem 153 includes a perfusate pump 106 interconnected to the pump interface assembly 300, as further detailed above with reference to FIG. 8A-10. As shown in FIG. 15, the controller 150 Halls the drive signal 399 to the brushless three-phase pump motor 360. Activate the pump injection subsystem 153 by sending with Sensor feedback. The drive signal 339 causes the pump motor shaft 337 to rotate, causing the pump screw 341 to move upwards and / downwards with the pump drive 334. In the illustrated embodiment, the drive signal 339 is controlled to change the rotation direction and rotation speed of the motor shaft 337 to periodically move the pump drive device 334 up and down. This periodic movement injects perfusate 108 into system 100.

During operation, the controller 150 receives the first signal 387 from the Hall sensor 388, which is integrally located inside the pump motor shaft 337, to rectify the hoisting current of the motor, the pump motor shaft 337. Indicates the position of. The controller 150 receives a second, higher resolution signal 389 from the shaft encoder sensor 390 indicating the exact rotational position of the pump screw 341. The controller 150 calculates a suitable drive signal 339 (both amplitude and polarity) from the current motor rectifying phase position 387 and the current rotation position 389 to cause the required rotational change of the motor shaft 337. , A vertical position change suitable for the pump screw 341 to achieve the desired pumping action. The controller 150 pumps by changing the amplitude of the drive signal 339 to change the pump speed (ie how often and how often the pump injection cycle is repeated) and by changing the direction of rotation. -The stroke amount (for example, by changing how far the pump drive 334 moves in one cycle) can be changed. Generally speaking, the periodic pumping rate regulates the pulsatile rate at which the perfusate 108 is provided to the heart 102, while the pumping stroke (at a fixed rate) provides the perfusate to the heart 102. The amount of 108 is adjusted.

Both velocity and stroke volume affect the flow rate of perfusate to and from the heart 102, and indirectly affect its pressure. As mentioned with respect to FIG. 1, the system includes three flow velocity sensors 134, 136 and 138 and three pressure sensors 126, 128 and 130. As shown in FIG. 15, sensors 134, 136, and 138 provide corresponding flow velocity signals 135, 137, and 130 to controller 150. Similarly, sensors 126, 128 and 130 provide the corresponding pressure signals 129, 131 and 133 to controller 150. The controller 150 utilizes all of these signals in feedback to ensure that the commands it provides to the perfusion pump 106 have the desired effect on the system 100. In some cases, and as further detailed below with reference to FIG. 17A-17J, the controller 150 responds to a signal indicating that a particular flow rate or fluid pressure is out of acceptable range. Various alarms may be generated. In addition, by utilizing multiple sensors, the controller 150 can distinguish between mechanical problems in the system 100 (eg, breakage of conduits) and biological problems in the heart 102.

According to one of the features of the present invention, the pump injection system 153 may be configured to control the position of the pump drive 334 during each moment of the pumping cycle to fine-tune the pumping speed and capacitance profile. Good. The pump system 153 can then supply the perfusate 108 to the heart in the desired pulsatile pattern. In one exemplary embodiment, the rotational position of shaft 337 is detected by shaft encoder 390 and adjusted by controller 150 by at least about 100 increments per rotation. In another exemplary embodiment, the rotational position of shaft 337 is detected by shaft encoder 390 and adjusted by controller 150 by at least about 1000 increments per rotation. In a further exemplary embodiment, the rotational position of shaft 337 is detected by shaft encoder 390 and adjusted by controller 150 by at least about 2000 increments per rotation. The vertical position of the pump screw 341 and thus the pump drive 334 is initially calibrated to a zero or ground position corresponding to the reference position of the pump screw 341.

In an exemplary embodiment, the positional accuracy of the pump subsystem 153 allows the controller 150 to precisely regulate the pump injection of perfusate 108 through the heart 102. This process of synchronizing the pulsatile flow of the perfusate to the natural velocity of the heart is referred to herein as "r-wave entrainment," which will be described with reference to FIGS. 2, 15, and 16. A normally functioning heart has a two-phase pumping cycle, diastole and systole. During diastole, also known as "telogen," the heart's atria 157 and 152 contract, opening valves between the atria 157 and 152 and between the ventricles 154 and 156, allowing blood flow to the ventricles 154 and 156. Inflow and load is applied. During systole, the loaded ventricles eject blood and the atriums 157 and 152 are opened and filled with blood. During this process, the periodic expansion and contraction of the heart 102 can be represented by graphing the ECG waveform of the ventricles shown in 414 of FIG. 16 of the heart. FIG. 16 shows the ECG waveform 414 tuned to an exemplary wave 385 representing the pumping output of subsystem 153.

The pumping subsystem 153 is configured to provide maximum power at a time when delivery of perfusate 108 to the heart 102 occurs at the most favorable time. In the illustrated embodiment, the pumping subsystem 153, in retrograde mode, is when the maximum pump output 382 begins after the S peak shown in FIG. 16 and the left ventricle 156 finishes ejecting perfusate 108 through the aorta 158. The perfusate 108 is configured to be pumped into the heart 102 so that it occurs during the diastolic phase of the heart. By timing the pump output in this way, the user can maximize the injection of perfusate 108 into the coronary sinus 155 through the aorta 158. The timed pumping begins before time point 382 and at time point 377 on wave 385, which corresponds to the peak of the cardiac r-wave pulse 380 and the midpoint of the ventricular contraction period. Thereby, such timed pump injection is achieved. Time point 377 is selected to anticipate the time lag between the time when the signal is delivered from the controller 150 and the fluid is pumped and the time when the pumped perfusate 108 is actually delivered to the heart 102. In another example, in normal flow mode, where the left side of the heart is filled and ejects perfusate (as further detailed with reference to FIG. 24A), controller 150 pumps subsystem 153 with r-wave 380. Synchronize to initiate pumping at a later fixation point to match the natural filling cycle of the left atrium 152. This tuning may be adjusted and fine-tuned by the operator through a pre-programmed routine in the operating software of System 100 and / or as further detailed below with reference to FIG. 17A-17J. Adjustments and fine-tuning may be made by manually manipulating the control of the user interface display area 410.

To tune the pump output, the controller 150 predicts when the r-wave pulse 380 of the heart will occur and pump it to the pump at an appropriate time in the ECG 414. To make this prediction, controller 150 measures r-wave pulses 380 of varying lengths from electrical signals 379 and 381 provided by electrodes 142 and 144, respectively. The controller 150 tracks the time elapsed from one pulse 380 to the next from these pulses, and uses this information to divide the two consecutive r-wave pulses into a time-length moving average. To calculate. From this information, the controller 150 predicts (and optimally) the time point of the next r-wave by adding the average time separating the two consecutive r-wave pulses to the time point of the previous r-wave 380. Determine when pumping should begin before the predicted r-wave or after the predicted r-wave to achieve output delivery). Based on this moving average of the separation times between the R waves, the controller 150 moves to the next r wave, which is reflected in the movement of the wave 385 to the left or right along the ECG 414, as shown by arrow 383 in FIG. You have the option of adjusting the pump output time point accordingly. Thus, adjusting the wave 385 allows the user to optimize the filling of the heart by adjusting and customizing the timing of the output by the pump 106. In addition, the amount of perfusate 108 provided by the pump 106 may be optimized by adjusting the pump 106 to increase or decrease the pump stroke amount, and this is done in coordination with the tuning of the r-wave. Alternatively, it may be performed independently of the tuning of the r wave.

Note that subsystem 153 is specifically tuned to r-wave period 385, but this is not always the case. In an alternative embodiment, subsystem 153 may be pumped in synchronization with any cardiac characteristic available, including hydraulic pressure into or out of a particular chamber or vessel. .. Further, subsystem 153 may be programmed to pump in any pattern, whether periodic or non-periodic.

Referring again to FIG. 11, the data management subsystem 151 receives and stores data and system information from various other subsystems. If desired by the operator, this data and other information may be downloaded to a portable storage device and configured in a database. The stored data and information can be accessed by the operator and displayed through the operator interface subsystem 146.

Returning to the operator interface subsystem 146, FIG. 17A-17J shows various display screen examples of the operator interface subsystem 146. The display screen of FIG. 17A-17J allows the operator to receive information from the system 100 and provide instructions to the system 100. FIG. 17A shows a top-level home page display screen 400 according to an exemplary embodiment of the invention. The operator can access all of the data available from the data acquisition subsystem 147 from this display screen 400 and can also provide any desired command to the controller 150. As further detailed with reference to FIG. 17B-17J, the display screen 400 of FIG. 17A allows the operator to further obtain information, provide instructions, and set parameters that the operator can select. You can also access a more detailed display screen to do this.

With reference to FIG. 1, the display screen 400 includes a display area 402 showing a number of numerical and geographical indicators related to the operation of the system 100. Specifically, the display area 402 is a numerical reading of the aortic output pressure (AOP) 404 of the perfusate 108 exiting the aortic interface 162 on the organ chamber assembly 104 and a waveform diagram 406 of the aortic fluid pressure (AOP) 404. And an AOP alarm image 408 showing whether the hydraulic pressure 404 is too high or too low (alarm 408 is shown as "off" in FIG. 17A). The display screen 400 shows the numerical index 412 of the speed at which the heart 102 is beating, the ECG 414 of the heart 102, and the heart speed indicating whether the heart speed (HR) 412 is above or below the operator set threshold. (HR) Alarm image 416 and display area 410 with a time log and 418 showing how long the system 100 has been operating, including priming time (more detailed below with reference to FIG. 20). Including. The numerical display 419 indicates the time when the system 100 has supported the heart 102 by that time. The indicator alarm 413 indicates this when the time preset by the operator is exceeded.

The display screen 300 includes a number of additional display areas 420, 424, 432, 438, 444, 450, 456, 460, 462, 466, 472, 480, and 482. Display area 420 shows a numerical reading of pulmonary arterial pressure (PAP) 422. PAP422 is an index of the pressure of the perfusate 108 flowing from the pulmonary artery 164 of the heart, as measured by the pressure sensor 130. The display area 420 also provides a PAP alarm indicator 424 that signals when the PAP 422 is outside the operator's preset range. Display area 426 shows the temperature (Temp) 428 of the perfusate 108 as it exits the heater 110. The display area 426 also includes a Temp alarm indicator 430 that responds and signals when the Temp 428 is outside the operator's preset range. The upper limit of the preset range of the operator is shown in 427. Display area 432 shows the numerical reading of the hematocrit (HCT) 434 of the perfusate 108 and the HCT alarm indicator 436 that signals the operator when the HCT 434 falls below the operator's preset threshold. Display area 438 is the oxygen saturation (SvO) of perfusate 108.₂) Indicates 440. In addition, display area 438 is the SvO of perfusate 108.₂SvO indicating when 440 falls below the operator's preset threshold₂Also includes alarm 442. Display area 444 shows the aortic output flow velocity (AOF) 446 as the perfusate 108 flows out of the aorta 158. AOF446 is measured by the flow velocity sensor 134. The AOF alarm 448 indicates whether the flow velocity 446 is outside the operator's preset range. Display area 450 indicates organ chamber flow velocity (CF) 452. CF452 is an index of the flow velocity as the perfusate 108 exits the organ chamber 104, as measured by the flow velocity sensor 136. The display area 450 also includes a CF alarm 454 that gives a signal in response to the CF 454 when it is outside the operator's preset range. Display area 456 contains graphic 458 indicating that a file transfer to a memory card is occurring.

Display area 460 shows a graphic display 459 of how much each of the batteries 352a-352c (discussed above with reference to FIG. 14) is charged. The display area 460 also provides a numerical indicator 461 of the amount of time remaining that the batteries 352a-352c can continue to operate the system 100 in the current operating mode. Display area 462 reveals whether operator interface module 146 is operating in wireless 464 mode, along with a graphic display 463 of the strength of the wireless connection between operator interface module 146 and the rest of system 100. To. In addition, display area 462 includes a graphic indicator of charging 467 remaining on the operator interface module battery 368 (discussed above with reference to Figure 14) and the operator interface module dry cell battery 368 in wireless mode. It provides a numerical indicator 465 of the amount of time remaining that can be assisted. Display area 466 shows the flow rate 468 of oxygen from the gas flow chamber 176. It also provides a graphic indicator 469 of how full the onboard oxygen tank is, and a numerical indicator 470 of the amount of time remaining until the onboard oxygen tank is empty. Display area 472 indicates the heart rate of the heart 102 and the amount of time 476 the heart 102 has been cannulated into the system 100. This area is an overlap of the above-mentioned area 419. Display areas 480 and 482 indicate the current time and date of operation of system 100, respectively.

Activating a dial (or mouse, or other control device) such as dial 626 shown in FIG. 18A on operator interface 146 opens configuration menu 484, such as that shown in display screen 401 in FIG. 17B. As shown, accessing configuration menu 484 covers display areas 402 and 410, so they do not subsequently show a graphic display of pressure 406 and heart rate 414 and continue to display important alpha // numerical information. Further, as shown, all other display areas remain unchanged. This allows the operator to adjust the operation of the system 100 while continuing to observe important information. In one feature, the configuration menu 484 allows the operator to pre-program preferred operational parameters for the system 100. The display screen 401 allows the operator to monitor / edit the operating mode and extended (or retrograde) mode alarms, respectively, by selecting areas 488 and 490. The operator can set specific ECG and LAP graphic options by selecting areas 492 and 494. In addition, the operator can set the oxygen flow rate and perfusate temperature, respectively, by selecting regions 496 and 498. Selecting area 500 allows the operator to set the time and date, while selecting area 502 allows the operator to select the original language in which the information is to be displayed. At the bottom of the display area 484, the operator returns to the display screen 400 504, cancels any changes made to the operational settings 506, saves the changes as new defaults 508, or operational You have the option of resetting the set value to the factory default value 510.

Referring to FIG. 17C-17D, selecting the monitoring / editing work mode alarm area 488 opens the work mode alarm dialogue 512 of FIG. 17D within the display area 484 of FIG. 17C. This working mode dialog 512 displays parameters related to normal flow mode (see FIGS. 1 and 3 above) and is used to set numerical thresholds for each of the normal flow mode alarms. Includes area. More specifically, Dialogue 512 has a CF alarm area 514; PAP. Alarm area 516; AOP alarm area 518; LAP Alarm area 520; Perfusate Temp Alarm area 524; SvO₂Includes alarm area 526; HCT alarm area 528; and HR alarm area 530. By selecting a particular alarm area and activating the up 532 and / or down 534 arrows, the operator adjusts the acceptable upper and / or lower thresholds for each of the parameters associated with each of the alarms. be able to. Dialog 512 further includes alarm graphics 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 the relevant alarm graphic 536a-536i. Any changes made using Dialogue 512 will be reflected in the corresponding area of display screen 400 of FIG. 17A.

Referring to FIGS. 17A, 17B and 17E, selecting the monitoring / editing inactive mode alarm area 490 opens the hibernate mode alarm dialogue 538 of FIG. 17E within the display area 484 of FIG. 17C. The dormant mode dialogue 538 displays parameters associated with retrograde mode (discussed above with reference to FIGS. 1 and 4) and includes an area for setting numerical thresholds for each of the retrograde mode alarms. According to an exemplary embodiment, the alarms available for normal and retrograde modes are similar, but not necessarily the same. Furthermore, even if they are the same, the threshold values may be different. Therefore, in the present invention, the operator can select different alarms and / or different thresholds for each of the working flow modes. More specifically, Dialogue 538 has a CF alarm area 540; PAP alarm area 542; AOF alarm area 544; AOP. Alarm area 546; LAP alarm area 548; Perfusate Temp alarm area 550; SvO₂ Includes alarm area 552; HCT alarm area 556; and HR alarm area 558. By selecting a particular alarm area and activating the up 560 and / or down 562 arrows, the operator adjusts the acceptable numerical upper and / or lower thresholds for each of the parameters associated with each of the alarms. can do. Dialogue 538 also includes alarm graphics 564a-564i, each associated with a particular normal flow mode alarm. The operator can enable / disable any of the above normal flow mode alarms by selecting the relevant alarm graphic 564a-564i. As with Dialogue 512, any changes made with Dialogue 538 will be reflected in the corresponding area in display screen 400 of FIG. 17A. In one example, the system 100 may be configured to automatically switch between several sets of alarm limits for a particular liquid flow mode when the liquid flow mode is changed.

With reference to FIGS. 17A, 17B, 17F and 17G, the operator interface 146 also provides a graphic mechanism for adjusting various parameters. For example, as described above with reference to FIG. 16, one of the advantages of the user display area 402 is that it allows the operator to observe (and adjust) the pumping of subsystem 153. The display area 410 reveals the ECG waveform 414 of the heart 102, and the display 402 shows the pressure of the fluid flowing through the aorta in the waveform 406. These two displays allow the operator to observe the effect of the pumping profile on the ECG414 of the heart so that the user can adjust the stroke amount of the pumping subsystem 153 or the subsystem 153 during pumping. To adjust the rate of the perfusate 108 pumped through the system 100 (and thus the flow rate of the perfusate 108 pumped through the system 100), manually prompt the start of the subsystem or adjust the time point (eg r-wave 380 and the start of the pumping cycle (By imposing a certain delay during), or if necessary to properly fill the heart according to whether the heart is perfused in retrograde or normal mode, prescribed along the ECG waveform 414 of the heart. The pumping subsystem 153 can be automatically programmed to pump at this point. These pumping adjustments could be made using the various graphic frames of operator interface 146. For example, when the operator selects the ECG graphic frame option 492 located in the display area 484 of the display screen 401, the operator interface 146 displays the dialogue 568 of FIG. 17F in response. Dialogue 568 shows the graphic display 572 of ECG414 along with the cursor 570. The position of cursor 570 is the point at which pumping subsystem 153 will initiate an output pumping stroke against ECG414 of heart 102 (ie, during the pumping cycle, pump motor 106 irrigates. The part that pushes the running fluid 108 toward the heart 102) is shown. By rotating the mechanical knob 626 (shown in Figures 18A and 18B) on the operator interface 146, the operator moves the cursor 570 to the pumping subsystem 153 with respect to the r-wave pulse 380. Adjust when the output pumping stroke will begin. As mentioned above with reference to FIGS. 15 and 16, the pumping subsystem 153 receives the r-wave signal 380 from the ECG sensors 142 and 144. The pumping subsystem 153 uses the r-wave signal 380 in conjunction with pumping regulation information from the cursor 570 to synchronize the pumping of the perfusate with the beating of the heart 102. In another example, the operator interface 146 displays the dialogue 574 of FIG. 17G in response to the operator pressing the pump adjustment button 625. From this dialogue 574, the operator can select pointer 576 and rotate knob 626 to turn the pump motor 106 on and off. In addition, the operator can select the bar graphic 578 and rotate the knob 626 to adjust the amount of perfusate to be pumped, displayed in liters / minute. By rotating, the operator moves the position of the cursor 570 to adjust when the pumping subsystem 153 will initiate an output pumping stroke for the r-wave pulse 380. As mentioned above with reference to FIGS. 15 and 16, the pumping subsystem 153 receives the r-wave signal 380 from the ECG sensors 142 and 144. The pumping subsystem 153 uses the r-wave signal 380 in conjunction with pumping regulation information from the cursor 570 to synchronize the pumping of the perfusate with the beating of the heart 102. In another example, the operator interface 146 displays the dialogue 574 of FIG. 17G in response to the operator pressing the pump adjustment button 625. From this dialogue 574, the operator can select pointer 576 and rotate knob 626 to turn the pump motor 106 on and off. In addition, the operator can select the bar graphic 578 and rotate the knob 626 to adjust the amount of perfusate to be pumped, displayed in liters / minute. By rotating, the operator moves the position of the cursor 570 to adjust when the pumping subsystem 153 will initiate an output pumping stroke for the r-wave pulse 380. As mentioned above with reference to FIGS. 15 and 16, the pumping subsystem 153 receives the r-wave signal 380 from the ECG sensors 142 and 144. The pumping subsystem 153 uses the r-wave signal 380 in conjunction with pumping regulation information from the cursor 570 to synchronize the pumping of the perfusate with the beating of the heart 102. In another example, the operator interface 146 displays the dialogue 574 of FIG. 17G in response to the operator pressing the pump adjustment button 625. From this dialogue 574, the operator can select pointer 576 and rotate knob 626 to turn the pump motor 106 on and off. In addition, the operator can select the bar graphic 578 and rotate the knob 626 to adjust the amount of perfusate to be pumped, displayed in liters / minute.

In addition, operator interface 146 also provides multiple warning / reminder messages. For example, in FIG. 17H, the operator interface 146 displays a message reminding the operator to connect to AC power and charge the batteries. This message appears in response to, for example, when the controller 150 detects that the low battery state is near. The operator interface 146 displays a message in Figure 17I to confirm that the user wants to enter standby mode or to download and store information about a particular use of the system 100, magnetic or optical. Remind the operator to insert a portable storage device such as a portable disk drive, flash memory card or other suitable storage device. The operator interface 146 responds to an error message such as the error message shown in FIG. 17J in response to a identifiable failure. The error message of FIG. 17J includes, for example, error information 580 to assist the repair technician in diagnosing and / or repairing the failure.

Having described the exemplary control system of the system 100 and the method for causing it to operate, an example of the mechanical features of the system 100 is illustrated by the components between the disposable module 634 and the multi-use module 650 device. We will discuss it together with the target division. More specifically, FIGS. 18A-18B show the mechanical system design 600 of the system of FIG. 1 according to an exemplary embodiment of the present invention. As shown, the illustrated system design 600 includes a housing 602 and a cart 604. The housing 602 is conceptually divided into an upper 602a and a lower 602b housing portion, including a front 606a, a rear 606b, a left 606c, and a right 606d side surface. Cart 604 includes platform 608 and wheels 610a-601d for moving System 600 between locations. The latch 603 secures the housing 602 to the cart 604. To further support portability, the system 600 has a handle 610 hinged to the upper portion 602a of the left side surface 606c of the housing 602 to the lower portion 602b of the left side 606c and right side 606d of the housing 602. Included in conjunction with two fixedly mounted handles 612a and 612b mounted.

The housing 602 further includes a removable top top surface 614 and a front panel 615 having an upper panel 613 and an intermediate panel 616 hinged to the lower panel 617 by hinges 616a and 616b. The top surface 614 includes handles 614a and 614b to aid in removal. In the illustrated embodiment, the upper panel 613 is screwed, bolted, or otherwise connected to the upper surface 614 so that the panel 613 also disengages when the upper surface 614 is removed.

As shown in FIG. 18A, the system 600 places the AC power cable 618 together with the frame 620 for fixing the power cable 618 on the lower portion 602b of the left side 606c of the housing 602. Including in the state. A software reset switch 622, also located in the lower portion 602b of the left side surface 602c, allows the operator to restart the system software and electronic components.

As shown in FIGS. 18A and 18B, the system design 600 includes an operator interface module 146 in conjunction with a cradle 623 for holding the operator interface module 146. The operator interface module 146 includes a display 624 for showing information to the operator, for example, the display screen of FIGS. 17A-17J. As mentioned above, the operator interface module 146 includes a rotatable and pressable knob 626 for selecting various parameters and a display screen of FIG. 17A-17J. The knob 626 may also be used to set parameters for automatic control of the system 100 and to manually control the operation of the system 100. For example, the knob 626 may be used to provide the controller 150 with instructions to increase the perfusate flow rate, such as gas flow rate. Further, as discussed above with respect to FIGS. 1, 14 and 17A-17J, the operator interface module 146 may include its own batteries 368, which can be removed from the cradle 623 for use in wireless mode. May be good. When inside the cradle 623, the operator interface module 146 can be charged by connecting to a power source. As shown, the operator interface module also controls pumps, stops or disables alarms, enters or exits standby mode, enters or adjusts ECG tuning mode, and manages organs. It also includes a control button 625 for activating a perfusion clock that initiates the display of the data obtained during.

As shown in FIG. 18B, the illustrated system design 600 further includes a battery compartment 628 and an oxygen tank bay 630 both located on the lower portion 602b of the right side 606d of the housing 602. As shown, the battery compartment 628 houses the three system batteries 352a-352c described above with reference to FIG. In one feature, the dry cell compartment 626 includes three dry cell locking portions 632a-632c. As described above with reference to FIG. 14, the overbattery locking portions 632a-632c mechanically interact so that only one of the three dry batteries 352a-352c can be removed at any time.

The disposable module 634 and the multi-use unit 650 are made of durable but lightweight materials. In some exemplary embodiments, polycarbonate plastic is used to form one or more of the parts of units 634 and 650. To further reduce weight, the chassis 635 and multi-use module chassis 602 are lightweight, such as carbon fiber epoxy composites, polycarbonate ABS-plastic mixes, fiberglass reinforced nylon, acetal, single ABS, aluminum or magnesium. Formed from material. In one exemplary embodiment, the overall weight of the system 100 is less than about 85 lbs, including multi-use modules, hearts, batteries, gas tanks, and priming, nutrients, preservatives and perfusate, such portions. Excluding, it is less than about 50 pounds. In another exemplary embodiment, the disposable module 634 weighs less than about 12 lbs, excluding any solution. In a further exemplary embodiment, the multi-use module 650, excluding all fluids, batteries 352a-352c and oxygen covalent 172, weighs less than about 50 lbs.

Continuing with reference to FIGS. 19A-19C, a variety of system designs 600 in FIGS. 18A and 18B, with the top surface 614 and the upper front panel 613 removed and the front intermediate panel 616 open, according to an exemplary embodiment of the invention. Drawing is shown. With reference to Figure 19A-19C, System 100 includes a single-use module 634 (shown below and detailed with reference to Figure 24A-24C) and a multi-use module 650 (shown without a single-use module in Figure 20). Is configured as. As discussed in more detail below, one feature of the exemplary embodiment is that all of the blood contact components of System 100 are contained in the Disposable Module 634 after use. You can dispose of the whole thing, install a new module 634 for reuse in a very short time, and get the system 100.

In one exemplary embodiment, the retaining module 634 includes a chassis 635 for supporting all of the components of the retaining module 634. As further detailed with reference to FIG. 24A-25C, the components of the shunt module 634 are the organ chamber assembly 104, perfusate reservoir 160 and oxygen detailed above with reference to FIG. 5A-5F. Includes adder 114, perfusate pump interface 300, all of the various fluid flow conduits, and peripheral observation component 633.

As shown in Figure 19A-20A, removing the top surface 614 and opening the front panel 616 gives the operator easy access to many of the parts of the disposable 634 and multi-use 650 modules. For example, the operator could install, remove, and observe the levels of nutrients 116 and preservatives 118 supplies in the nutrient subsystem 115. In addition, the operator could control the operation of the nutrient 116 and preservative 118 infusion pump 182. The operator could cannulate an organ, such as the heart 102, into the organ chamber assembly 104. As detailed below with reference to FIGS. 21A-21C, this configuration also provides the operator with sufficient access for attachment and detachment of the use module 634 to and from the multiple use module 650.

FIG. 20A shows a front perspective view of the multiple use module 650 with the use module 634 removed. As shown, the multi-use module 650 is: the car and 604; all of the externally mounted parts and the lower part 602b of the housing 602 with those contained inside it (Figures 21A-21C and 23A). (Refer to -23C for further details); all externally attached components to the upper part 602a of the housing 602, including the top cover 614, handles 610, 612a, and 612b, and front panel 616. Includes operator interface module 146; and perfusate pump motor assembly 106. As detailed below with reference to FIG. 21A-21C, the multi-use module 650 also includes a bracket assembly 638 for receiving and in-situ locking the storage module 534.

As shown in FIG. 20A and further detailed below with reference to FIG. 22A-22C, the multi-use module 650 further includes a circuit board at the front end of the disposable module 634 (shown at 637 in FIG. 24D). It also includes a front end interface circuit board 636 for interface. As also detailed with reference to FIG. 22A-22C, the power and drive signal connections between the multiplex module 650 and the disposable module 634 are front-end interface circuit board 636 and front-end circuit board 637, respectively. Made via the corresponding electromechanical connectors 640 and 647 above. For example, the front end circuit board 637 receives power for the disposable module 634 from the front end interface circuit board 636 via the electromechanical connectors 640 and 647. The front-end circuit board 637 further sends drive signals for various components (eg, heater assembly 110 and oxygen adder 114) from controller 150 via front-end interface circuit board 636 and electromechanical connectors 640 and 647. To receive. The front-end circuit board 637 and the front-end interface circuit board exchange control and data signals (eg, between the controller and the disposable module 134) using an optical connector (shown by 648 in FIG. 22B). As detailed with reference to FIG. 22A-22F, the configuration of the connectors used between the front end 637 and the front end interface 636 circuitry allows for significant power between the dual-use and multi-use modules 634 and 650, respectively. And data interconnections can continue to work each day, even on bumpy roads that may be encountered during organ transport.

As shown in FIG. 20A, another feature is that the upper portion 602a of the housing 602 captures any perfusate 108 and / or nutrient 116 and / or preservative 118 solution that could inadvertently leak out. Includes a fluid-dense tub 652 constructed in. The tub 652 also prevents the leaked perfusate 108 or solution 116/118 from reaching the lower portion 602b of the housing 602. In this way, the tub 652 shields the electronic components of System 100 from any such leaked perfusate 108 or solution 116/118. Blocked components include switchboard 720, which is further illustrated and detailed below, with reference to, for example, FIGS. 23C and 23D. The tub 652 includes a portion 658 that extends above the perfusate pump 106 and shields the perfusate pump 106 from any accidentally leaked fluid. Another feature is that the tub 652 is sized to fit the entire volume of perfusate 108 (including maintenance solution 116/118) contained within system 100 at some point.

Also with reference to FIG. 20B, as a further feature of the illustrated embodiment, the outer side surface 659 of the pump cover portion 658 of the tub 652 includes a slot 660. As further described below with reference to FIGS. 21A-21C and 24A, slot 660 engages the protrusion 662 of the storage module 634 when the storage module 634 is installed within the multiple use module 650. To do.

Looking at the installation of the Reservation Module 634 on the Multiple Use Module 650, FIG. 21A shows to receive the Reservation Module 634, receive the Reservation Module 634, and lock the Reservation Module 634 in place. , A detailed drawing of the bracket assembly 638 placed on the multi-use module 650 is shown. FIG. 21B shows a side perspective view of the use module 634 installed in the multiple use module 650 on the bracket assembly 638, and FIG. 21C shows the use module 634 installed in the multiple use module 650. A side view is shown. With reference to FIGS. 21A and 21B, the bracket assembly 638 includes two mounting brackets 642a and 642b that are mounted on the inner side surfaces of the rear panel 654 of the upper housing portion 602a via mounting holes 644a-644d, respectively. .. A horizontal bar 641 extends between the mounting brackets 642a and 642b and is rotatably attached to them. The locking arms 643 and 645 are spaced apart from each other and extend radially from the horizontal bar 641. Each locking arm 643 and 645 includes locking projections 643a and 645b extending downward, respectively. Lever 639 is attached to the horizontal bar 641 and extends radially upward from the horizontal bar 641. Activating the lever 639 in the direction of arrow 651 causes the locking arms 643 and 645 to rotate toward the back surface 606b of the housing 602. Activating the lever 639 in the direction of arrow 653 causes the locking arms 643 and 645 to rotate toward the front surface 606a of the housing 602.

As mentioned above with reference to FIG. 10, the perfusion pump interface assembly 300 includes four protruding heat caulking points 321a-321d. As shown in FIG. 24A, the pump interface assembly 300 is assembled by aligning the protrusions 321a-321d with the corresponding holes 657a-657d and heating the protrusions 321a-321d through the holes 657a-657d. The outer side surface 304 is immovably attached to the C-shaped bracket 656 of the module chassis 635.

Referring to FIGS. 10, 20B, 21A, 21B and 24A, during the first stage of installation, the module 634 is tilted forward (shown in FIG. 21B) while the module 634 is used multiple times. Drop in. In this process, the protrusion 662 of FIG. 24A slides into the slot 660 of FIG. 20B. As shown in FIG. 10, this further places the flange 328 of the pump interface assembly 300 within the docking port 342 of the perfusion pump assembly 106 and the tapered protrusion of the pump interface assembly 300. Parts 323a- and 323b are located on the corresponding clockwise side of one of the features 344a and 344b of the pump assembly bracket 346. In the second step, the retaining module 634 is engaged by the locking arm cradle 672 and 674 of the retaining module chassis 635 with the protrusions 643 and 645 of the spring-loaded locking arm 638. Rotate backwards until engaged with the protrusions 643 and 645, with the protrusions 643 and 645 up until the locking protrusions 643a and 645a do not interfere with the height of the locking arm cradle 672 and 674. When rotated towards (direction 651), at this point the spring causes the locking arm 638 to rotate downward (direction 653) and the locking projections 643a and 645a lock the disposable module chassis 635. It will be able to be unlockably locked to the arm cradle 672 and 674. This movement causes the curved surface 668 of the disposable module chassis protrusion 662 of FIG. 24A to rotate and engage the flat side surface 670 of the tub slot 660 of FIG. 20B. Lever 639 can be used to rotate the locking arm 638 upward (direction 651) as the retaining module 635 is released.

As shown in FIG. 10, this motion further causes the pump interface assembly 300 to rotate counterclockwise with respect to the pump assembly 106, sliding the flange 328 into slot 332 of docking port 342. At the same time, the tapered protrusions 323a and 323b are slid below the bracket features 344a and 344b. When the tapered protrusions 323a and 323b slide below the bracket features 344a and 344b, the inner surface of the bracket features 344a and 344b becomes the tapered outer surface of the tapered protrusions 323a and 323b. Engaging and pulling the inner side surface 306 of the pump interface assembly 300 towards the pump drive 334 creates a fluid tight seal between the pump interface assembly 300 and the pump assembly 106. To. Locking the lever 639 in place will allow the disposable module 634 to be securely held within the multi-use module 650.

As briefly mentioned above with reference to FIG. 20A, when the use module 374 is mutually locked in the multiple use module 650, the front end interface circuit board 636 on the multiple use module 650 and the use module An electrical and optical interconnection is formed with the front end circuit board 637 on the 634. This electrical and optical connection allows the multi-use module 650 to power, control and collect information to the utility module 634. FIG. 22A is on the front end circuit board 637 of the disposable module 634, which is used to communicate with the corresponding optical coupler and electromechanical connector on the front end interface circuit board 636 of the multiple use module 650. It is a conceptual diagram which shows various optical couplers and electromechanical connectors. Since this correspondence is one-to-one, various optical couplers and electromechanical connectors are described with reference only to the front-end circuit board 637, not also to the front-end circuit board 650.

In an exemplary embodiment, the front end circuit board 637 receives a signal from the front end interface circuit board 636 via both an optical coupler and an electromechanical connector. For example, the front end circuit board 637 receives power 358 (also shown in FIG. 14) from the front end interface circuit board 636 via the electromechanical connectors 712 and 714. The front end circuit board 637 then supplies power to the components of the storage module 634, such as the various sensors and converters of the storage module 634. Optionally, the front end circuit board 637 converts this power to a suitable level before distribution. Further, the front end interface circuit board 636 provides the heater drive signals 281a and 281b of FIG. 13 to the applicable connection points 282a on the heater 246 of FIG. 6E via electromechanical connectors 704 and 706. Similarly, the electromechanical connectors 708 and 710 connect the heater drive signals 283a and 283b of FIG. 13 to the applicable connection point 282b of the heater 248. The front-end circuit board 637 may receive a defibrillation command from the front-end circuit board 636 via the electromechanical connector 687. In response, the front end circuit board 637 generates a defibrillation signal 143 with suitable current and voltage levels, which electrical interface to the organ chamber assembly 104, as shown in FIG. 5E. Connect via connection points 235a-235b.

In another exemplary embodiment, 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 FIGS. 5E and 1, an external defibrillator can be plugged into the electrical coupler 613 shown in FIG. 24E, which is connected to electrical interface connection points 235a-235b. The external defibrillator sends a defibrillator signal 143 to electrodes 142 and 144 through combiner 613 and interface junctions 235a and 235b. Electrodes 142 and 144 then deliver this signal 143 to the heart 102. This alternative embodiment allows the user to provide defibrillation (and pacing) without passing signal 143 through circuit boards 618, 636, and 637. An example of an external defibrillator would include the Zoll M-series portable defibrillator.

According to the exemplary embodiment described above, the front end circuit board 637 receives signals from temperature, pressure, fluid flow velocity, oxygenation / hematocrit and ECG sensors, amplifies these signals and digitalizes these signals. -Convert to formats and provide them to the front end interface circuit board 636 using an optical coupler. For example, the front end circuit board 637 provides a temperature signal 121 from the sensor 120 on the heater plate 250 (shown in FIGS. 6A and 13) to the front end interface circuit board 636 via an optical coupler 676. Similarly, the front end circuit board 637 provides the temperature signal 123 from the sensor 122 on the heater plate 252 (shown in FIGS. 6A and 13) to the front end interface circuit board 636 via the optical coupler 678. .. Further, the front end circuit board 637 provides the perfusate temperature signals 125 and 127 from the thermistor sensors 124 (shown in FIGS. 6A and 13) to the front end interface circuit board 636 via the optical couplers 680 and 682, respectively. To do. Perfusate pressure signals 129, 131 and 133 are provided from the pressure transducers 126, 128 and 130 to the front end interface circuit board 636 via the optical couplers 688, 690 and 692. Further, the front end circuit board 637 provides the perfusate flow velocity signals 135, 137 and 139 from the flow velocity sensors 134, 136 and 138 to the front end interface circuit board 636 via the optical couplers 694, 696 and 698. To do. In addition, the front end circuit board 637 provides oxygen saturation 141 and hematocrit 145 signals from the oxygen saturation sensor 140 to the front end interface circuit board 636 via the optical couplers 700 and 702, respectively.

In another exemplary embodiment, one or more of the above sensors are wired directly to the main system panel 718 (discussed below with reference to FIG. 23D) for processing and analysis. The front end interface board 636 and the front board 637 are bypassed together. Such an embodiment would be preferred if the user wants to reuse one or more of the sensors until disposal. In one such example, the flow velocity sensors 134, 136 and 138 and the oxygen and hematocrit sensors 140 are electrically connected directly to the system main board 718 through the electrical coupler 611 shown in FIG. 23C to provide a circuit board. Bypass both connections with 636 and 637.

As mentioned above with respect to FIG. 11-16, the controller 150 utilizes the signal provided to the front end interface circuit board 636 along with other signals to transmit data, otherwise the system 100. Control the operation. As described with reference to FIGS. 17A-17J, the controller 150 further displays sensor information, but the operator may be presented with various alarms related to the sensor information via the operator interface module 146. ..

FIG. 22B shows the operation of an exemplary electromechanical connector pair of the types used for electrical interconnection between circuit boards 636 and 637. Similarly, FIG. 22C shows the operation of the type of optical coupler pair used for the optically connected interconnect between circuit boards 636 and 637. One of the advantages of using both electrical connectors and optical couplers is that they allow them to be mounted on wheels, for example on the runway of an airport, transported within an airport in bad weather, or ambulances on bumpy roads. This is to ensure the integrity of the connection, even when the system 100 is transported over bumpy roads, such as when transported by. In addition, the optical coupler electrically insulates the temperature, pressure and ECG sensors from the rest of the system 100, preventing defibrillation signals from damaging the system 100. The power for the front end board 637 is isolated in a DC power source located on the front end interface board 636.

As shown in FIG. 22B, the electromechanical connector such as the connector 704 is the electromechanical connector such as the connector 704 with a portion such as portion 703 and a front end located on the front end interface circuit board 636. Includes parts such as part 705, located on the circuit board 637. Part 703 includes an enlarged head 703 mounted on a substantially straight and rigid stem 703b. The head 703 includes a substantially flat surface 708 facing outward. The portion 705 includes a substantially straight and rigid pin 705, including an end 705a in contact with the surface 708 and a spring loaded end 705b. The pin 705 can maintain electrical contact with the surface 708 of the magnified head 703a while moving in and out axially as indicated by the directional arrow 721. This feature allows the storage module 634 to maintain electrical contact with the multi-use module 650 even during the mechanical impact associated with transportation on bumpy roads. The advantage of the flat surface 708 is that it allows easy cleaning of the inner surface of the multi-use module 650. In this exemplary embodiment, the system 100 utilizes connectors for electrical interconnection between disposable 634 and multi-use 650 modules. An example of a connector is number 101342 manufactured by Interconnect Devices. However, any suitable connector may be used.

Optical couplers such as the optical couplers 684 and 687 of the front end circuit board 637 are used, among which the corresponding relatives such as the optical couplers 683 and 685 of the front end interface circuit board 636 are used. included. The optical transmitter and optical receiver portion of the optical coupler may be located on either the circuit board 636 or 637. For example, in the case of the ECG signal 379, the optical transmitter 684 is located on the circuit board 637 to receive the electrical signal 379 and optionally connect it to the optical receiver 683 on the circuit board 636. If the defibrillation signal is transmitted through circuit boards 636 and 637 (rather than being sent directly to the main board 718), the optical transmitter 685 on circuit board 636 selectively sends this signal to circuit board 637. Connect to the optical receiver 687 above.

As with the electromechanical connector used, due to the optical alignment tolerance between the optical transmitter and the corresponding optical receiver, circuit boards 636 and 637 are optical even during transportation on bumpy roads. Stay in touch. In the illustrated embodiment, system 100 is part number SFH485P and / or SFH203PFA by Osram. The optical coupler manufactured in is used. However, any suitable coupler may be used.

The coupler and connector facilitate data transmission within the system 100. The front-end interface circuit board 636 and the front-end board 637 transmit data about the system 100 at intervals. As shown in FIG. 22C, the circuit board 636 transmits a clock signal synchronized with the clock signal meter to the front end board 637. The front-end circuit board 637 receives this clock signal and uses it to synchronize its system data (temperature, pressure ECG, r-wave detection, or other desired information) transmission with the clock period of controller 150. .. This data is digitized by the front-end circuit board 637 processor according to the clock signal and the order of the preset data type and source address (ie, the type and location of the sensor providing the data). Will be done. The front end interface circuit board 636 receives data from the front end board 637, transmits this data set to the main board 618, and evaluates, as described above with reference to FIGS. 11, 12 and 14. Directed to the use of controller 150 in display and system control. An additional optical coupler can be added between the multiple use module and the single use module to allow control data from the multiple use module to be transmitted to the single use module, including a heater control signal or a pump control signal.

Having described the mechanical, electrical and optical interconnections between the single-use module 634 and the multi-use module 650, the additional components of the multi-use module 650 are discussed below with reference to Figures 23A-23D. Next, the mechanical configuration of the parts of the module 634 will be explained with reference to FIGS. 24A-28C. When the wall of the housing 602 is removed, as shown in Figure 23A-23D, the multi-use module 650, in addition to the parts discussed so far, has an on-board gas supply 172 located in the lower part 602b of the 602 today. Including. The gas supply unit 172 is shown as a tank in FIGS. 23A-23D and is arranged in the gas tank bay 630 by an instruction structure 712 that abuts on the tank 172. Optionally, the gas supply 172 may be further secured within the gas tank bay 630 by a string and buckle assembly 714 or other suitable mechanism. In particular, with reference to FIG. 23B, and as described above with reference to FIG. 1, the gas supply unit 172 provides the system 100 with gas via the gas regulator 174 and the gas flow chamber 176. The gas pressure sensor 132 measures the gas pressure at the gas supply unit 172, and the gas pressure gauge 178 provides a visual indicator of the filling degree of the gas supply unit 172. In addition, the electrical connection between the controller 150 and the gas flow chamber 176 allows the controller 150 to automatically regulate the gas flow to the oxygen adder 114.

As most clearly shown in Figure 23C, battery bay 628 houses batteries 352a-352c. As described above with reference to FIG. 14, a locking mechanism is used to prevent two or more of the batteries 352a-352c from coming off the battery bay 628 at any point during system 100 operation.

As discussed above, the system 100 includes a plurality of interconnected circuit boards to facilitate power distribution and data transmission to and from the system 100. In particular, as discussed above with reference to FIGS. 22A-22E, and as shown in FIG. 23C, the multiple use module 650 is optically and electromechanically to the front end circuit board 637 of the use module 650. Includes front end interface circuit board 636 to connect. Further, as shown in FIG. 23C, the system 100 further includes a main board 718, a power circuit board 720, and a battery interface board 711 arranged on the multiple use module 650. The main board 718 is a system 100 in that the main board 718 stores pumping and heating parameters in non-volatile memory in the event of a failure in the operation of a circuit board (as shown in Figure 23D). It is configured to be fault tolerant. When System 100 reboots, it can recapture such parameters and continue to run.

With reference to the conceptual diagram of FIG. 23D, the cabling 731 carries power (eg, AC power 351) from power supply 350 to power circuit board 720 via connectors 744 and 730. The power supply unit 350 converts AC power into DC power and distributes this DC power as described above with reference to the power subsystem of FIG. Further referring to FIGS. 14 and 22A, the power circuit board 720 connects DC power and data signal 358 via cables 727 and 729 from connectors 726 and 728 to the corresponding connectors 713 and 715 of the front end interface circuit board 636. Connect to. Cable 729 carries both power and data signals to the front end interface panel 636. Cable 727 carries power to the heater 110 to the front end interface board 636. The connectors 713 and 715 are fitted with the corresponding connectors 712 and 714 (described above with reference to FIG. 22A) of the front end circuit board 637 of the recess module 634 to provide power to the recess module 634.

As shown in FIG. 23D, the power circuit board 720 further cables 733 and 735 DC power 358 and data signals from connectors 732 and 734 of the power circuit board 720 to the corresponding connectors 736 and 738 of the main circuit board 718. Provided through. Further referring to FIGS. 14 and 19A, the cable 737 transfers DC power 358 and data signals from connector 740 of the main circuit board 718 to operator interface module 146 via connector 742 of operator interface module cradle 623. Connecting. In addition, the power circuit board 720 provides DC power 358 and data signals from connectors 745 and 747 to connectors 749 and 751 of the battery interface board 711 via cables 741 and 743. Cable 741 carries DC power signals, and cable 743 carries data signals. The dry cell interface board 711 distributes DC power and data to the dry batteries 352a, 352b and 352c. Since the batteries 352a, 352b and 352c contain electronic circuits that allow them to communicate with each other to observe each charge, as described above with reference to FIG. 14, the controller 150 contains the batteries 352a-. The charging and discharging of the 352c can be observed and controlled.

In some illustrated embodiments, the controller 150 is located on the main circuit board 718 to perform all the controls and processing required by the system 100. However, in other exemplary embodiments, the controller 150 is distributed down, some processing functions are located on the front end interface circuit board 636, some are located on the power circuit board 720, and / Alternatively, some are located in the operator interface module 146. Depending on whether the controller 150 is distributed within the system 100 and the degree of distribution, suitable cabling is provided among the various circuit boards.

As mentioned above with reference to FIGS. 19A-19C and 23A-23C, the system 100 is mechanically divided into a disposable module 634 and a multi-use module 650. As mentioned above, in an exemplary embodiment, the idle module 634 has all or substantially all of the perfusate 108 contact element / assembly of system 100, a variety of peripheral components, flows for activating blood contact components. Included, along with conduits, sensors and support electronics. As discussed above with reference to FIGS. 22A and 23D, according to an exemplary embodiment, module 634 does not include a processor and instead, for example, front end interface circuit board 636, power circuit board 720, operation. It relies on a controller 150, which may be distributed for control between the interface module 146 and the main circuit board 718. However, in other exemplary embodiments, the discretionary module 634 may include its own controller / processor, eg, on the front end circuit board 637.

With reference to FIGS. 24A-28C, the module 634 will be explained next from the viewpoint of the parts contained therein. An exemplary forward and reverse flow mode is then tracked through the described parts.

With reference to FIG. 24A first, the disposable module 634 includes a chassis 635 with upper 750a and lower 750b portions. The upper part 750a contains a platform 752 that supports a variety of components. The lower portion 750b supports the platform 752 and includes a structure that swingably connects to the multi-use module 650. More specifically, the lower chassis portion 750b slides into and elastically into slot 660 of FIG. 20B with a C-shaped fixture 656 that is fixedly attached to the perfusate pump interface assembly 300. Includes a protrusion 662 that fits into. In addition, the lower chassis portion 750b also provides a structure for mounting the oxygen adder 114. As shown in FIGS. 25A and 25C, the lower portion 750b further includes a structure for mounting the heater assembly 110. In addition, the reservoir 160 is mounted underneath the platform 725 and extends into the lower chassis portion 750b. O₂Saturation and hematocrit sensor 140 (shown in Figure 24A, detailed below with reference to Figures 28A-28C), flow velocity sensor 136 (shown in Figure 24A), flow velocity sensor 138 (shown in Figure 25B), and more. Sensors are placed and / or mounted within the lower chassis portion 750b. The flow pressure compliance chamber 188 (shown in Figure 25B) is also located in the lower chassis portion 750b. As shown in FIG. 24D, the lower chassis portion 750b is further attached to the front end circuit board 637. The conduits located within the lower chassis portion 750b are further detailed below with reference to the normal and retrograde flow paths through the storage module 634.

With reference to Figure 24A-25C, and as mentioned above, the upper chassis portion 750a includes the platform 752. Platform 752 includes handles 752a and 752b formed to assist installation and attachment / detachment of the use module 634 to the multiple use module 650. Alternatively, such handles can be placed on platform 757 for easy access when installing the use module on the multi-use module. As most clearly shown in Figure 24C, the tilted platform 757 is mounted on platform 752. The organ chamber assembly 104 is attached to this tilted platform 757. In the illustrated embodiment with the use module 634 installed in the multiple use module 650, the platform 757 is tilted approximately 10 to about 80 degrees horizontally and is located within the organ chamber assembly 104. At that time, it is the optimum operating angle for the heart 102. In some exemplary embodiments, the platform 757 is tilted from about 20 degrees to about 60 degrees, or about 30 degrees to about 50 degrees with respect to the horizontal. The flow mode selection valve 112, flow rate sensor 134, and perfusion flow pressure compliance chambers 184 and 186 are also mounted on the tilted platform 757.

With reference to Figure 24E, several perfusate ports are installed on platform 752. For example, perfusate sampling port 754 allows the operator to sample perfusate inflowing and / or outflowing into the aorta 158 via the cannula insertion interface 162 of the organ chamber assembly 104. The perfusate sampling port 755 also allows the operator to sample perfusate inflowing and / or outflowing into the left atrium 152 via interface 170 of the organ chamber assembly 104. In addition, the perfusate port 758 allows the operator to sample the coronary flow out of the pulmonary artery 164 through the pulmonary artery interface 166 of the organ chamber assembly 104. In an exemplary embodiment, the operator can rotate each valve 754a, 755a or 758a to obtain fluid flow from sampling ports 754, 755 and 758. The flow from the particular port selected is provided by one common outlet 764. As a feature, only the flow from the leftmost selected port is provided at the outlet 764. As an example, when the operator opens both ports 755 and 758, only the liquid flow from port 755 is provided at outlet 764. In this way, the system 100 reduces the possibility of the operator mixing samples from multiple ports.

The single-use module 634 also includes a general purpose injection port that can be operated with a valve 762a to allow the operator to inject the drug into the perfusate 108 via a reservoir 160 or the like. Both sampling 764 and inhalation 762 ports are mounted on platform 752. Further, the upper chassis portion 750a is provided with an injection port 766 that can be operated by a valve 766a to allow the nutrient 116 and the preservative 118 to flow into the perfusate 108. Further, the upper chassis portion 750a contains a tube 774 that fills the reservoir 160 with phlebotomy from the donor. As shown in FIG. 24D, the waste module 634 also includes a non-exhaust cap that replaces the exhaust cap of the selected fluid port used during the flow of sterile gas through the waste module 634 during sterilization. Preferably, such sterilization is performed prior to packing the storage module 634 for sale.

The upper chassis portion 750a further includes a flow clamp 190 for cannulating the heart 102 and adjusting the negative pressure applied to the left atrium 152 while operating in normal flow mode within the organ chamber assembly 104. The upper chassis portion 750a further includes a trickle valve 768. By opening and closing this trickle valve 768 with the handle 768a, a slight fluid flow to the left atrium 152 may be adjusted to moisten the left atrium 152 during the retrograde mode. The upper chassis portion 750a further includes a port 770 for injecting additional solution and a port 772 for purging the oxygen accumulator 114 operable at each valve 770a and 772a.

As most clearly shown in FIGS. 24A and 24D, the upper chassis portion 750 further includes the penstock probes 126, 128 and 130. As described above with reference to FIG. 1, probe 126 measures the pressure of perfusate 108 in and out of the aorta 158. The probe 128 measures the pressure of perfusate 108 in and out of the left atrium 152 through the pulmonary vein 168. The probe 130 measures the pressure of the perfusate 108 flowing out of the pulmonary artery 164. Each probe includes connectors 126a, 128a and 130a (shortened for clarity) to connect signals 129, 131, and 133 to the front end circuit board 637.

Reservoir 160 contains several parts, especially with reference to the cross-sectional side view of Module 654, FIG. 24C. More specifically, the Reservoir 160 includes four inlets 782, 784, 786 and 788. The suction port 782 transfers the perfusate 108 from the drain 201 of the organ chamber 194 to the reservoir 160. The inhalation port 784 receives phlebotomy from tube 774. The inhalation port 786 receives the oxygenated perfusate 108 from the oxygen adductor 114, and the inhalation port 788 receives the perfusate 108 from the aorta 158 via the back pressure clamp 190. The reservoir 160 also has a discharge port 790 that provides the perfusate to the one-way suction valve 191. Reservoir 160 contains defoaming agent 778 and filter 780. Defoamer 778 removes foam from the perfusate as it enters Reservoir 160. According to an exemplary embodiment, the defoaming agent is formed from a porous polyurethane foam coated with a defoaming agent. The filter 780 is a polyester felt that filters out debris, blood particles, embolisms, and bubbles as the perfusate enters the reservoir 160.

As mentioned above in the overview, the O used in the module 634₂The saturation and hematocrit sensor 140 has important advantages over conventional methods. Figures 28A-28C show the O of the present invention.₂An exemplary embodiment of the saturation and hematocrit sensor 140 is shown. As shown in FIG. 28A, the sensor 140 includes an in-line cuvette portion of the tube 812 connected to the conduit 798, which in-line cuvette portion is the optics through which the infrared sensor can provide infrared light. It has at least one window that is transparent to the surface. An example of a sensor used in an in-line cuvette tube 812 is the Datamed BL0P4. As shown in the cross-sectional view of FIG. 28B, the cuvette 812 is an integrally molded portion having connectors 801a and 801b. The connectors 801a and 801b are configured to be adjacent to the connecting receptors 803a and 803b of the conduits 798a and 798b, respectively. Such an interconnection between the cuvette 812 and the conduit ends 798a and 798b is configured so that the cross-flow area inside the conduit 798 and the cuvette 812 is substantially constant. This configuration thus reduces the discontinuity at interfaces 814a and 814b between the cuvette 812 and conduit 798, and is substantially eliminated in some embodiments. Due to the reduction / removal of discontinuities, the blood-based perfusate 108 is less lysed and disturbed by red blood cells and can flow through the cuvette, resulting in a more accurate reading of perfusate oxygen levels. This also reduces the damage to the perfusate 108 by the system 100 and ultimately the damage to the heart 102 during perfusion by the system 100.

According to an exemplary embodiment, the cuvette 812 is formed from any suitable light-transmitting material such as light-transmitting glass or polymer. As shown in FIG. 28A, the sensor 140 further directs a light wave to the perfusate 108 passing through the cuvette 812 and measures light transmission and / or light reflectance to determine the amount of oxygen in the perfusate 108. Includes an optical transmitter / receiver 816 for As shown in FIG. 28C, in some embodiments, the optical transmitter / receiver is located on one side of the cuvette 812 and the detector that measures the light transmission through the perfusate 108 is located on the opposite side of the cuvette 812. To. FIG. 28C shows an upper cross-sectional view of the cuvette 812 and the transmitter / receiver 816. In the transmitter / receiver 816, the flat surfaces 811 and 813 inside the transmitter / receiver face the flat surfaces 821 and 823 of the cuvette, respectively, while the convex surface inside the transmitter / receiver 816 is the convex surface 819 of the cuvette 812. Fits around the cuvette 812 so that it faces. During operation, when UV light passes through the transmitter / receiver 816, it travels from the flat surface 811 through the perfusate 108 in the cuvette 812 and is received by the flat surface 813. This flat surface 813 could be configured with a detector that measures the light transmission through the perfusate 108.

The liquid flow path through the idle module 634 in both normal and retrograde modes will be described with reference to FIGS. 24A-24D and 25A. As described above with reference to FIG. 1-4, the system 100 can maintain the heart 102 in two modes of operation: the normal flow mode shown in FIG. 3 and the retrograde flow mode shown in FIG. As mentioned above with reference to FIG. 1, the system 100 provides a liquid flow mode selection valve 112 detailed in FIGS. 26A and 26B to switch between normal flow and retrograde flow modes. To operate in normal flow mode, the operator sets the liquid flow mode selection valve handle 112e to the position shown in FIG. 24A. This has the effect of aligning the flow path through the selection valve 112 as shown in FIG. 26A. Specifically, in normal flow mode, perfusate can flow into port 112b through the flow channel 112f and out of port 112c. In addition, perfusate can flow into and out of port 112d through the flow channel 112g. To operate in retrograde mode, the operator sets the liquid flow mode selection valve handle 112e to the position shown in FIG. 24B. This has the effect of aligning the flow path through the selection valve 112 as shown in FIG. 26B. Specifically, in retrograde mode, perfusate can flow into port 112b through the flow channel 112h and out of port 112d.

With reference to FIG. 24A, in normal flow mode, the reservoir 160 provides the perfusate 108 to the unidirectional injection valve 191 of the perfusion pump interface assembly 300. Referring to FIG. 25A, the perfusion pump 106 draws the perfusate 108 out of the discharge valve 310. Referring to FIG. 25C, the perfusate 108 then flows through conduit 792 and compliance chamber 188 into the suction port 110a of the heater assembly 110. The heater assembly 110 heats the perfusate 108 and then drains it through the heater outlet 110b. Referring to FIG. 24A, the heated perfusate 108 flows from the heater outlet 110b of the lower chassis portion 750b through the chassis plate 752 into the port 112b of the mode selection valve 112 via the conduit 794. Referring to FIG. 24D, perfusate 108 flows from mode valve port 112c through compliance chamber 186, conduit 796 and pressure sensor 128 into the pulmonary vein cannula insertion interface 170 of organ chamber assembly 104.

Referring to FIG. 24A, in normal flow mode, the heart 102 aspirates the perfusate 108 from the pulmonary artery 164 through the pulmonary artery interface 166 and the pressure sensor 130. Conduit 796 then perfusate 108 from pulmonary artery interface 166 through plate 752, and O₂Flow through saturation and hematocrit sensor 140. Referring to FIGS. 25A and 25C, the conduit 798 then causes the perfusate 108 from the sensor 140 to flow into the oxygen adder 114 through the flow rate sensor 136. The conduit 800 returns the perfusate 108 from the oxygen adder 114 into the reservoir 160 via the reservoir inlet 786.

With reference to FIGS. 24A, 24D and 24E, in normal flow mode, the heart 102 also sucks perfusate 108 from the aorta 158 through the aorta interface 162 and the pressure sensor 126. The conduit 802 flows the perfusate 108 from the pressure sensor 126 through the flow rate sensor 134 and returns it into the port 112d of the liquid flow mode selection valve 112. Clamp 804 holds conduit 802 in place. The conduit 806 drains the perfusate 108 from the fluid flow mode selection valve 112 through the compliance chamber 184 and the back pressure adjustment clamp 190 through the port 112a. As mentioned above, the clamp 190 is designed to regulate the back pressure exerted on the aorta 158 during normal flow mode by limiting flow through conduit 806 to more ideally simulate normal physiology. You may adjust. This compliance chamber 184, which can expand and contract as the perfusate 108 pumps in and out of the compliance chamber 184, works normally by interacting with the clamp 190 to dampen the flow pressure spikes. Further improve the simulation of physiological conditions close to. The clamp 190 after loading is configured to mimic the systemic vascular resistance of the human body affecting aortic pressure, left atrial pressure and coronary flow. The conduit 808 returns the perfusate 108 into the reservoir 160 through the reservoir suction port 788.

In retrograde mode, the liquid flow mode selection valve 112 is arranged as shown in FIG. 24B. With reference to FIG. 24B, the reservoir 160 provides the perfusate 108 to the inlet valve 191. As shown in FIG. 25A, the perfusion pump 106 sucks the perfusate 108 out of the discharge valve 310. As shown in FIG. 25C, the perfusate 108 then flows through conduit 792 into the compliance chamber 188 and the suction port 110a of the heater assembly 110. The heater assembly 110 heats the perfusate 108 and then causes it to flow out of the heater outlet 110b. Referring to FIG. 24B, the heated perfusate 108 flows from the heater outlet 110b of the lower chassis portion 750b through the chassis plate 752 to the inlet 112b of the mode selection valve 112 via the conduit 794. Further referring to FIG. 24D, the perfusate 108 flows from the mode valve outlet 112d into the conduit 802 through the flow velocity sensor 134 and the pressure sensor 126 into the aorta 158 and through the aorta interface 162. The perfusate 108 then flows through the coronary sinus 155 and other parts of the coronary structure.

Referring to FIG. 24B, in retrograde mode, the heart 102 pumps perfusate 108 from the pulmonary artery 164 through the pulmonary artery interface 166 and the pressure sensor 130. Conduit 796 then drains perfusate from pulmonary artery interface 166 through plate 752, and O₂Saturation and flow into the hematocrit sensor 140. Further also referring to FIGS. 25A and 25C, the conduit 798 then causes the perfusate 108 from the sensor 140 to flow into the oxygen adder 114 through the flow rate sensor 136. The conduit 800 returns the perfusate 108 from this oxygen adder 114 to the reservoir 160 via the reservoir suction port 786. In retrograde mode, virtually no perfusate is pumped into or sucked into the left atrium 152 via the pulmonary vein 168 and the pulmonary vein interface 170, with the exception of A small amount of perfusate is branched from the conduit 794 around the flow mode selection valve 112 to the compliance chamber 186 by the trickle valve 768. As mentioned above, this trickle provides sufficient perfusate 108 to keep the left atrium 152 moist during retrograde flow.

As mentioned above, the system 100 of the exemplary embodiment has one or more sensors or probes for measuring fluid flow and pressure. Standard commercially available probes and / or sensors will be available. The flow velocity sensors 134, 136 and 138 are conventional ultrasonic flow sensors, such as those available from Transonic Systems, Ithaca, NY. Hydraulic probes 126, 128 and 130 are MSI or GE It may be a conventional strain gauge pressure sensor available from Thermometrics. Alternatively, a pre-calibrated pressure transducer chip can be embedded within the organ chamber connector and wired to a data collection site such as the anterior end disc 637.

Having described the electrical and mechanical components and functionality of System 100 in an exemplary embodiment, and some of their modes of operation, the System 100 is then referenced in the illustrated organ collection and transplantation methods in Figures 29A and 29B. I will explain while doing it. More specifically, FIG. 29A is a flow diagram 900 showing an example of a method of collecting a donor heart 102 and cannulating it into system 100 at the donor location. FIG. 29B shows specific points to keep in mind when manipulating the heart 102 during cannulation adjustment, and FIG. 30 is an example of how the donor organ 102 is removed from system 100 and transplanted into the patient at the recipient site. It is a negative row figure 902 of.

As shown in FIG. 29A, the process of obtaining and adjusting the heart 102 for cannulation and transport begins with providing a suitable organ donor 904. The process of transporting this organ donor to the donor location and receiving and adjusting the donor heart 102 for cannulation and transport proceeds through two intersecting pathways 906 and 908. Route 906 primarily involves adjusting the donor heart 102 for transplantation, while Path 908 primarily receives the donor heart 102 and then recipients this heart 102 through system 100. Includes steps to adjust System 100 for transport to the site.

With particular reference to FIG. 29A, the first pathway 906 includes step 910 to exsanguinate the donor, step 914 to stop the donor's heart, step 916 to explant the heart, and the heart towards cannulation into system 100. Includes step 918 and adjusting 102. Specifically, in phlebotomy step 910, donor blood is taken and set aside for use in perfusion of heart 102 during storage in System 100. This step is performed by inserting a catheter into the vascular structure of either the donor's arteries or veins, thus allowing the donor's blood to flow out of the donor and collect in a blood collection bag. The donor's blood is drained until the required blood volume, typically 1.0-2.5 liters, has been collected, at which point the catheter is removed. The blood extracted by phlebotomy is then filtered and added to the perfusate reservoir 160 of system 100 as a conditioning step for use in the system. Alternatively, blood can be exsanguinated from the donor and white blood cells and platelets can be filtered in a single step using a device with a filter integrated into the cannula and blood collection bag. An example of such a filter is Pall BC2B filter. As an adjustment for the collection of the heart 102, after phlebotomy of the donor's blood, the donor's heart 102 is injected in step 914 with a cardiac paralytic solution to temporarily stop the beating.

After stopping the heart 102, the heart 102 is explanted from the donor 916 and adjusted for loading into the system 100 918. In general, step 916 to explant the heart and step 918 to adjust for loading are steps to disconnect the connection between the vascular liver of the heart 102 and the donor's internal thoracic cavity, and various disconnected connections. Includes a step of suturing the heart and then lifting the heart 102 from this thoracic cavity.

More specifically, as shown in FIG. 29B, the right and left pulmonary arteries 164a and 164b are cut and the dorsal artery 164a is tied with surgical suture 901a or other suitable mechanism. This fastening prevents the perfusate from flowing out through the amputated end 903a of the left dorsal artery 164a. As described above with reference to FIGS. 24A-24B, the perfusate 108 is routed through the left pulmonary artery 164b by leaving the left pulmonary artery 164b unfastened and allowing it to be cannulated into the organ chamber assembly 104. , Flow through the pulmonary artery cannula insertion interface 170 and return to the reservoir 160. The left pulmonary veins 168b and 169b and the right pulmonary veins 168a and 169b are also cut and all but one pulmonary vein 169b are tied with surgical sutures 901b, 901c, and 901d, respectively. This impedes the flow of perfusate from the amputated ends 903b and 903c of the right pulmonary veins 168a and 169a or the amputated ends 903d of the left pulmonary vein 168b, but organs unconcluded pulmonary veins. It can be cannulated into the chamber assembly 104 through the pulmonary vein interface 170. As described above with reference to FIGS. 24A-24B, this configuration allows perfusate 108 to flow through the right pulmonary artery 164b, through the pulmonary artery interface 166, and back into the oxygen adder 114. Alternatively, blood can be exhaled from the right ventricle, which is cannulating the pulmonary trunk. The pulmonary trunk is not shown, but includes the 164 portion of the pulmonary artery between the branches 164a and 164b of the pulmonary artery 164 and the right ventricle 159. The superior vena cava 161 is also cut and the heart is connected to the system 100 and tied with a thread 901e when the beating begins to prevent perfusate from flowing out of its end 903e. The inferior vena cava 163 is also cut and tied with thread 901f or overlocked to prevent perfusate from flowing out of its end 903f. The aorta 158 is also cut (at a point downstream from the coronary sinus 155 in the illustrated embodiment), but not tied and the organ cha Allow it to be cannulated into the number assembly 104. In one embodiment, the aorta 158 is cannulated into the aorta connector so that it can be easily attached to the aorta interface 170.

Continuing with reference to the flowchart of FIG. 29A, after cutting and appropriately tying the vascular structure of the heart, the heart 102 is inserted into the organ chamber assembly 104, and the aorta 158, left pulmonary artery 164b, and pulmonary vein 169b are inserted into the organ chamber. Load the system 100 by cannulating the assembly 104 in a suitable location.

Often, a heart obtained from a donor, such as one that also donated lungs, may have lost some or all of the left atrium 152. In this case, the aorta 158 is still cannulated with either the right pulmonary artery 164a or the pulmonary trunk (not shown, but described above) and the remaining 152 portion of the left atrium is retained during storage. By leaving it open, the heart 102 can be utilized and perfused in retrograde mode.

Continuing with reference to FIG. 29A, during adjustment of the heart through route 906, system 100 is primed as soon as heart 102 is adjusted and waits for heart 102 for cannulation and transport in route 908. Adjusted through steps. By rapidly transporting the heart 102 from the donor to the system 100 and subsequently perfusing the heart 102 with perfusate 108, the medical operator reduces the amount of time oxygen and other nutrients are depleted from the heart 102. This allows it to reduce ischemia and other adverse effects that occur with current organ management techniques. In some embodiments, the amount of time between infusion of the cardiac paralytic solution into the heart and the flow of perfusate 108 into the heart 102 through the system 100 is less than about 15 minutes. In other exemplary embodiments, the time during this period is less than about half an hour, less than about an hour, less than about two hours, or even less than about three hours. Similarly, the time between the time when the heart is transplanted into the organ management system 100 and the time when the heart 102 is brought to a temperature close to physiological temperature (for example, about 34 ° C to about 37 ° C) is within the heart tissue. It's a quick time to reduce ischemia in the heart. In some exemplary embodiments, the time is less than about 5 minutes, but in other applications, less than about half an hour, less than about an hour, less than about two hours, or less than about three hours. There may even be. In some exemplary embodiments, the heart can be transferred directly from the donor to System 100 without the use of a heart attack, and in such applications, at the time of passing 108 streams of warm perfusate, and /. Alternatively, the time point at which the heart reaches a temperature close to physiological temperature is similarly less than about 5 minutes, less than about 1/2 hour, less than about 1 hour, less than about 2 hours, or even less than about 3 hours. In one embodiment, the donor's heart is not stopped prior to removal from the donor and the heart 102 is placed in system 100 while still beating.

As shown in FIG. 29A, the system 100 is tuned on path 908 through a series of steps, in which the step of adjusting the shunt module 634 (step 922), priming the system 100 with a priming solution. (Step 924), filtering blood from the donor and adding it to System 100 Reservoir 160 (Step 912), and connecting the heart 102 to System 100 (Step 904). Specifically, step 922 of adjusting the waste module 634 includes assembling the disposable module 634. Suitable assemblies are shown, for example, in FIGS. 24A-24D, 25A-25C, and 26. After assembling module 634 or providing it in a suitable assembly, it is inserted into the multi-use module 650 through the process described above with reference to Figure 21A-21C.

In step 924, the loaded system 100 is primed with a priming solution as described in more detail below with reference to Table 1. In one feature, to aid in priming, System 100 provides the organ bypass conduit 810 shown mounted in the organ chamber assembly 104 of FIG. 27A. As shown, the bypass conduit comprises three segments 810a-810c. Segment 810a is attached to the pulmonary artery cannula insertion interface 170. Segment 810b is attached to the aortic cannula insertion interface 810b, and segment 810c is attached to the pulmonary vein cannula insertion interface 166. By using the / cannulated bypass conduit 810 thus attached to the organ chamber assembly 104, the operator circulates the perfusate 108 through the system 100 through all of the pathways used during actual operation. be able to. This allows the system 100 to be thoroughly inspected and the heart 102 to be primed prior to in-situ cannulation.

In the next step 912, blood from the donor is filtered and added to Reservoir 160. This filtration process reduces the inflammatory process by completely or partially removing white blood cells and platelets. In addition, donor blood is mixed with one or more nutrients 116 and / or preservative 118 solutions to form perfusate 108. In step 926, the perfusate 108 is pumped into the system 100 in retrograde mode, as described above with reference to FIG. 24B, and with the bypass conduit 810 in place. Prime with. While the perfusate 108 circulates through the system 100 in priming step 926, it is warmed to the desired temperature as it passes through the heater assembly 110. This desired non-degree range and application of heating are described with reference to FIGS. 6A-6E and with respect to FIG. In step 920, after priming the system 100 with perfusate 108, the bypass conduit 810 is removed and the heart 102 is installed in the system 100 as described above and as shown in FIG. 27B.

After the heart 102 is installed in the system 100, the pump 104 is activated, the fluid flow mode valve 112 is placed in retrograde mode (described above with reference to FIGS. 1 and 4), and the perfusate 108 is placed in retrograde mode. Pump into the vascular structure of heart 102 through the aorta. By pumping a warm, oxygen- and nutrient-enriched perfusate 108 through the heart 102, the heart 102 can function ex vivo in near-normal physiological conditions. Specifically, the warm perfusate 108 may warm the heart 102 as it perfuse through it, thereby causing the heart 102 to resume beating in its natural manner. In some cases, it is preferred to assist the heart 102 in resuming its beating, which may be done by providing a hand massage or defibrillation signal 143 (shown in FIG. 22E) to the heart 102. This may be done as described above for the organ chamber assembly in Figures 5A-5F and for the operator interface 146 in Figures 17A-17J.

After installing the heart in system 100 in step 920, then steps 928 and 930 allow the operator to inspect the heart 102 and system 100 and evaluate their respective conditions. To describe, step 928 assesses ECG signals 379 and 381 from sensors 142 and 144 (arranged as shown in Figure 27A) and hematocrit 145 and oxygen saturation 141 levels of perfusate 108 from sensor 140, respectively. Includes steps to do. As further explained with reference to FIGS. 12 and 17A-17I, the operator can also observe the fluid flow, pressure, and temperature of the system 100 while the heart 102 is cannulated. As described above with reference to FIGS. 5E and 5F, examination step 928 further involves lifting the outer lid 196 of the organ chamber 104 and indirectly touching / examining the heart 102 through the flexible membrane 198b. , May include a step of having the operator touch / examine the heart 102. Based on the data and other information obtained during evaluation step 930 and inspection step 928, the operator should and how to adjust the characteristics of the system 100 (eg, fluid flow, pressure, and temperature). Determine if to regulate and whether additional defibrillation, or other required form of treatment, should be provided to the heart 102. The operator repeats steps 928 and 930 after making any such adjustment in step 932 to re-examine and re-evaluate the heart 102 and system 100. In some embodiments, the operator may choose to perform a surgical, therapeutic or other procedure on the heart 102 during adjustment step 932. For example, the operator can make an assessment of the physiological health of the heart, such as performing ultrasound or other imaging tests, performing echocardiography or diagnostic tests on the heart, arterial blood gas levels and other assessments. Inspection can be performed.

In another example, during or after step 932, system 100 allows the medical operator to evaluate the organ for the suitability of the recipient after explantation, but prior to transplantation to the donor. it can. For example, an operator can perform a human leukocyte antigen (HLA) compatibility test on an organ with the organ cannulated into system 100. Such tests require more than 12 hours and are used to confirm the compatibility of the organ with the recipient of interest. Organ storage using System 100 as described above allows storage time beyond the time required to complete HLA conformance, which will probably improve post-transplant results. In this HLA conformance test example, the HLA test can be performed on the heart while pumping the preservative solution to the heart.

In a further exemplary embodiment, after the heart has been determined to be functioning by step 932, the operator may perform surgery on the heart, or immunotherapy, chemotherapy, genetic testing and both. , Or treatments such as radiotherapy or other treatments can be provided. System 100 allows the heart 102 to be perfused at temperatures close to physiological temperatures, fluid rates, and oxygen saturation levels for long periods of time after regulatory step 932 (eg, at least 3 days, at least 1 week, at least 3). Since the heart 102 can be maintained for weeks, or longer than a month or more), the evaluation and treatment can be repeated.

In an exemplary embodiment, inspection 928, evaluation 930 and adjustment 932 steps may be performed on system 100 operating in retrograde mode or on system 100 operating in normal flow mode. Good. In normal flow mode, the operator can test the function of the heart 102 under normal or near-normal physiological blood flow conditions. Based on rating 930, adjust system 100 settings to step 932 if necessary to change fluid flow, heating and / or other features to stabilize heart 102 in step 934, step 936. May be adjusted for transport to the recipient site in. Once the heart 102 and system 100 have been inspected and evaluated for adequate performance, the system 100 loaded with the heart 102 is transported to the recipient site in step 936.

Now referring to FIG. 30, the first step 942 of the transplantation process involves repeating the examination 928 and evaluation 930 steps just before leaving the donor site. If the function and characteristics of the heart 102 are unacceptable, the system 100 may be adjusted as appropriate to provide suitable perfusate oxygenation or nutrient levels, or to raise or lower the appropriate perfusate temperature. Can be done. As mentioned above, surgical and / or other therapeutic / therapeutic techniques may be performed on heart 102 in conjunction with examination 928 and evaluation 930. According to the illustrated embodiment, the inspection at the recipient site may be performed in a retrograde flow mode, a normal flow mode, or a combination of both.

In step 946, after the inspection is completed, the system 100 is put into the normal / forward flow mode. In some embodiments, this step 946 is not initiated until cannulation into the left atrium 152 and pulmonary vein 164, the system has sufficient working solution, the heart exhibits stable electrical activity, ABG and electrolytes It is within an acceptable range, SvO2 is above 80%, and blood temperature is between about 34 ° C and about 36 ° C. Step 946 may be performed by slowing and / or stopping retrograde pumping of system 100 and then resuming pumping in the forward direction. In some embodiments, before resuming the forward mode, the user opens the aortic sampling port 754a, releases it by turning the pressure control clamp 190 counterclockwise, and then increases the flow velocity of the pump 106. Raise to about 1.0 L / min, set the liquid flow control valve 112 to normal / forward flow, and increase the flow velocity of the pump 106 to about 2.0 L / min. Allows blood 102 to displace the air in the perfusate line (eg, 802) of system 100 and pass through the left side of heart 102 to reach the return line 808 of the reservoir. The user then closes the aortic sampling port 754a.

The flow rate of the perfusate 108 discharged from the pump 106 is then increased to a clinician-selected level (typically between about 1 L / min and about 5 L / min) in step 950, with a normal beat. It approaches the physiological flow velocity provided by the heart 102 functioning in dynamic mode. The heart 102 and system 100 are again examined in step 952 in a manner similar to that described above for steps 928 and 930. The clinician will also perform any other examination or assessment of the heart, such as echocardiography, electrolyte measurements, cardiac enzyme measurements, metabolite measurements, intravascular ultrasound assessments, pressure-volume loop assessments, and Millar pressure assessments. You may choose to do.

In the third stage, 946, at the recipient site, the heart is tuned for transplantation to the recipient. This step involves dampening the pump 106 to stop the flow of perfusate 108, step 956. Step 958 then stops it by injecting, for example, a cardiac paralytic solution into the heart 102 at the donor site in a manner similar to that performed in step 914. In step 960, the cannula is removed from the heart 102 and removed from the organ chamber assembly 106. In step 962, after first removing the sutures 901a-901f, the heart is inserted into the recipient's thoracic cavity and various cardiac sac (eg, 158, 164a, 164b, 168a, 168b, 169a, 169b and 903a-903f) are removed. The heart 102 is transplanted into the recipient's patient by suturing to their suitable mating cardiac sac within the recipient.

We have described external devices and methods for defibrillating the heart, delivering pacing signals to the heart, and performing chemical analysis of blood on samples taken from perfusate, but these features are integrated into the portable system in question. It would also be beneficial to make it. Such features include defibrillation, pacing, diagnostic ECG detection, and hemochemical analysis.

As described above, the system 100 utilizes the priming solution and further combines the nutrient supplement 116 solution and the preservative solution 118 with the blood product or synthetic blood product to form the perfusate 108 to form the perfusate 108. Use. Next, the priming, auxiliary agent 116, and preservative 118 solutions will be described.

According to some embodiments, solutions with specific solutes and concentrations are selected and formulated so that the organ can function in physiological or near physiological conditions. For example, such conditions include maintaining organ function at or near physiological temperature and / or preserving the organ in a state capable of normal cell metabolism such as protein synthesis. Is done.

In some embodiments, the components are formed from the composition by blending with a fluid derived from a higher concentration solution by dilution or by blending with a fluid derived from a thinner solution by concentration. To do. In some embodiments, suitable solutions include an energy source, one or more stimulants that help the organ continue its normal physiology during pre-transplant and discoloration, and the organ's cells during perfusion. Includes one or more amino acids, selected and formulated to continue metabolism. Cell metabolism includes, for example, protein synthesis while functioning during perfusion. Some exemplary solutions are aqueous based, while other exemplary solutions are non-aqueous, for example organic solvent based, ionic liquid based, or fatty acid based.

The solution may contain one or more energy-rich components that help the organ perform its normal physiology. These components may include metabolizable, energy-rich substances and / or components of such substances that can be used by organs to synthesize energy sources during perfusion. Examples of sources of energy-rich molecules include, for example, one or more sugars. Examples of sugars include monosaccharides, disaccharides, oligosaccharides, polysaccharides, or combinations thereof, or precursors or metabolites thereof. Although not intended to be limiting, examples of monosaccharides suitable for the solution include octose; heptose; hexoses such as octose, allose, altrose, glucose, mannose, growth, idose, galactose, and talose; ribose, There are pentoses such as arabinose, xylose, and hexose; tetrose such as erythroth and treose; and trioses such as glyceraldehyde. Although not intended to be limiting, examples of disaccharides suitable for the solution include (+)-maltose (4-O- (α-D-glucopyranose) -α-D-glucopyranose), (+)-Cellobiose (4-O- (β-D-glucopyranose) -D-glucopyranose), (+)-lactose (4-O- (β-D-galactopyranosyl) -β-D-gluco Pyranose), sucrose There is (2-O- (α-D-glucopyranosyl) -β-D-fructofuranoside). Although not intended to be limiting, examples of polysaccharides suitable for the solution include cellulose, starch, amylose, amylopectin, sulfomcopolysaccharides (eg, dermatan sulfate, chondroitin sulfate, sulodexide), mesoglycans, Heparan sulfate, idsan, heparin and heparinoids), and glycogen. In some embodiments, monosaccharides, disaccharides, and polysaccharides of both aldoses, ketose, or combinations thereof are used. One or more isomers, including monosaccharides, disaccharides, and / or polysaccharides enantiomas, diastereomas, and / or tautomers, both described and unexplained here, are described here. It may be used for the solution to be used. In some embodiments, one or more monosaccharides, disaccharides, and / or polysaccharides may be chemically modified, for example by derivatization and / or protection of one or more functional groups (with protecting groups). .. In some embodiments, sugars such as dextrose or other forms of glucose are preferred.

Other possible sources of energy include adenosine triphosphate (ATP), coenzyme A, pyruvate, flavin adenine dinucleotide (FAD), thiaminepyrophosphate chloride (co-carboxylase), β--nicotinamide adenine dinucleotide ( NAD), β-nicotinamide adenine dinucleotide phosphate (NADPH), and phosphate derivatives of nucleosides, ie, nucleotides containing mono-, di-, and tri-phosphate (eg UTP, GTP, GDF, and UDP), coenzyme. , Or other biomolecules with similar cell metabolic function, and / or their metabolites or precursors. For example, adenosine, guanosine, thymidine (5-Me-uridine), cytidine, and phosphate derivatives of uridine, as well as other naturally occurring and chemically modified nucleotides are considered.

In some embodiments, one or more carbohydrates are provided in conjunction with a phosphate source such as a nucleotide. Carbohydrates help organs produce ATP or other sources of energy during perfusion. Phosphate sources may be provided directly through ATP, ADP, AMP or other sources. In another exemplary embodiment, the phosphate is provided through a phosphate such as glycerophosphate, sodium phosphate or other phosphate ion. Phosphoric acid may include these types in any ionic state, including protonated types and types with one or more counterions.

The solution may contain one or more organ stimulants that support the normal physiological function of the organ during perfusion. In some exemplary embodiments, if the organ to be transplanted is the heart, a cardiac stimulant is provided so that the heart can continue to function (eg, continue to beat) during perfusion and transplantation. To. Such stimulants may include catecholamines that stimulate the heartbeat, such as epinephrine and / or norepinephrine. For example, certain forms of peptides and polypeptides (eg vasopressin, anthroproylin-A and anstoproylin-B) and / or β1 / β2-adrenergic receptor blockers (such as CGP 12177), bupulinalol, pindolol, alprenolol. Rolls and other cardiac stimulants such as cardiotonic glycosides may be used. One or more natural products such as digitalis (digoxin), pulsetrin, and / or ferulic acid may also be used. Stimulants such as those mentioned above can be included in the solution or added at the time of use by the user.

In some cases, it provides additional components to assist the organ in its metabolism during perfusion. These components include, for example, adenine and / or adenosine forms or derivatives that will be used for ATP synthesis to maintain endothelial function and / or reduce ischemia and / or reperfusion injury. In some embodiments, the magnesium ion source is provided with phosphate, and in some embodiments, adenosine is provided to further enhance intracellular ATP synthesis in perfused organs.

The solution described herein may contain one or more amino acids, preferably multiple amino acids, to aid protein synthesis by cells of an organ. Suitable amino acids include, for example, any of the natural amino acids. Amino acids can be of a variety of enantioma or diastereomas. For example, the solution may utilize either D-type or L-type amino acids, or a combination thereof, and the solution may be a more enantio-rich solution of a D-type or L-type isomer or a racemic solution. .. Suitable amino acids may be non-natural or modified amino acids, such as β-amino acids such as citrulline, ornithine, homocysteine, homoserine, β-alanine, amino-caproic acid, or combinations thereof.

Examples of some solutions include some, but not all, naturally occurring amino acids. In some embodiments, the solution contains essential amino acids. For example, the solution may be prepared with one or all of the following amino acids:

<tables num="8"><img file="JP5113522B2_D0001.tif" /></tables><img file="JP5113522B2_D0002.tif" />

In some embodiments, non-essential and / or semi-essential amino acids are not included in the solution. 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. Thus, in other embodiments, asparagine, glutamine, and / or cysteine are included.

The solution may further contain electrolytes that promote enzymatic reactions, contractility of the heart, and / or condensation within the organ, especially calcium ions. Other electrolytes such as sodium, potassium, chloride, sulfate, magnesium and other inorganic and organic charged species, or combinations thereof may be used. As far as charge and stability allow, any of the components presented here may be suitable as an ionic, protonated or aprotonated, salt or free base, or as an ionic or covalent substituent. It should be noted that, if appropriate, it may be provided in combination with other components that are hydrolyzed to make the component available in aqueous solution.

In some embodiments, the solution comprises a buffer component. For example, suitable buffer systems include 2-morpholinoetan sulfonic acid monohydrate (MES), cacodylic acid, H.₂CO₃ / LVDS₃(pK_a1), Citric acid (pK_a3), Bis (2-hydroxyethyl) -imino-tris- (hydroxymethyl) -methane (Bis-Tris), N-carbamoylmethyl imidazole acetic acid (ADA), 3-bis [tris (hydroxymethyl) methylamino] propane (Bis-Tris Propane) (pK_a1), Piperazine-1,4-bis (2-ethanesulfonic acid) (PIPES), N- (2-acetamide) -2-aminoethanesulfonic acid (ACES), imidazole, N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (BES), 3- (N-morpholino) propanesulfonic acid (MOPS), NaH₂PO₄/ Na₂HPO₄(pK_a2), N- and lis (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), trishydroxymethylaminoethane (Tris), glycinamide, N, N-bis (2-hydroxyethyl) glycine (bisine) , Glysil glycine (pK_a2), N-tris (hydroxymethyl) methyl-3-aminopropanesulfonic acid (TAPS), or a combination thereof. In some embodiments, the solution comprises sodium bicarbonate, potassium phosphate, or TRIS buffer.

The solution may contain other components that help maintain the organ and protect it from ischemia, reperfusion injury and other pathological effects during perfusion. In some exemplary embodiments, these components include hormones (eg insulin), vitamins (eg adult multivitamins such as multivitamin MVI-adult), and / or steroids (eg dexamethasone and solumedrol). Will be included.

In another aspect, the solution is provided to the blood product to help the organ during metabolism. Examples of suitable blood products may include whole blood and / or one or more components thereof such as serum, plasma, albumin, and red blood cells. In embodiments where whole blood is used, pyrogens, antibodies and / or other substances that can cause inflammation in the organ may be removed through a filter that removes white blood cells and platelets from the blood. Thus, in some embodiments, the solution utilizes whole blood that is at least partially depleted of white blood cells and / or whole blood that is at least partially depleted of platelets.

The solution is preferably provided at a physiological temperature and maintained at a temperature in the vicinity thereof throughout perfusion and recirculation. The "physiological temperature" as used herein is between about 25 ° C and about 37 ° C, for example between about 30 ° C and about 37 ° C, for example about 34 ° C to about 37 ° C. It says the temperature such as between.

Table 1 lists the components used in the examples of aqueous priming solutions. The amount of the component in Table 1 is relative and is relative to the amount of the aqueous solvent used in the solution (about 500 mL in the illustrated embodiment), but may be increased or decreased in proportion as appropriate. In some embodiments, the amount of aqueous solvent varies from ± about 10%.<tables num="1"><img file="JP5113522B2_D0003.tif" /></tables>

An exemplary priming solution is added to system 100 through priming step 924, as more fully described with reference to FIG. 29A.

With respect to the nutrient supplement solution 116, in some embodiments, it comprises one or more carbohydrates, but may also include a phosphate source. Nutrient supplement solution 116 is typically maintained at about 5.0 to about 6.5, for example about 5.5 to about 6.0.

Table 2 lists the ingredients used in 116 examples of nutrient supplement solutions. In some embodiments, the nutrient solution 116 further comprises sodium glycerol phosphate. The amount of the component in Table 2 is relative to the amount of the aqueous solvent used in the solution 116 (about 500 mL), but may be increased or decreased in proportion as appropriate. In some embodiments, the amount of aqueous solvent varies from about ± 10%.

<tables num="2"><img file="JP5113522B2_D0004.tif" /></tables>

In some embodiments, the nutrient solution 116 comprises one or more carbohydrates, but may further comprise a phosphoric acid source. Nutrient solution 116 is typically maintained at a pH of about 5.0 to about 6.5, such as about 5.5 to about 6.0.

The preservative solution 118 may contain one or more preservatives. In one exemplary embodiment, one or more cardiac stimulants are included to support the normal physiological function of the heart 102 during perfusion and discoloration. Such stimulants may include catecholamines that stimulate the heartbeat, such as epinephrine and / or norepinephrine.

Other ingredients may be added to the preservative solution 118, including adenosine, magnesium, phosphoric acid, calcium, and / or sources thereof. In some cases, it provides additional components to help the organ metabolize during perfusion. These components may include, for example, various forms of adenosine that may be used in ATP synthesis to maintain endothelial function and / or reduce ischemia and / or reperfusion injury. Ingredients may further include other nucleosides such as guanosine, thymidine (5-Me-uridine), cytidine, and uridine, as well as other naturally and chemically modified nucleosides, including their nucleotides. In some examples, a phosphate source is provided for the magnesium ion source, and in some embodiments, adenosine is provided to further enhance intracellular ATP synthesis in perfused organs. Multiple amino acids may be added to aid in protein synthesis by cells in heart 102. Applicable amino acids may include, for example, any of the natural amino acids or those described above.

Table 3 lists the components that may be used in solution 118 to preserve the organs as described herein. Solution 118 may contain one or more of the components listed in Table 3.

<tables num="3"><img file="JP5113522B2_D0005.tif" /></tables><img file="JP5113522B2_D0006.tif" /><img file="JP5113522B2_D0007.tif" />

Table 4 lists the components used in 118 preservative solutions. The amounts introduced in Table 4 are suitable amounts for the other components in the table, and may be increased or decreased proportionally in order to provide a sufficient amount of the composition. In some embodiments, the amounts listed in Table 4 can be varied by ± about 10% and can still be used in the solutions described herein.

<tables num="4"><img file="JP5113522B2_D0008.tif" /></tables><img file="JP5113522B2_D0009.tif" />

In an exemplary embodiment of solution 118, the components in Table 4 are blended in the relative amounts listed here per approximately 1 L of aqueous fluid to form solution 118. In some embodiments, the components of Table 4 are blended with the relative amounts listed here per about 500 mL of aqueous fluid, and then also blended with about 500 mL of solution 116 to provide about 1 L of aqueous fluid maintenance solution 116. Provide / 118. In some embodiments, the amount of aqueous fluid in solutions 116, 118, and / or 116/118 can be varied by ± about 10%. The pH in Table 119 may be adjusted between about 7.0 and about 8.0, for example from about 7.3 to about 7.6. Solution 118 may be sterilized by, for example, an autoclave to increase its purity.

Table 5 lists another exemplary preservative solution 118, which contains tissue culture groups having the components identified in Table 5 and blended with an aqueous fluid. Will be used in perfusate 108 as described in. The amounts of the components listed in Table 5 are relative to each other and to the amount of aqueous solution used. In some embodiments, about 500 mL of aqueous fluid is used. In another embodiment, about 1 L of aqueous fluid is used. For example, a combination of about 500 mL of preservative solution 118 and 500 mL of nutrient solution 116 produces about 1 L of maintenance solution 116/118. In some embodiments, the amount of aqueous solution can be varied by ± about 10%. The amount of the component and the amount of the aqueous solution may be increased or decreased in proportion to use. The pH of the preservative solution 118 in this embodiment may be adjusted to about 7.0 to about 8.0, for example about 7.3 to about 7.6.

<tables num="5"><img file="JP5113522B2_D0010.tif" /></tables><img file="JP5113522B2_D0011.tif" />

Since amino acids are the building blocks of proteins, the unique characteristics of each amino acid provide some important properties for proteins, such as providing structure and catalyzing biochemical reactions. Depending on the selection and concentration of amino acids provided in the preservative solution, for example, sugar metabolism to provide energy, regulation of protein metabolism, mineral transport, nucleic acid (DNA and RNA) synthesis, regulation of blood glucose, and In addition to providing protein structure, such as support for electrical activity, support for normal physiological function is provided. In addition, the concentration of certain amino acids found in the preservative solution can be used to predictably stabilize the pH of maintenance solution 116/118 and perfusate 108.

Some embodiments of the preservative solution 118 include epinephrine and a plurality of amino acids. In some embodiments, the preservative solution 118 comprises an electrolyte such as calcium and magnesium.

In one embodiment, maintenance solution 116/118 is made from a combination of preservative solution 118 containing one or more amino acids and nutrient solution 116 containing one or more sugars, such as glucose or dextrose. In addition, maintenance solution 116/118 may have additives such as those described herein, which are applied during use prior to injection into the organ perfusion system. For example, additional additives that can be included with the solution or added at the time of use by the user include hormones and steroids such as dexamethasone and insulin, and such as MVI-Adult. There are adult multivitamins, such as adult multivitamins for infusion. Additional small and macromolecular molecules, such as therapeutic agents and / or components typically associated with blood or plasma, such as albumin, may be included in the solution or at the time of use by the user at port 762. May be added.

In some embodiments, the compositions, solutions, and therapeutic agents that may be included in the system described herein include T.₃And / or T₄There are hormones such as thyroid hormones such as thyroid hormones. Additional therapeutic agents that may be included include drugs such as antiarrhythmic agents and beta blockers for the treatment of the heart. For example, in some embodiments, one or more thyroid hormones, one or more antiarrhythmic agents, and one or more beta blockers are added to nutrient solution 116, preservative solution 118, and / or maintenance solution 116/118. Add either before or during perfusion of the organ. In addition, the above therapeutic agents may be added directly to the system, such as perfusate 108, before or during organ perfusion.

With reference to Table 4, some of the components used in 118 preservative solutions include low organic molecules or macrobiological molecules that can be degraded or denatured and inactivated if passed through sterilization. It is a molecule. In system 100, the inactivating component of solution 118 may be prepared separately from the remaining components of solution 118. This split preparation involves the step of purifying each component separately through known techniques. The remaining components of solution 118 are sterilized, for example in an autoclave, and then blended with the biological components.

Table 6 lists some biological components that may be purified separately according to this two-step process and added to the solutions described herein after sterilization. These additional or ancillary components are added to solutions 118, 116, 116/118, priming solutions or combinations thereof, individually, in various combinations, at once as a composition or as a compounded solution. Good. For example, in some embodiments, the epinephrine, insulin, and MVI-Adult listed in Table 6 are added to the maintenance solution 116/118. In another example, the solution rolls and sodium bicarbonate listed in Table 6 are added to the priming solution. Further additional components may be blended in one or more combinations or in bulk and placed in solution 116, 118, 116-118, and / or prior to addition to the priming solution. In some embodiments, additional components are added directly to the perfusate 108 through port 672. The amounts of components listed in Table 6 are mutually and / or the amounts of components listed in one or more of Tables 1-5, solutions 116, 118, 116/118, and / or priming. It is relative to the amount of the aqueous solution used in preparing the solution, and may be appropriately increased or decreased in proportion to the required amount of the solution.

<tables num="6"><img file="JP5113522B2_D0012.tif" /></tables>

In one embodiment, the composition used in maintenance solution 116/118 is provided to include one or more sugars, one or more organ stimulants, and multiple amino acids free of asparagine, glutamine, or cysteine. To do. The composition may also include other substances, such as those used in the solutions described herein.

In another embodiment, a system for perfusing an organ such as the heart is provided such that it comprises an organ and a substantially cell-free composition, wherein the substantially cell-free composition is one or more sugars. Includes quality, one or more organ stimulants, and multiple amino acids free of asparagine, glutamine, or cysteine. Virtually cell-free includes 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 containing one or more organ maintenance solutions. An example of a maintenance solution would include the above components in one or more fluid solutions for use in organ perfusate 108. In some embodiments, the maintenance solution 116/118 may contain multiple solutions such as storage solution 118 and nutrient solution 116 and / or ancillary compositions or solutions, or may be regenerated in fluid. It may contain a dry component capable of forming one or more solutions 116/118. The kit may further contain components from solution 116 and / or 118 as one or more concentrated solutions, where diluting this concentrated solution is as described herein. Storage, nutrients, and / or supplemental solutions are provided. The kit may further include a priming solution. In certain exemplary embodiments, the maintenance solution includes a storage solution 118 and a nutrient solution 116, such as those described above, and a priming solution, such as those described above.

In some embodiments, the kit is provided as a single package, in which case the kit is required to formulate one or more solutions (or by mixing with a suitable fluid). Ingredients) and instructions for temperature control and use during sterilization, fluid flow and perfusion, as well as other information necessary or appropriate for adapting the kit to organ perfusion. In some embodiments, the kit is provided with only one type of solution 116, 118 and / or 116/118 (or a set of dry components used in a solution to be mixed with a suitable fluid), said type of solution 116. , 118, and / or 116/118 (or a set of dry ingredients), along with other information or substances necessary or useful for operating solutions 116, 118 and / or 116/118 in system 100. ..

In another aspect, the system, solution and method may be used to deliver the therapeutic agent to the perfused organ. For example, one or more of the solutions and / or systems described above may include one or more drugs, biologics, gene therapy vectors, or other therapeutic agents delivered to an organ during perfusion. Suitable therapeutic agent examples may include drugs, biologics, or both. Suitable drugs include, for example, antifungal drugs, antimicrobial or antibiotics, anti-inflammatory drugs, antiproliferative drugs, antiviral drugs, steroids, retinoids, NSAIDs, vitamin D3 and vitamin D3 analogs, calcium channel blockers, etc. It may include complement neutralizers, ACE inhibitors, immunosuppressants, and other drugs. Suitable biologics may include proteins. Suitable biologics may also include vectors loaded with one or more genes for gene therapy applications.

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, alcromethasone, clobetasol, fluticasone, fluocortolone, diflucortolone, fluticasone, halcinonide, mometasone, prednisone, prednisolone, methylprednisolone, triamquinolone, betamethasone, and dexamethasone. There are various esters and acetamides of these.

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

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

Suitable vitamin D3 analogs include, but are not limited to, doxercalciferol, theocalcitol, calcipotrien, tacalcitol, calcitriol, ergocalciferol, and calcifediol.

Suitable antiviral agents include, but are not limited to, trifluridine, cidofovir, acyclovir, pencyclovir, famcyclovir, balcyclovir, gancyclovir, and docosanol.

Suitable human decarboxylase 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 antibiotics (antimicrobial agents) include, but are not limited to, vancomycin, chlorhexidine, chlorhexidine digluconate, ciprofloxacin, clindamycin, erythromycin, gentamycin, romefloxacin, metronidazole, minocycline, moxyfloxacin, There are mupirocin, neomycin, ofloxacin, polymyxin B, rifampicine, rufurosacin, tetracycline, tobramycin, triclozan, and vancomycin. Responsive systemic infections may be treated as appropriate with the antiviral and antibacterial prodrugs described herein.

In some embodiments, the solution system for use in perfusate 108 is a first solution, such as Conserved Solution 118, which comprises one or more cardiac stimulants and multiple amino acids free of asparagine, glutamine, or cysteine. Includes a first chamber containing, and a second chamber containing a second solution, such as a nutrient solution 116 containing one or more sugars, such as dextrose. The system may further include a sterilization system for sterilizing the first and second solutions before using the solution to perfuse the heart. In some embodiments, one or more of the solutions 118 and 116 comprises one or more therapeutic agents. In some embodiments, the solution system comprises a third chamber containing a priming solution that may contain one or more sugars, such as those described above. In some embodiments, the first solution 118 comprises epinephrine, adenosine, insulin, one or more immunosuppressants, multivitamins, and / or one or more electrolytes.

Some experimental data can be used to illustrate the solutions described herein and specific embodiments of their use in organ perfusion. Some data are given in Figure 31-33. FIG. 31 shows a chart demonstrating electrolyte stability of an organ during perfusion in the forward mode by System 100 of one embodiment. In an embodiment related to FIG. 31, the organ is the heart 102 and perfusion is directional (as described above) by pumping perfusate 108 containing solution 106/108 into the left atrium 152 from the aorta 158. It is done in mode. The perfusion rate is approximately 30 mL / hr. As can be seen in FIG. 31, the levels of various electrolytes: sodium, potassium, calcium, and chloride ions, as well as the levels of dissolved glucose, were introduced into the system 100 before the organ was cannulated into the perfusion system 100. It remains at a stable level throughout the perfusion course up to 6 hours after insertion of the cannula.

FIG. 32 shows a chart demonstrating electrolyte stability of an organ during retrograde perfusion by System 100 in another embodiment. In an embodiment related to FIG. 32, the organ is the heart 102 and perfusion is performed by pumping perfusate 108 containing solution 116/118 into the aorta 158 and through the coronary sinus 155. The perfusion rate is approximately 30 mL / hr. As can be seen in Figure 32, the levels of various electrolytes: sodium, potassium, calcium, and chloride ions, as well as the levels of lysed glucose, were 6 hours before and 6 hours after cannulation of the organ into the perfusion system 100. It remains at a stable level throughout the perfusion process leading up to. Figure 32 also demonstrates that electrolyte and glucose levels remain similar to baseline (BL) normal physiology for organs.

FIG. 33 shows a chart demonstrating the aortic blood gas profile of an organ being perfused in another embodiment according to the invention. As can be seen in Figure 33, the levels and pH of various blood gases: carbon dioxide and oxygen remain stable over the entire 6-hour perfusion. Figure 33 also demonstrates that carbon dioxide, oxygen, and pH levels remain similar to the two baseline (BL) measurements of normal physiological conditions for the organ. Figures 31-33 also demonstrate the capabilities of the system and how to maintain organs in stable, physiological or near-physiological conditions.

Although the present invention has been described above in relation to various embodiments, the above description is intended to give examples of the present invention and limits the scope of the present invention as defined by the accompanying claims. Please understand that this is not intended. For example, a variety of systems and / or methods could be implemented under the present disclosure and would fall within the scope of the present invention. Other aspects, benefits, and changes are within the scope of the following claims. The full text of all references cited herein shall be incorporated herein by citation and shall be part of this application.

The following drawings show exemplary embodiments of the invention, in which similar reference numbers refer to similar elements. It should be understood that these illustrated embodiments are not actual sizes, but are examples of the present invention and do not limit the scope of the invention as defined in the appended claims.

<figref num="1">FIG. 1 is a schematic diagram of a portable organ management system according to an exemplary embodiment of the present invention.</figref><figref num="2">FIG. 2 is a diagram showing the collected hearts.</figref><figref num="3">FIG. 3 is a conceptual diagram showing the collected heart of FIG. 2 interconnected to the organ management system of FIG. 1 in a normal flow mode configuration according to an exemplary embodiment of the invention.</figref><figref num="4">FIG. 4 is a conceptual diagram showing the collected heart of FIG. 2 interconnected to the organ management system of FIG. 1 in a retrograde mode configuration according to an exemplary embodiment of the present invention.</figref><figref num="5">5A-5F show various drawings of the types of organ chamber assemblies used in the organ management system of FIG. 1 according to certain exemplary embodiments of the invention.</figref><figref num="6">6A-6F show various drawings of the types of perfusion heater assemblies used in the organ management system of FIG. 1 according to certain exemplary embodiments of the invention.</figref><figref num="7">FIG. 7 shows a more detailed drawing of an exemplary resistant heater element of the type used in the heater assembly of FIGS. 6A-6F.</figref><figref num="8">8A-8C show various drawings of a perfusion pump interface assembly according to an exemplary embodiment of the invention.</figref><figref num="9">FIG. 9 shows a perspective view of the pump drive side of the type of perfusate pump assembly shown in FIG. 1, along with a bracket that attaches to the perfusion pump interface assembly.</figref><figref num="10">FIG. 10 shows a side view of the perfusate pump interface assembly of FIGS. 8A-8C, paired with the pump drive side of the perfusate pump assembly of FIG.</figref><figref num="11">FIG. 11 shows a block diagram of an exemplary control scheme for controlling the operation of the organ management system of FIG.</figref><figref num="12">FIG. 12 is a block diagram of an exemplary data acquisition subsystem of the type that may be used in conjunction with the exemplary organ management system of FIG.</figref><figref num="13">FIG. 13 is a block diagram of an exemplary heating control subsystem of the type that may be used to maintain the perfusate temperature of the exemplary organ management system of FIG.</figref><figref num="14">FIG. 14 is a block diagram of an exemplary power management subsystem of the type that may be used in the exemplary organ management system of FIG.</figref><figref num="15">FIG. 15 is a block diagram of an exemplary pumping control subsystem of the type that may be used to control the operation of the perfusate pump of the exemplary organ management system of FIG.</figref><figref num="16">FIG. 16 is a graph showing r-waves synchronized by the pumping control subsystem of FIG. 15 according to an exemplary embodiment of the invention.</figref><figref num="17">FIG. 17A-17J shows an exemplary display screen of a type that may be used in an operator interface according to an exemplary embodiment of the invention.</figref><figref num="18">18A and 18B show a system design example of the system of FIG. 1 according to an exemplary embodiment of the present invention.</figref><figref num="19">19A-19C show various drawings of the system of FIGS. 18A and 18B, with the top surface removed and the front panel open, according to an exemplary embodiment of the invention.</figref><figref num="20">FIG. 20A is a front perspective view of the system of FIGS. 18A and 18B according to an exemplary embodiment of the invention, with the top surface removed, the front panel open, and the disposable module removed. FIG. 20B is a side view of a slot formed in the cradle of the multi-use module of FIG. 20A to engage the corresponding protrusion of the disposable module.</figref><figref num="21">FIG. 21A shows a mounting bracket for receiving a disposable module in the multiple use module of FIG. 20A and locking it in place. 21B and 21C show the installation of a single-use disposable module in a multi-use module using the mounting bracket of FIG. 21A, according to an exemplary embodiment of the present invention.</figref><figref num="22">22A-22C shows an example of a mechanism for automatically making an electronic-optical interconnection between a disposable module and a multi-use module during installation in FIGS. 21B and 21C.</figref><figref num="23">23A-23C show various drawings of the system of FIGS. 18A and 18B according to an exemplary embodiment of the invention, with all of the exterior walls removed. FIG. 23D is a conceptual diagram showing the interconnection between the circuit boards of FIGS. 23A-23C according to an exemplary embodiment of the present invention.</figref><figref num="24">FIG. 24A-24E shows various top perspective views of a disposable module according to an exemplary embodiment of the present invention.</figref><figref num="25">25A-25C shows various bottom perspective views of the exemplary disposable module of Figure 24A-24D.</figref><figref num="26">26A and 26B show the operation of the liquid flow mode selection valve according to an exemplary embodiment of the present invention.</figref><figref num="27">27A and 27B show various top views of the disposable module of Figure 19A-19C, with the top surface of the illustrated organ chamber removed.</figref><figref num="28">28A-28C show various drawings of examples of hematocrit and oxygen saturation sensors of the type used in the exemplary disposable module of FIG. 19A-19C.</figref><figref num="29">FIG. 29A is a flow diagram showing a donor-side process of removing an organ from a donor and placing it within the organ management system of FIG. 1 according to an exemplary embodiment of the invention. FIG. 29B is a diagram showing a heart collected with a suture and cannula insertion site according to an exemplary embodiment of the invention.</figref><figref num="30">FIG. 30 is a flow diagram showing a recipient-side process for removing an organ from the organ management system of FIG. 1 and transplanting it into a recipient according to an exemplary embodiment of the invention.</figref><figref num="31">FIG. 31 shows a diagram demonstrating electrolyte stability of an organ during perfusion in the forward mode according to an embodiment of the present invention.</figref><figref num="32">FIG. 32 shows a diagram demonstrating electrolyte stability of an organ during perfusion in retrograde mode according to another embodiment of the invention.</figref><figref num="33">FIG. 33 shows a diagram demonstrating the aortic blood gas profile of a perfused organ according to an embodiment of the present invention.</figref>