Microfabricated devices for the delivery of molecules into a carrier fluid

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DESCRIPTION

Microfabricated devices for the delivery of molecules in carrier fluids.

Description of the invention

This invention generally relates to minimized devices for the delivery of chemical molecules in the carrier fluid.

The precise delivery of the small requires quantities of one or more chemicals within a carrier fluid that is of great importance in many different fields of science and industry. Examples in medicine include the delivery of drugs to patients using intravenous methods, by pulmonary or inhalation methods, or by the delivery of drugs from vascular tissue devices. Examples in diagnostics include switch-off reagents in fluids to conduct DNA or genetic analysis, combined chemistry, or the detection of a specific molecule in an environmental example. Other applications involving the delivery of chemicals within a carrier fluid include the displacement of fragrances and therapeutic aromas from the devices into the air and the disconnection of flavor agents within a liquid to achieve beverage products.

US Patent No. 5,547,470 to Johnson, et al. develops automatic devices for the delivery of intravenous medication in which the drainage channels independently emanate medication and fluid. These devices and delivery methods require that the medications be carefully pre-mixed and stored in liquid form. A liquid form can, however, reduce the stability of some drugs and therefore can cause undesirable variability in drug concentration. It would be desirable for a more accurate and more reliable measurement of the amount of medication introduced into the intravenous carrier fluid, as well as storing the medication in a more stable form, for example as a solid.

US Patent No. 5,972,027 for Johson's discoveries of the use of stentor metal pores as drug delivery devices. The devices reportedly delivered a drug from the pore structure of the stentor to surrounding tissue. Such devices, however, are limited to the number of drugs they can deliver and are severely limited in controlling both the rate and time of delivery of the medication, when the rate of delivery is governed by the porous structure.

ie the medication is passively relaxed. It would be advantageous to provide active and more precise control over the timing and rate of delivery of one or more variety of drugs from the rales into, for example, the imposed stentor of traversing the bloodstream.

Microchip delivery systems, described in United States Patents No. 5,797,898 and No. 6,123,861 to Santini et al., Provide meaning to control both the ratio and time of disconnection of a variety of molecules, such as drugs, in any of them a continuous or impulsive way. The devices also provide a means to store chemistry in its most stable form. These patents describe, for example, implanting the microchip devices themselves in a patient for the delivery of medication. It would be advantageous, however, to tailor the precise control of molecule shutdown provided by these microchip devices into a variety of other utilities.

It is then an object of the present invention to provide devices and methods for accurate and successful delivery of molecules in a fluid carrier, such as a drug in an intravenous delivery fluid.

It is a further object of the present invention to provide devices and methods for conveniently reserving molecules stably for release into the carrier fluid.

Another object of the present invention is the stentor devices having precise control over the timing and rate of drug delivery.

More additions that are defined are claims 2 through 21.

Summary of the invention

A device is provided according to claim 1.

Brief description of the drawings

Figure 1 is a perspective view of a typical microchip chemical delivery device.

Figures 2a-e are schematic cross-sectional views of various device structures having substrates formed from two fabricated substrate portions that have been joined.

Figures 3a-c are cross-sectional perspectives showing the active release of molecules from a microchip device into a liquid carrier.

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Figures 4a-c are cross-sectional perspectives showing a reserve outcrop of a microchip device that is split by a direct application of a mechanical force.

Figures 5a-b are cross-sectional perspectives showing a reserve outcrop of a microchip device that is divided by the application of ultrasound.

Figures 6a-c are cross-sectional perspectives showing a passive release of molecules from a microchip device into a liquid carrier.

Detailed description of the invention

I. Supply devices and systems

Delivery systems include one or more microchip devices, as described, for example, here and in US Patents No. 5,797,898 and No. 6,123,861 to Santini et al. See, for example, Figure 1, which illustrates a typical microchip device (10) with substrate (12), reserve (16), and emanation reserve (14).

A. Microchip Devices

Microchip devices typically include a substrate having a plurality of reservoirs containing a delivery system that includes the molecules to be released. Microchip devices in some structures also include one or more reserve outcrops covering the reserve openings. These reserve outcrops can be designated and formed from a material selectively permeable to molecules, which disintegrates upon release of the molecules, which divides upon release, or a combination accordingly. Active release of systems may further include facility control and a power source.

1. Substrate

The substrate contains the fabrication, molding, or machined reserves and serves as the support for the microchip. Any material that can serve as a support, is workable to be etched, molded, or machined, and is impermeable to the molecules to be delivered to the surrounding fluids, for example water, organic solvents, blood, electrolytes or other salts, can be used as a substrate. Examples of material substrates include ceramics, semiconductors, and degradable and non-degradable polymers. For in vivo applications such as delivery of the emerging drug in vascular fluids, an aseptic, biocompatible material is preferred. However, the toxic or otherwise non-biocompatible materials may be encapsulated in a biocompatible material, such as polyethylene glycol or tetrafluoroethylene materials, prior to use.

An example of a strong, non-degradable, easily etchable substrate that is impermeable to the molecules to be released and the silicone from the surrounding fluids. An example of a class of strong, biocompatible materials are the polyanhydride-coimides described in Uhrich et al., "Synthesis and characterization of degradable polyanhydride-coimides", Macromolecules, 28: 2184-93 (1995).

The substrate can be formed from only one material or it can be a composite or multi-laminate material, eg, several results of the same or materials from different substrates that are joined together. Multi-portion substrates can include any number of ceramic, semiconductor, metal, polymer, or other substrate materials. Two or more full microchip devices may also be joined to form multi-portion substrate shaped devices, as illustrated for example in Figures 2a-e. Figure 2a, by comparison, shows a "unitary" substrate device (200), having the substrate (210), in which the reservoirs (220) are filled with molecules to be released (240). The reserves (220) are covered by the reserve springs (230) and sealed with a support sheet (250) or another type of sealing. Figure 2b shows the device (300) having a substrate formed by a maximum substrate portion (310a) attached to the bottom of the substrate portion (310b). The reservoirs (320a / 320b) are filled with molecules to be released (340) and are covered by the reservoir sprouts (330) and sealed with the support sheet (350) or another type of closure. Figure 2c shows a device (400) having a substrate formed of a portion (410a) attached to the supporting substrate portion to portion (410b). The maximum substrate portion of (410a) has reserve (420a) which is in communication with reserve (420b) in the background substrate portion (410b). Pool 420b is much larger than pool (420a) and pools (420a / 420b) contain molecules to be released (440). The reservoirs (420a / 420b) are filled with release molecules (440) and are covered by the pop-up reservoir (430) and sealed with the support sheet (450) or other type of sealing. Figure 4d shows a device 500 having a substrate formed of a high substrate portion (510a) attached to the bottom substrate portion (510b). The larger substrate portion (510a) has the pool of (520a) which first contains molecules to be released (540a). The bottom substrate portion (510b) has the reservoir (520b) that contains secondary molecules to be released (540b). The first molecules to be released (540a) can be the same or different from the secondary molecules to be relaxed (540b). The reservoir (520a) is covered by the pop-up reservoir (530a) and closed by the pop-up reservoir (530b) (formed of an anode material) and partially by the bottom substrate portion (510b). The tank (520b) is covered by the emergent internal tank (530b) and closed with the support sheet (550) or another type of closure. The cathodes (560a) and (560b) are positioned to form an electrical potential with the emerging anode reservoir (530b). In the structure of the device shown in Figure 2d, secondary molecules to be released (540b) are first released from the deposit (520b), through or following the disintegration of the emerging deposit

ES 2 332 869 T3 (530b), within the reservoir (520a), where the secondary molecules mix with the first molecules to be released (540a) before the mixture of molecules is released from the reservoir (520a) through or following the disintegration of the emerging deposit (530a). Figure 2e shows another tank configuration in cross section. The substrate portions (310a / 410a / 510a) may be formed from the same or different materials and may have the same or different thickness as substrate portions (310b / 410b / 510b). These substrate portions may be attached or attached after they have been individually processed (eg, etched), or they may be formed before they have any of the deposits or other etched or micro-machined structures within them (as in SOI substrates).

2. The Liberation System

The molecules to be delivered can be inserted into the reservoirs in their pure form, as a liquid salt or gel, or they can be encapsulated internally or by a delivery system. As used herein, "the delivery system" includes both the situation where the molecules are in their pure form, like any solid or liquid, or are in a matrix formed of degradable material or a material that releases the incorporated molecules by diffusion. outside the disintegration of the womb. Molecules can sometimes be contained in a delivery system because the deterioration, dissolution, or diffusion properties of the delivery system provide a method of controlling the release rate of the molecules. The molecules can be homogeneously or heterogeneously distributed with the delivery system. The selection of the delivery system is dependent on the desired rate of release of molecules. Both non-degradable and degradable systems can be used for the delivery of molecules. Appropriate delivery systems include polymers and polymeric matrices, non-polymeric matrices, or inorganic and organic excipients and diluents as such, but not limited to calcium carbonate and sugar. Delivery systems can be natural or synthetic, however synthetic delivery systems are typically preferred due to the better characterization of the delivery structures.

The release system is selected based on the period over which release is desired. Release times for in vivo applications, such as delivery of the medication stentor, are generally within the range of several minutes to a year. In some cases, continuous (constant) release from a reservoir can be most helpful. In other cases, a pulse release (bulge) from a reservoir may provide more effective results. A simple pulse from a reservoir can be transformed into pulsatile release by multiple use of reservoirs. It is also possible to incorporate various outputs from a delivery system and other materials into a single reservoir to achieve pulsatile delivery from a single reservoir. Continuous release can be achieved by incorporating a release system that deteriorates, dissolves, or allows the diffusion of molecules through it over an extended period of time. Furthermore, the continuous release can be simulated by releasing several pulses of molecules in rapid succession.

The material of the delivery system can be selected such that molecules of various molecular weights are released from a reservoir by diffusion out of or through the material or by deterioration of the material. In the case of in vivo applications, it is preferred that biodegradable polymers, bioerodible hydrogels, and protein delivery systems are used for the release of molecules by diffusion, deterioration, or dissolution. In general, these materials deteriorate or dissolve either through enzymatic hydrolysis or by exposure to water, or by surface erosion or bulk. Representatively synthetic, biodegradable polymers include: polyamides such as polyamino acids and polypeptides; polyesters such as polylactic acid, polyglycolic acid, coglycolic polylactic acid, and polycaprolactone; polyanhydrides; polyorthoesters; polycarbonates; and consequently chemical derivatives (substitutions, additions of chemical groups, eg, alkyl, alkylene, hydroxylations, oxidations, and other routine modifications made by those skilled in the art), copolymers and blends accordingly. Representative synthetic, non-degradable polymers include: polyethers such as polyethylene oxide, polyethylene glycol, and polytetramethylene oxide; vinyl polyacrylate polymers and polymethacrylates such as methyl, ethyl, other alkyl, hydroxyethyl methacrylate, acrylic and methacrylic acids, and others such as polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetate; polyurethanes; cellulose and its derivatives such as alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and various cellulose acetates; polysiloxanes; and consequently any chemical derivatives (substitutions, additions of chemical groups, eg, alkyl, alkylene, hydroxylations, oxidations, and other modifications made routinely by those skilled in the art), copolymers and blends accordingly.

3. Emanation deposit (i) Passive release by disintegration or diffusion

In the passive release of the drug measured in time from the delivery mechanisms, the deposit of emanations is formed from a material that deforms or dissolves over time, or that does not degrade or dissolve, but is permeable to the molecules to be supplied. These materials are preferably polymeric materials. Materials can be selected for use as a fume reservoir to give a variety of deterioration rates, dissolution rates, or permeabilities to allow the passage of molecules from different reservoirs at different times, and, in some cases, different rates. To obtain different release times (delayed release time amounts), fumes can be formed from different polymers, the same polymer with different degrees of cross-linking, or a polymerizable UV polymer. In the latter case, varying the exposure of this polymer to light UV results in varying degrees of cross-linking and giving the emergent material different diffusion properties or deterioration or dissolution rates.

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Another way to obtain different release times is by using a polymer, but varying the thickness of that polymer. Thicker sheets of some polymers result in delayed release time. Any combination of polymer, degree of cross-linking, or polymer thickness can be modified to obtain a specific release time or ratio. In one structure, the delivery system containing the molecules to be released is covered by a degradable emergent material that is almost impermeable to the molecules. The release time of the molecules from the reservoir will be limited by the time required for the emerging material to deteriorate or dissolve. In another structuring, the emergent material is non-degradable and is permeable to the molecules to be delivered. The physical properties of the material used, its degree of cross-linking, and its thickness will determine the time required for the molecules to diffuse through the emergent material. If diffusion outside the delivery system is limiting, the emerging material delays the release operation. If the diffusion through the emergent material is limiting, the emergent material determines the release rate of the molecules in addition to delay the operation of the release.

(ii) Active release by disintegration

In a timed active release structuring of the mechanisms, the emanation deposit consists of a thin sheet of conductive material that is deposited in said reserve, patented with a desired geometry, and serves as an anode. The cathodes are also fabricated on the device with their size and location dependent on the device application, and method of controlling the electric potential. The anode is defined as the electrode where oxidation occurs. Any conductive material capable of dissolving in the salt or forming soluble ions or oxidation compounds depending on the application of an electric current potential (electrochemical solution) can be used for the manufacture of anodes and cathodes. In addition, materials that normally form soluble ions or oxidation products in response to an electrical potential that can be used if, for example, the local pH changes near the anode cause these oxidation products to become soluble. Examples of appropriate emerging deposit materials include metals such as copper, gold, silver, and zinc, and some polymers, as described, for example in Kwon et al., "Electrically erodible polymer gel for controlled drug release." , Nature, 354: 291-93 (1991); and Bae et al., "The pulsatile drug released by electrical stimuli," ACS Symposium Series 545: 98-110 (1994).

(iii) Release on break

In another structure the emanation from the reservoir is positioned in the reservoir on the molecules, which are released from the reservoir upon heating or cooling the device, or a portion consequently, to break the emergent reservoir. As used herein, the term "rupture" includes fracture or some other forms of mechanical failure, as well as the loss of structural integrity due to a phase of change, eg melting in response to a change in temperature, unless a specific mechanism of these is indicated.

In a preferred structuring, the heating or cooling causes of the molecules in the reservoir to thermally expand (ie increase in volume). For a given temperature (T1), the release system completely fills the reservoir volume of the reservoir. After heating the temperature T2, the relaxation system begins to expand and applies a force to the emerging reservoir. Once this force exceeds the potential for surge fractures, the emerging deposit fractures and the molecules are released. In a variation of this structure, the molecules can vaporize or entrain a reaction, thereby raising the pressure within the reservoir sufficiently to cause the emerging reservoir to rupture due to mechanical stress. Prior to the application of heat, the pressure within the reservoir is lower than that required to break the emerging reservoir. The addition of the heat increases the equilibrium pressure within the reservoir and the forces acting on the rising material increase. Further increases in temperature cause the pressure to continue increasing until the internal pressure exceeds the force of the emerging reservoir fracture. Typically the thermal expansion, vaporization, or reaction is induced by heating the molecules in the reservoir, eg, above ambient temperatures.

In a structuring, the emergent deposit is fractured by physical and chemical (ie structural) changes in the reservoir of the emergent material, for example, a change caused by a change in temperature. For example, the pop-up reservoir can be made of or include a material that expands when heated. When the pop-up reservoir is secured in a fixed position and heated up, the pop-up reservoir expands until it breaks or fractures due to increased volume. This structuring allows heating of the pop-up reservoir with minimal or no heating of the reservoir contents, a modality that is particularly important when the reservoir contains heat-sensitive molecules, such as protein drugs, that can become denatured by excessive exposure to heat.

In another structure using an active release mechanism, the reservoir of emerging material is melted (ie undergoes a phase change) using resistant heat. For in vivo applications, the emerging deposit is preferably composed of biocompatible copolymers, such as organic acid derivatives of hydroxide (eg, lactic and lactones), which can offer a range of selective melting temperatures (see PCT WO 98/26814) . The temperatures of the particular melt, for example between 2 ° C above normal body temperature, can be selected for emerging deposits by the appropriate selection of starting monomer ratios and the resulting molecular weight of the copolymer. This type of reservoir opening the mechanism offers at least two supply schemes. A first scheme is based on individual emergent deposits that have various melting temperatures. By heating the device, or consequently portion, to a constant temperature, only the 5

ES 2 332 869 T3 emerging deposits melt, opening the reservoir and exposing the molecules. The application of the structures of the different temperatures consequently provides a selective molecular release. A second scheme focuses on all the insurgents having a fixed and uniform composition in melting temperature. Insurgency is a solid phase at temperature Ti. Locally heating the fume tank to temperature T2 causes said tank to become molten. The fluidized deposit of emanations is then movable, which facilitates the opening of the reservoir and releases the molecules.

In passive release structures, rupture of the emergent reservoir is triggered by changes in ambient temperature, for example due to installation of the device within or within the human or other animal body. The passive mechanism differs from the active mechanism in that the breakdown of the reserve of the active device is triggered by an applied temperature change rather than an environmental one.

In a passive device structure, the pop-up deposit is thermally stimulated to facilitate deterioration. For example, the degradation of the emerging kinetic deposit may be at a very low ambient temperature and the deposit may be considered chemically stable. However, kinetic degradation is significantly increased by increasing the temperature of the emergent material eg, by in vivo implantation. The absolute rate of deterioration can be selected by controlling the composition of the reservoir of emerging material. For example, the rate of deterioration of biocompatible copolymers (eg, lactones and lactics) can be between several hours and several years, preferably between two days and a year at a temperature of 37 ° C, depending on the specific molar proportions of the structural primary units. Using a matrix of emergent deposits, each having a different composition, the molecular compound releases structures that can be achieved once the device reaches a critical temperature defined by its environment.

In another passive device structure, all pop-up reservoirs have constant decay rates (eg, independent temperature) and the release pattern is controlled by the selection of the physical dimensions of the pop-up reservoir material. By setting the decay rate, the moment for emergent decay is dependent on the thickness of the emergent deposit material. For example, in a structure in which all emerging deposits have identical compositions, molecular release may be controlled by the variety in thickness of the insurgency.

In both active and passive devices, the emergent deposit is formed of a material having a performance or sensible force behind that the material fails due to fracture or a material that entails a phase change (for example, castings) with changes in temperature. selected. The material is preferably selected from metals, such as copper, gold, silver, platinum, and zinc; glasses; ceramics; semiconductors; and brittle polymers, such as semi-crystalline polyesters. Preferably the pop-up reservoir is in the form of a thin sheet, eg, a sheet having a thickness between 0.1mm. and 1 mm. However, because the thickness depends on the particular material and the rupture mechanism (ie electrochemical vs. Mechanical interruption), thicker emerging deposits, eg, having a thickness between 1 mm. and 100 mm. or more, may work better for some materials, such as certain brittle materials.

The pop-up deposit can optionally be coated with a protective material to structurally reinforce the breakable material produced until the protective material has been substantially removed by dissolving, eroding, biodegrading, oxidizing, or otherwise deteriorating, such as exposure to water in vivo. Representative suitable deteriorating materials include synthetics or biodegradable polymers.

Emerging deposits in active or passive structures can be formed of a material that functions as a permeable or semi-permeable membrane depending on the temperature.

In a preferred structure of the release device, a rheostat is integrated into a reservoir or accumulated near a reservoir, which depending on an application of electrical current through the rheostat, heats the contents of the reservoir, the emerging material, or both. . In typical structures, the rheostats are located at the bottom or along the inside of the tank walls, or they can be located near the emerging tanks covering the openings of the small tank. The rheostat is generally a thin sheet, which can be integrated with the reservoir during the manufacturing process. Such rheostats can be made of metals such as platinum or gold, ceramics, semiconductors, and some polymers. Methods for making these rheostats are described, for example, in Wogersien et al. "Fabrication of Thin Sheet Rheostats and Silicone Microstructures Using a Frequency Bent Nd: YAG-Laser," Proc. SPIE-Int. Soc. Opt. Eng., 3680: 1105-12 (1999): Bhattacharya & Tummala, “Next Generation in Integral Liabilities: Materials, Processes, and Integration of Rheostats and Electrical Capacity Capacitors in PWB Substrates,” J. Mater. Sci.-Mater. Electron. 11 (3): 253-68 (2000); and Vladimir-sky et al., "Thermal Micro-Sensors Metal Sheet," Proc. SPIF-Int. Soc, Opt. Eng., 2640: 184-92 (1995). Alternatively, the small rheostat chips may be surface mounted in a device in proximity to the pop-up reservoir reservoir.

Four. Molecules to be Supplied

As is customary herein, the term "medication" includes therapeutic, prophylactic, and diagnostic agents, unless otherwise indicated. Drug molecules to be released during intravenous delivery applications include, but are not limited to, antibiotics, chemotherapeutic agents, diagnostic agents

ES 2 332 869 T3 in vivo, (eg, agent contract), sugars, vitamins, antidote toxins, anti-inflammatory agents, pain relievers, and medications useful for renal processes such as dialysis (eg heparin).

An in vivo framework for molecular delivery is cutting off drug delivery in vascular fluids. Possible molecules to be released include anti-resinous compounds, proteins, nucleic acids, polysaccharides and organic synthetic molecules, having a bioactive effect, for example, anesthetics, vaccinosis, chemotherapeutic agents, hormones, pain relievers, metabolites, sugars, immunomodulators, antioxidants. , ion channel regulators, and antibiotics. The drugs can be in the form of a single drug or drug mixtures and can include pharmaceutically acceptable carriers.

B. The elaborations

In the device according to the present invention, an elaboration has a plurality of microfabricated tanks.

The preparations are commonly used in a range of medical applications, usually to prevent reocclusion of a vein. Examples include cardiovascular workouts from gastroentology. Generally these preparations are non-degradable. Diuretic and uretic preparations are used to relieve obstruction in a variety of benign, malignant and post-traumatic conditions such as the presence of stones and / or stone fragments, or other urethral obstructions such as those associated with urethral structure, carcinoma of abdominal organs, retroperitoneal fibrosis or urethral trauma, or in association with Extracorporeal Shock of Surge of Lithotripsy. The elaboration can be placed using the endoscope of the surgical techniques or cutaneously. Examples of state-of-the-art fabrications include Flexible Metal Coupling Urethra Double Draft (CR Bard, inc. Covington, GA), Spiral Fabrication (Uresurge, Coralville, IA), and Urethra Urological Kitchen and Fabrications ( Urological Kitchen, Spencer, IN).

Bioabsorbable preparations are particularly desirable in applications such as urological applications, since a second procedure does not require removing the preparation. In addition, one of the major problems in using metal products in cardiovascular applications is subsequent retinosis caused by overgrowth of the endothelial wall, which is believed to be due, at least in part, to irritation caused by metal products in the wall of the veins (see Behrend, American J. Cardiol. p. 45, TCT Abstracts (Oct. 1998); Unverdorben, et al., American J. Cardiol. p. 46, TCT Abstracts (Oct. 1998). A bioabsorbable formulation made from or lined with appropriate materials should not cause irritation. Bioabsorbable preparations can be manufactured using methods known in the art, for example the methods and procedures described in US Patent Nos. 5,792,106; 5,769,883; 5,766,710; 5,670,161; 5,629,077; 5,551,954; 5,500,013; 5,464,450; 5,443,458; 5,306,286; 5,059,211, and 5,085,629. See also Tanquay, Clínicas de Cardiología, 23: 699-713 (1994), and Talja, J. Endourology, 11: 391-97 (1997).

II. The fluid carrier

The molecules contained in the reservoirs of the microchip device can be released into a variety of carrier fluids, depending on the particular application. The carrier fluid can be essentially any composition that takes the form of a fluid. As used herein, the term "fluid" includes, but is not limited to, liquids, gases, supercritical fluids, salts, suspensions, gels, and pastes.

Representative examples of fluid carriers for medical applications include biological fluids and other physiologically acceptable fluids such as water, saline, sugar salt, blood plasma, and whole blood, as well as oxygen, air, nitrogen, and inhalation of propellants. . The carrier fluid alternative depends on the particular medical application, eg, elaborate applications, intravenous delivery systems, implantation delivery systems, or systems for respiratory (eg, pulmonary) administration.

III. Operation and molecular release

A preferred structure is the active displacement of molecules within a carrier liquid from a microchip that releases the molecules in response to the electrochemical stimulus, shown in Figure 3. The application of an electrical potential (see Figure 3a) causes the material to emergent dissolves (see Figure 3b) providing for the displacement of molecules within the liquid that flows adjacent to the reservoir opening as shown in Figure 3c. In a preferred structure, the electrical current is modulated, rather than held at a constant value.

An alternative structure of an active displacement device uses rupture of the membrane by a mechanical force as the displacement mechanism. See eg, US Patent No. 5,167,625 to Jacobsen et al., Which discloses that rupture means that it can be modified or adapted to the devices described herein. A non-limiting example is the rupture of insurgencies by the forced contact of the emergent surface with a corbel axis that are manufactured using MEMS scimitar techniques or any other machinery technique (see Figure 4). Ultrasonic waves are an alternative method capable of breaking the emerging material to expose the displacement system and release the molecules (see Figure 5). The actuation of the piezoelectronic elements in or near the reservoir produces sonic waves that break up the emerging material. Piezoelectronic elements can be composed of any material having a crystal structure that is non-centrosymmetric. Preferred piezoelectric materials are ceramics, such as BaTiO₃, LiNbO₃ and ZnO (Chiang, Y., "Physical Ceramics", John Wiley

ES 2 332 869 T3 e Hijos, Inc., New York, pp. 37-66 (1997), and polymers, such as polyvinylidene (Hunter & Lafontaine, "A Comparison of Muscle with Artificial Actuators," 1992 Technical Summary of the Solid Sensor State and Actuator Workshop, pp. 178-85 (1992). These actuators can be manufactured in the form of thin sheets using standard techniques such as the sparking ion (Tjhen, et al., "Piezoelectronic Properties of Thin Sheets for Micromechanical Mechanism Systems", Procedures - lEEE Micro Electro Mechanical Systems, pp. 114- 19 (1991) and the sol-gel process as described, for example, in Klein, "Sol-Gel Optics: Applications and Processes", Kluwer Academic Editors, 1994). Ultrasonic energy can be replaced by components located in the delivery device, in the carrier fluid, or outside of the delivery carrier device. Methods for selecting which reserve exposed include, for example, the interference wave using secondary ultrasonic waves. The secondary waves can act to destructively interfere with the primary ultrasonic waves thus restructuring the application of energy to only a selected set of reservoirs.

Additional structures involve the passive release of molecules into the carrier fluid. A general example of this application is the deformation of the displacement system when located within or exposed to the fluid carrier. The chemical nature of the fluid, eg, acidic versus basic or polar versus nonpolar, can cause the emerging material to warp or dissolve (see Figure 5b). Once the emerging material is completely dissolved, the molecules will be displaced into an adjacent flowing liquid for the opening of the reservoir (see Figure 5c). The fluid can be any liquid or any gas that causes disintegration of the emergent material release system.

IV. Methods for manufacturing or assembly

Microchip devices can be made, for example, using techniques known in the art, particularly the methods described in US Patent No. 6,123,861 to Santini et al. However, the manufacturing of methods described in the patent using microfabrication and microelectronic process techniques, it is understood that the manufacture of the active and passive chemical microchip delivery devices is not limited to materials such as semiconductors or processes typically used in microelectronic manufacturing. . For example, other materials, such as metals, ceramics, and polymers, can be used in the devices. Similarly, other manufacturing processes, such as plating, casting, molding, can also be used to make them.

In a structuring, the deposits can also be formed using silicone-in-insulator (SOI) techniques, as described in S. Renard, "Industrial MEMS at SOI," J. Micromech Microeng. 10: 245-249 (2000). SOI methods can be usefully adapted to the shape of reservoirs having complex reservoir shapes, for example, as shown in Figures 2b, 2c, and 2e. SOI plates behave essentially like two substrate portions that have been bonded on a molecular atomic scale before any deposit has been made within each portion. SOI substrates react essentially as two substrate portions that have been attached to an atom or molecular scale before any reserves have been etched into either portion. SOI substrates easily allow the reservoirs (or reserve sections) on each side of the produced insulation to be manufactured independently, allowing the reservoirs on each side of the insulating product to take on different shapes. The deposit (portions) on either side of the insulating product can then be connected to form a simple deposit that has a complex geometry by removing the insulating product between the two reservoirs using methods such as reactive ion etching, laser, ultrasound, or etching. of wet chemistry.

The components of another system are provided from known sources or can be easily manufactured or adapted from known devices and methods.

IV. Applications

The delivery systems microchip can be used for drug delivery from the builds.

It is understood that the number, geometrically, and the location of each reservoir, pop-up reservoir, or other object (eg resistors (heaters), electrodes, or channels) in or near each reservoir can be modified for a particular application. For simplicity, only one tank is shown in some Figures. However, it is understood that a microchip component or device would contain at least two, and preferably many more reservoirs.

Supply of Prepared Medication

A structuring of a microchip device for the displacement of molecules within a carrier fluid involves the integration of one or more microchips of medication supplies within an elaborate, such as the vascular elaboration. The microchip-containing medication is preferably provided with one or more processing surfaces. Microchip mechanisms can be present in the build during implantation and during build expansion.

In a preferred structure, the microchips of the microchip brewing device are programmed or activated remotely or without wiring means delivering drugs directly from the brewing.

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A preferred application of the microchip-crafted device is the local delivery of anti-resin drugs to an artery that has recently undergone an angioplasty repair process. In another embodiment, microchip processing devices are used for the systematic delivery of one or more drugs to a patient via the flow of blood through the processing. In another structure, the brews may be designed and manufactured to have medication reserves and emergent as part of the brewing itself, which is, not as a separate microchip device, but rather as part of a monolithic brewing device. It is understood that both systematic and local supplies of any drug are possible using the technology microchip in combination with the manufactured ones.

The elaborate-microchip medication delivery devices are not limited to arterial and vascular applications. Integrated microchips with manufacturing technology can be used to deliver drugs through a variety of other channels in the human and animal body. Representative examples include the gastrointestinal tract, respiratory passages, reproductive and urinary tracts, renal veins, cerebrospinal fluid passages, and sinuous.

References cited in description

This list of references cited by the applicant is solely for the convenience of the reader. It is not part of the European Patent document. Although great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims any liability in this regard.

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