WO2007090044A2

WO2007090044A2 - Non-recirculating organ perfusion device

Info

Publication number: WO2007090044A2
Application number: PCT/US2007/061101
Authority: WO
Inventors: Gary Durack
Original assignee: Transplan, Inc.
Priority date: 2006-01-27
Filing date: 2007-01-26
Publication date: 2007-08-09
Also published as: WO2007090044A3; JP2009524693A; EP1981335A2

Abstract

The invention relates to a portable organ perfusion device to be used for storage and transport of an ex vivo organ, comprising a compression means for removing perfusion fluid from a perfusion fluid container, a means for adjusting flow rate of perfusion fluid, an organ container for receiving an organ and a quantity of perfusion fluid, an organ connector for forming a fluid connection between the means for adjusting flow rate and the vasculature of the organ, and a waste container for receiving used perfusion fluid. The components of the device are connected by medically suitable tubing and the explanted organ and perfusion fluid are maintained at a hypothermic temperature.

Description

NON-RECIRCULATING ORGAN PERFUSION DEVICE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 60/762,711, filed January 27, 2006, the contents of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to devices for perfusion of organs ex-vivo, in particular human organs such as the heart, liver, kidney and lungs for use in transplant operations. The invention further relates to methods of ex-vivo perfusion of such organs.

BACKGROUND

[0003] Surgical transplantations of hearts and lungs, first performed in around 1960, have become frequent procedures owing to the improvement of surgical techniques, the introduction of by-pass circulation and the development of drugs that suppress immune rejection of the donor organ. At the present time, the donor organ is conventionally harvested under sterile conditions, placed in a plastic bag submerged in a buffered salt solution, cooled to about 4°C and kept over crushed ice until the organ is finally transplanted into the recipient. The solution is not oxygenated and is not perfused through the organ blood vessels.

[0004] The lack of donor organ availability, particularly hearts, lungs, and livers, is a limiting factor for the number of organ transplants that can be performed. At the present time, less than 23% of patients who require a heart transplant ever receive a new heart, and less than 10% of patients who require a lung transplant receive one. In the United States the greatest number of heart transplants were performed in 1998, 2,334; the number has declined each year since, 2,182 were performed in 2002. A major consideration is the length of time that a donor organ will remain viable after it is harvested until the transplant surgery is completed. For hearts, using conventional storage techniques, this interval is about four hours. In four hours, 12% of the transported organs "die" or become unusable, and all the organs are damaged at the cellular level even during this short period. The donor heart must be harvested, transported to the recipient, and the transplant surgery completed within this four-hour time limit. Thus, at present donor hearts can be used only if they are harvested at a site close to the location where the transplant surgery will take place. [0005] It has been found that donor hearts and lungs will survive ex-vivo for a longer time if they are cooled to 4°C and actively perfused through their vascular beds with a buffered salt solution containing nutrients. It has also been found that ex-vivo survival of an isolated organ can be further extended if the solution is oxygenated. Several factors play a role in the prolonged survival. At 4°C metabolism is greatly reduced, lowering the requirements for nutrients and oxygen, and the production of lactic acid and other toxic end products of metabolism is also greatly reduced. Circulation of the perfusion fluid provides oxygen, replenishes the nutrients available to the tissue, and removes the lactic acid and other toxic metabolites. The buffered solution maintains the intracellular pH and electrolyte concentrations of the tissue close to physiological.

[0006] There have been previous attempts to develop workable systems for low temperature preservation of organs. One device that has been proposed for maintaining organs in vitro is described in US Patent No. 3,545,221. The device comprises a pressurized organ preservation receptacle in which e.g. a kidney may be immersed in a preserving solution at a temperature of 0 to 4⁰C. The organ may be supplied with a perfusion solution by gravity feed from a suspended container.

[0007] According to an alternative device known from US Patent No. 3,995,444 a pulsatile flow of cold perfusate is circulated through a harvested organ. The organ is supported in an organ chamber on a perforated panel that allows perfusate draining from the organ to collect in a well at the bottom of the chamber.

[0008] Another organ preservation system is disclosed in US Patent No. 5,326,706 which discloses an outer insulated container containing an inner organ chamber for holding a donor organ. A perfusion solution is circulated around a circuit, passing through the organ. The perfusate pressure is measured and a pump control circuit adjusts the pump pulse rate in accordance with the pressure of the perfusate. The pump comprises a flexible membrane, actuated by a source of carbon dioxide gas.

[0009] A device that discloses a combined pumping and oxygenation function is known from US Patent No. 5,362,622. The organ is stored in a compliant chamber submerged in a perfusate. In this device, a cyclically pumped source of oxygen acts on a gas permeable membrane to simultaneously oxygenate the perfusate and pump the oxygen-enriched perfusate through the organ. The device may be placed in an insulated container provided with cool packs to maintain the organ a temperature of around 4⁰C.

[0010] An alternative device that can be used for static storage or perfusion of an organ is known from US Patent No. 5,586,438. The device comprises an organ container in which an organ may be supported between pads of soft sterile foam material. The organ is connected via a perfusion tube to a bubble trap. The bubble trap is in turn connected to an arterial line while a venous line has an open end at the bottom of the organ container. For the purpose of perfusion, the venous and arterial lines extend outside the container for connection to an appropriate pump. The entire device may be inserted into an insulated and cooled organ shipping box for transport.

[0011] More recently, further developments have attempted to maintain organs at a substantially normothermic temperature. One such device is described in US Patent No. 6,100,082 in which an organ is enclosed in a preservation chamber or pouch. In the described example, fluid connections to the aorta, pulmonary artery and left atrium are provided to permit various possible perfusion flows of warmed, oxygenated blood to a beating heart.

[0012] An alternative support system for maintaining an organ at a near normal metabolic rate is disclosed in US Patent No 6,642,045. The organ is supported on an organ support within an organ chamber. Perfusate is pumped to the organ through a heat exchanger, to bring the perfusate temperature to 25 - 27⁰C, and an oxygenator. Venous effluent from the organ is collected in an effluent reservoir below the organ and may be recirculated. Various sensors are provided in the circuit to monitor parameters of the perfusate. The specific problems related to normothermic preservation of organs are well documented and may at least be partially overcome by the reduced temperature operation of the device according to the present invention.

[0013] Among the problems encountered in the prior art are a high degree of expertise required to handle the preservation apparatus, limited portability due to large and heavy devices, excessive reliance on electrical and mechanical parts that may malfunction and decrease chances for organ survival, recirculation of fluid containing cellular and tissue debris, and a lack of sterility. BRIEF SUMMARY OF THE INVENTION

[0014] The present invention is directed to a portable organ perfusion device that fulfills the considerations stated above. The device according to the invention is a self-contained unit designed to maintain viability of the human heart for 16 hours or more. After the donor heart is removed, the aorta is sewn to an adapter that snaps into an organ container filled with oxygenated perfusion fluid. Perfusion fluid is pre-oxygenated and supplied in a container similar to an i.v. bag. A force is applied (i.e. a spring-biased wall, compressed gas, weight) to push the fluid from the bag through flexible tubing to an adjustable fluid resistor which supplies the organ in the organ container with perfusion fluid at a rate of 2 ml/min to 20 ml/min. Perfusion fluid exits the organ container through an outlet through flexible tubing that is connected to a waste bag in which exiting fluid is collected. The organ perfusion system is contained within an insulated, protective housing. Use of one-way valve connections at the organ container inlet, organ container outlet, and waste container ensures that the flow of fluid will be in a single direction. The perfusion fluid and organ container are maintained at 4⁰C throughout the holding period by means of heat exchangers and/or cooling systems. Thus, the organ is fed with proper nutrients contained in the perfusion fluid, chilled to a temperature that sustains the organ for the appropriate period of time, and protected during transport. The result is an organ that can be stored for an extended period of time in transplantable condition.

[0015] Among the advantages of the present invention is that the perfusion fluid does not require an external oxygen source since it is pre-oxygenated. The elimination of the need for an oxygen tank provides for a more compact, portable organ preservation and transport system. Similarly, the flow of perfusion fluid is not necessarily dependent on an electrical pumping system that requires a power supply thereby allowing for greater portability. Moreover, elimination of the dependency on a connection to an external oxygen source or electrical pumping system decreases the likelihood of mechanical or electrical failures that may affect the viability of the organ.

[0016] In one embodiment, the invention comprises a perfusion system consisting of an outer insulated housing wherein the housing has a clam-shell design to facilitate the opening and closing of the device for a technician to replace used oxygenated perfusion fluid supply bags and waste bags as well as for ease of positioning the organ in the device. The replacement of the supply and waste bags is further facilitated by including cross-over valves on each to ensure the uninterrupted operation of the perfusion system. The walls of the clamshell casing may be filled with an insulation gel which when cooled retains a hypothermic temperature within the insulated casing upon refrigeration longer than if the gel were absent.

[0017] The portable organ perfusion device will deliver organs in better physiological condition, shorten recovery times, reduce overall cost, increase available time to improve tissue matching and sizing of an organ. Moreover, the device facilitates performing clinical chemistries and diagnostic testing for infectious diseases prior to transplantation, enlarges selection of donor organs, and widens the range of available organs.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The invention will now be further elucidated by way of exemplary embodiments that form no limitation to the appended claims, and with reference to the following drawings.

[0019] Figure 1 shows a diagram of the non-recirculating organ perfusion device according to the invention;

[0020] Figure 2 shows a perspective view of the non-recirculating organ perfusion device contained within an insulated housing.

[0021] Figure 3 shows a diagram of an alternate embodiment of the organ perfusion device according to the invention

DETAILED DESCRIPTION OF THE INVENTION

[0022] The invention is directed to a portable organ perfusion device that preserves organs for transplantation for 16 hours or more, thereby facilitating the transportation of organs ex vivo, allowing time to perform tests to rule out infection of the donor, reducing the pressure of transplant surgeons to complete surgery within a short time frame, and decreasing the damage to the organ due to lack of oxygenation. The device is non-recirculating, meaning that perfusion fluid passes through the donor organ once and is not recycled. The following description is made by way of example and is not intended to limit the invention as set out in the appended claims. A heart will be used by way of example to illustrate the advantages of the invention.

[0023] The organ perfusion device of the present invention comprises a compression means to force a pre-oxygenated perfusion fluid from a perfusion fluid container. The fluid then travels through an adjustable fluid resistor to control the flow of perfusion fluid. The fluid then perfuses the explanted organ in an organ container and exits the organ container through an outlet and is finally deposited in a waste container. The perfusion fluid container, adjustable fluid resistor, organ container, and waste container may be connected by medically suitable tubing.

[0024] After a donor heart is removed, the aorta is sewn to an adapter that snaps into an organ container filled with the oxygenated perfusion fluid. The perfusion fluid provides the heart with oxygen and nutrients. Perfusion is initiated upon attachment and deposit of the donor heat in the organ container. Perfusion occurs in a single direction and is powered by a compression means to apply force to the perfusion fluid container comprising the pre- oxygenated perfusion fluid. Oxygenated perfusion fluid exits the perfusion fluid container into a medically suitable tubing system. The device may comprise a crossover valve proximal to where the perfusion fluid exits the perfusion fluid container to facilitate switching perfusion fluid containers when one becomes depleted. The adjustable fluid resistor is located between the compression means and the organ container and limits the flow of the perfusion fluid whereby the flow of perfusion fluid to the donor heart preferably falls within the range of 2 ml/min to 20 ml/min. The perfusion fluid enters the donor heart via the aorta and passes to the coronary artery of the heart for perfusion through the circulatory system of the heart. The perfusion fluid exits from the cardiac system via the coronary vein and/or vena cava directly into the interior of the organ container. Used perfusion fluid exits the organ container through an outlet and flows into the waste container. A second crossover valve proximal to the waste container facilitates switching waste containers when one becomes full.

[0025] The perfusion system is contained within an insulated housing. The insulated housing may be of a clam shell design to facilitate the opening and closing of the device and switching of depleted pre-oxygenated perfusion fluid containers and full waste containers. [0026] The oxygenated perfusion fluid may be maintained at 4⁰C through the use of cooling packs which may be removable from the housing. A hypothermic temperature may be maintained by filling the walls of the housing with a hypothermic gel and refrigerating the housing prior to use. The walls of the housing may also be filled with ice. The organ perfusion device may also be cooled by filling the housing with ice which can be replaced by the technician when switching the pre-oxygenated perfusion fluid and waste containers.

[0027] The organ perfusion device can easily be loaded and unloaded by surgical personnel and the fittings require minimal dexterity to assemble and disassemble. The waste container allows for easy isolation and disposal of used perfusion fluid reducing the likelihood of the technician's exposure to biohazard waste. In a preferred embodiment, the portability of the device is improved by the use of a pre-oxygenated perfusion fluid which eliminates the necessity of an external oxygen source and reduces the size of the device although in alternate embodiments, a fluid oxygenation source may be used.

[0028] The present invention preferably uses mechanical means for powering the flow of perfusion fluid and preferably does not have to rely on electrically powered components such as pumps or temperature and pH monitors since the technician can frequently test these parameters each time the pre-oxygenated perfusion fluid container is switched. The lack of electrical components and external oxygen source reduces the likelihood of the device malfunctioning thereby improving the reliability of the device and the viability of the transplanted organ. Moreover, the use of a non-recirculating system alleviates the problem of circulating tissue debris which may disrupt proper perfusion of the donor organ.

[0029] Identical reference numerals used in the figures refer to similar parts.

[0030] Referring to Figure 1, where reference numeral 1 indicates the organ perfusion device according to the invention.

[0031] The organ perfusion device 1 is suitable for transport and storage of an ex vivo organ 2 and is comprised of a compression means 3 that acts upon a pre-oxygenated perfusion fluid container 4 thereby forcing the perfusion fluid to flow out of the container 4 toward an adjustable fluid resistor 5 that limits the flow of perfusion fluid between 2 ml/min to 20 ml/min. The perfusion fluid then enters an organ container 6 via the organ adapter 9 and perfuses the donor heart 2 located therein by entering the donor heart 2 through the aorta and exiting through the coronary vein and/or vena cava into the interior of the organ container. The used fluid then exits the organ container and is finally deposited in a waste container 7 all connected by medically suitable tubing 8. The compression means 3 may be a spring loaded wall, compressed gas, or a weight that forces fluid from the pre-oxygenated perfusion fluid container 4. A first crossover valve 11 is located proximal to the perfusion fluid container 4 and has a replacement connection 12 which allows the technician to replace used perfusion fluid containers 4 without disrupting organ perfusion. A second crossover valve 13 is located proximal to the waste container 7 and has a second replacement connection 14 which allows the technician to replace used waste containers 7 without disrupting organ perfusion.

[0032] Figure 2 shows a perspective view of the organ perfusion device 1 contained within an insulated housing 15. The housing 15 has a clamshell design with an insulated lid 16 that opens easily allowing the technician to replace depleted perfusion fluid containers 4, full waste containers 7, cooling packs, or ice. The walls of the insulated housing 17 may be hollow and filled with a gel to aid in maintaining a hypothermic temperature.

[0033] Figure 3 shows an alternate embodiment of the organ perfusion device according to the invention wherein the compression means 3 is a compressed gas that exerts force on the perfusion fluid container 4 thereby causing perfusion fluid to exit the perfusion fluid container 4 that are enclosed within a cooler 18. The compression means 3 exerting force on the perfusion fluid container 4 may also be in the form of a spring-biased wall or a weight. Upon exiting the perfusion fluid container 4, the fluid may optionally enter a bubble trap 19 to remove excess bubbles prior to entering the organ container 6. Using the heart 2 as an example, the perfusion fluid may enter the aorta, circulate through the vasculature and exit through the coronary vein and/or vena cava into the interior of the organ container 6. The organ container 6 is comprised of two outlets. Excess perfusion fluid exits the first outlet 10 and is deposited in the waste container 7. Perfusion fluid may optionally exit the organ container via a second outlet 20 by action of a pump 21. The optional pump 21 may direct the perfusion fluid to a water bath 22 comprising a cooling loop 23 or other cooling means which serves to chill the used perfusion fluid. The chilled used fluid exits the water bath 22 by either a) returning to the organ container via an inlet 24 to chill the explanted organ, or b) returning to the cooler 18 via a cooler inlet 25 to chill the fresh perfusion fluid in the perfusion fluid containers 4. The cooler comprises an outlet 26 which circulates chilled used fluid between the cooler 18 and the water bath 22 thereby maintaining a hypothermic temperature of both the perfusion fluid and the explanted organ 2.

Claims

1. A device for ex-vivo perfiαsϊon of an organ, the device comprising in a non- recirculating system; a compression means for removing perfusion fluid from a perfusion fluid

Container; a means for adjusting flow rate of perfusion fluid; an organ container for receiving an organ and a quantity of perfusion fluid; an organ connector for forming a fluid connection from the means for adjusting flow rate to the vasculature of the organ; and a waste container for receiving used perfusion fluid.

2. The device of claim 1 wherein said perfusion fluid container, means for adjusting flow rate, organ container, and waste container are connected by a means for transferring perfusion fluid comprising medically suitable tubing.

3. The device of claim 2 wherein the perfusion fluid container is connected to the means for transferring perfusion fluid by a crossover valve.

4. The device of claim 1 wherein said means for adjusting flow rate of perfusion fluid comprises a fluid resistor.

5. The device of claim 2 wherein the means for transferring perfusion fluid is connected to the waste container by a crossover valve.

6. The device of claim 1 wherein said organ container comprises a fluid inlet and a fluid outlet.

7. The device of claim 2 wherein means for transferring perfusion fluid transfers fluid in one direction.

8. The device of claim 1 wherein said compression means comprises a container with a spring biased wall.

9. The device of claim 1 wherein said compression means comprises a weight.

10. The device of claim 1 wherein said compression means comprises a pressurized chamber.

11. The device of claim 1 wherein said compression means, means for adjusting flow rate of perfusion fluid, organ container, organ connector, and waste container are located within the insulated casing.

12. The insulated casing claim 11 wherein said insulated casing has a clamshell design. lS. The device of claim 1 1 wherein said insulated casing further comprises a means for maintaining a hypothermic temperature.

14. The device of claim 13 wherein said means for maintaining a hypothermic temperature comprises a heat exchanger.

15. The device of claim 13 wherein said heat exchanger comprises cooling packs.

16. The device of claim 13 wherein said heat exchanger comprises a hypothermic gel.

17. The device of claim 13 wherein said heat exchanger comprises ice.

18. A fluid for the perfusion of organs wherein said fluid is pre-oxygenated.

19. The fluid of claim 18 wherein said fluid is pre-packaged in a container.