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WO2006118990A2 - Procede et dispositif destines a la perfusion d'organe - Google Patents

Procede et dispositif destines a la perfusion d'organe Download PDF

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Publication number
WO2006118990A2
WO2006118990A2 PCT/US2006/016163 US2006016163W WO2006118990A2 WO 2006118990 A2 WO2006118990 A2 WO 2006118990A2 US 2006016163 W US2006016163 W US 2006016163W WO 2006118990 A2 WO2006118990 A2 WO 2006118990A2
Authority
WO
WIPO (PCT)
Prior art keywords
organ
chamber
perfusion
fluid
perfusion fluid
Prior art date
Application number
PCT/US2006/016163
Other languages
English (en)
Other versions
WO2006118990A3 (fr
Inventor
Marlin L. Alford
Robert M. Dowben
Original Assignee
Transplan, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Transplan, Inc. filed Critical Transplan, Inc.
Priority to EP06751728A priority Critical patent/EP1879997A2/fr
Publication of WO2006118990A2 publication Critical patent/WO2006118990A2/fr
Publication of WO2006118990A3 publication Critical patent/WO2006118990A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/14—Mechanical aspects of preservation; Apparatus or containers therefor
    • A01N1/142—Apparatus
    • A01N1/143—Apparatus for organ perfusion
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts

Definitions

  • 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.
  • 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 4 0 C.
  • the organ may be supplied with a perfusion solution by gravity feed from a suspended container.
  • US Patent No. 5,326,706 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.
  • 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.
  • a cyclically pumped source of oxygen acts on a gas permeable membrane to simultaneously oxygenate the perfusate and pump the oxygen-enriched perflisate through the organ.
  • the device may be placed in an insulated container provided with cool packs to maintain the organ a temperature of around 4 0 C.
  • 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.
  • 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.
  • the device comprises a fluid circuit in which are arranged an organ chamber for receiving the organ and a quantity of a perfusion fluid; a pump for circulating the perfusion fluid around the fluid circuit; an oxygenator for oxygenation of the perfusion fluid; a pressure head device for maintaining a substantially constant pressure fluid supply to the organ; and an organ connector for forming a fluid connection from the pressure head device to the vasculature of the organ.
  • Prior art devices have attempted to provide constant pressure supply using pumps calibrated to an appropriate flow rate. As perfusion continues however, stricture may occur in certain vessels of the organ leading to localized increase in pressure. As the pressure backs up, further edema may occur leading to further pressure increase. By ensuring that a constant pressure is supplied to the organ, damage due to edema can be substantially eliminated
  • the organ chamber has an organ chamber inlet and an overflow connection is provided from the pressure head device to the organ chamber inlet.
  • an overflow connection is provided from the pressure head device to the organ chamber inlet.
  • the organ chamber is provided with a sealed closure with the organ connector passing through the closure.
  • the closure is of sufficient size and can be opened to allow insertion and removal of the organ from the organ chamber. This provides an extremely convenient arrangement for insertion of the organ into the chamber as e.g the arterial connection to the organ vasculature may be connected to the organ connector prior to inserting the organ into the organ chamber.
  • the organ connector may be clipped in to a further connector passing through a wall of the organ chamber.
  • the organ may itself be suspended from the closure by the organ connector. This is considered preferable to certain prior arrangements in which the organ is supported from below on a solid platform. In particular, if the organ is immersed or substantially surrounded by the perfusion fluid, good protection against shocks is ensured while the organ is optimally bathed by the perfusion fluid.
  • the organ chamber may be provided with a number of additional connections.
  • a filtered vent may be communicate with an upper part of the organ chamber allowing pressure equalization of the interior of the organ chamber.
  • the organ chamber may comprise a chamber outlet located at an upper level of the organ chamber. The height of the chamber outlet may determine the level of the perfusion fluid within the organ chamber by acting as an overflow. As the fluid level rises above the chamber outlet, the perfusion fluid will flow out of the chamber and may be recirculated.
  • the organ chamber may also preferably provide connections for insertion of various sensor probes for determining the condition of the perfusion fluid as will be explained in further detail below.
  • the pressure head device comprises a chamber having a free surface located at a vertical distance above the organ.
  • the pressure head device is itself located above the organ chamber but it is also within the scope of the invention inai only an upper portion of the pressure head device extends upwards and that the free surface is located in this upper portion.
  • free surface refers to a surface of the perfusion fluid which determines the pressure head pressure with respect to the organ. Such a free surface is preferably achieved by providing an overflow outlet to the pressure head chamber such that excess fluid in the chamber will overflow through the overflow connection to the organ chamber.
  • the pressure head device also comprises a filtered vent allowing pressure equalization of an interior of the pressure head device, then both the free surface of the pressure head device and that of the organ chamber will be at atmospheric pressure.
  • the total head is the vertical distance between the two free surfaces.
  • the location of these free surfaces may be adjustable to adjust the pressure of the fluid supply to the organ. This may be achieved by changing the relative heights of the respective chambers.
  • the pressure head device has been described as a gravity feed, the skilled reader will readily understand that alternative forms of pressure head device, such as pressure responsive valves, may be used that ensure that excess fluid is circulated instead of being delivered to the vasculature.
  • the oxygenator may be located in the fluid circuit between the pressure head device and the organ. In this way, only the fluid that is actually perfused to the organ vasculature is directly supplied with oxygen prior to entering the organ. The remainder of the fluid in the circuit will have a lower oxygen content. This provides for a greater efficiency of oxygen usage and also allows oxygen usage across the organ to be more readily monitored. This may be achieved by providing an upstream oxygen sensor located in the fluid circuit between the oxygenator and the organ. The sensor may sense the oxygen saturation level of the oxygenated perfusion fluid or any equivalent indicator of this value.
  • an oxygenator comprising an oxygen inlet and an oxygen outlet connected by an oxygen permeable member.
  • a source of oxygen connected to the oxygen inlet causes a flow of oxygen through the oxygen permeable member.
  • the oxygen permeable member preferably comprises a plurality of small bore silastic tubing elements arranged in parallel.
  • the oxygenator may further comprise an oxygenation chamber having an oxygenation inlet for perfusion fluid and an oxygenation ouiiel for oxygen enriched perfusion fluid, the oxygen permeable member being located within the oxygenation chamber between the oxygenation inlet and the oxygenation outlet. In this manner, perfusion fluid entering the chamber via the inlet is obliged to pass over the oxygen permeable member if it is to exit via the oxygenation outlet.
  • the oxygenator and the pressure head device may be combined as a single unit.
  • an overflow outlet and a filtered vent will be arranged at an upper level within the oxygenation chamber providing an alternative outlet for perfusion fluid to exit without passing over the oxygen permeable member.
  • a heat exchanger for cooling the perfusion fluid in the fluid circuit.
  • the heat exchanger may comprise an insulated container containing a cooling medium such as ice or equivalent cooling packs.
  • a heat exchange channel for the perfusion fluid can pass through the insulated container in heat exchanging relation with the cooling medium.
  • a copper coil has been found suitable for use as a heat exchange channel although the skilled person will be well aware of further heat exchange elements that could ensure adequate heat transfer from the perfusion fluid to the cooling medium. For longer-term perfusion, circulation of the cooling medium or further refrigeration capability could also be provided.
  • a bypass is provided allowing perfusion fluid to pass around the heat exchanger.
  • a flow control member controls the amount of bypass flow.
  • a number of sensors may be provided at various locations in and around the fluid circuit.
  • a temperature sensor for monitoring the temperature of the perfusion fluid and/or monitoring the temperature within the device may be provided.
  • Output of the temperature sensor or sensors may be used to control operation of the heat exchanger.
  • a downstream oxygen sensor for defecting an amount of oxygen entrained in the perfusion fluid after passing through the organ;
  • a pH sensor for detecting a pH value of the perfusion fluid;
  • a CO 2 sensor for detecting an amount OfCO 2 entrained in the perfusion fluid and further sensors for detecting other characteristics of the organ or parameters of the perfusion.
  • the above sensors may preferably be located in the organ chamber but may also be located at any other convenient location where they can provide a reliable and accurate indication of the sensed value.
  • the device comprises a monitoring unit operatively connected to receive sensor input from the above-mentioned sensors.
  • the sensor input provides an indication of actual parameters of the operation of the device.
  • a particularly important parameter for monitoring is the oxygen uptake across the organ which can be determined by monitoring the oxygen saturation level of the perfusion fluid upstream and downstream of the organ.
  • the device comprises a control unit operatively connected to receive user input from a user input device indicative of a desired value for certain parameters of operation of the device.
  • the control unit may then control operation of the device to achieve such desired parameters.
  • the control unit may control various elements of the device including but not limited to: the speed of the pump; the value of the constant pressure supply; the operation of the flow control member governing flow around the heat exchanger; the oxygen supply; and the addition of additional medication.
  • a source of cooling is also provided to the interior of the housing.
  • the housing is preferably also provided with a dedicated source of energy making the whole device easily portable for transport of an organ.
  • the device is particularly suited to perfusion of a heart.
  • Other organs such as the lungs, kidney and liver may also be treated as may other less conventionally transplanted organs and members such as severed limbs.
  • perfusion solution may be used according to the nature of the organ to be oerf ⁇ sed.
  • a Celsior type solution is preferred although adjustment of certain concentrations of elements may be required in order to optimize the preservation action at the chosen temperature.
  • the device further comprises a medication infusion device operative to controllably introduce a quantity of medication into the perfusion fluid circuit.
  • a medication infusion device operative to controllably introduce a quantity of medication into the perfusion fluid circuit.
  • a method of ex-vivo perfusion of an organ comprising: circulating a perfusion fluid at a first volumetric flow rate around the a fluid circuit; providing a supply of a perfusion portion of the perfusion fluid to the organ to realize a second volumetric flow rate through the vasculature of the organ, wherein the second volumetric flow rate is lower than the first volumetric flow rate; and supplying an overflow quantity of perfusion fluid, corresponding to the difference between the first and second volumetric flow rates, to a bypass line for bypassing the vasculature of the organ.
  • the method may be performed as further herein described below.
  • a self-contained unit designed to maintain viability of a human heart for 16 hours or more.
  • the aorta is sewn to an adapter that snaps into the organ chamber filled with oxygenated perfusion fluid.
  • the pressure head device combined with oxygenation chamber is mounted atop the organ chamber and partially filled with perfusion fluid.
  • the oxygenated fluid is maintained at 4° C throughout the holding period and continually circulated through the organ by gravity during storage.
  • the fluid is oxygenated as it passes through the oxygenator just before the fluid enters the organ.
  • the organ is fed with the proper nutrients contained in the perfusion fluid, chilled to a temperature that sustains the organ for the longest period of time, and protected from bruising during a potentially bumpy ride.
  • the result is an organ in pristine condition.
  • Perfusion that allows the transport of a harvested organ from a site distant from the location where the transplant surgery will be carried out requires the device to be lightweight, portable and to operates under sterile conditions for pumping the cold buffered nutrient salt perfusion soiuiion ihiough the organ blood vessels.
  • the device In order for one person to carry the entire assembly without assistance, and to transport it in an auto or airplane, it is preferably compact, sturdy and light-weight.
  • the system for loading the perfusion fluid is simple resulting in minimal spillage due in part to the large opening to the organ chamber. Appropriate arrangements are provided to ensure that sterility is maintained.
  • the device contains a source of oxygen, an energy source to operate the pump, sensors and alarms, and the housing is insulated, water tight and can be loaded with cold packs.
  • the insulated housing may be a single unit molded e.g. using polycarbonate and provided with the control panel and battery on the exterior. All fluid and gas lines may be color coded and supplied with quick connect closures. A "C" style oxygen bottle with regulator is preferred containing sufficient oxygen for 30+ hours of perfusion. Alarms may be included in the system in case of pump failure (loss of pressure), oxygen loss, or temperature spike, any of which could be fatal errors if not quickly corrected.
  • the organ perfusion device can be easily loaded and unloaded by double-gloved surgical personnel and the fittings require minimal dexterity to assemble and disassemble.
  • the device according to the invention will deliver organs in better physiological condition, shorten recovery times, reduce overall cost, increase the available time to improve tissue matching and sizing of the organ, to perform clinical chemistries and diagnostic testing for infectious diseases prior to transplantation, enlarge selection of donor organs, and widen the range of available organs.
  • Figure 1 shows a schematic circuit diagram of the fluid circuit of an organ perfusion device according to the invention
  • Figure 2 shows a perspective view of a preferred embodiment of an organ chamber according to the invention
  • Figure 3 shows the organ chamber of figure 2 in plan elevation;
  • Figure 4 shows a cross-section through the device of Figure 3 along line A-A;
  • Figure 5 shows a perspective view of a preferred embodiment of an oxygenator according to the invention
  • Figure 6 shows a side elevation of the oxygenator of Figure 5;
  • Figure 7 shows a front elevation of the oxygenator of Figure 5
  • Figure 8 shows a detailed view of the oxygen inlet of Figure 6
  • Figure 9 shows a cross-section through the oxygen inlet of Figure 6 along line C-C;
  • Figure 10 shows a cross-section through the device of Figure 7 along line D-D;
  • Figure 12 shows a front elevation of the organ perfusion device of Figure 11 ;
  • Figure 13 shows a side elevation of the organ perfusion device of Figure 11;
  • Figure 14 shows a plan elevation of the organ perfusion device of Figure 11 ;
  • Figure 15 shows an elevation of the organ perfusion device of Figure 11 in the direction F.
  • FIG. 1 there is disclosed a schematic representation of an organ perfusion device 1 for ex-vivo perfusion of an organ according to the present invention.
  • the device comprises a number of individual components, connected together to form a fluid circuit 2 and a number of further components, peripheral to and interacting with the fluid circuit.
  • a first item in the fluid circuit 2 is an organ chamber 10.
  • the organ chamber 10 has a chamber inlet 12 and a chamber outlet 14.
  • an organ 16 is suspended from an organ connector 18 and almost completely immersed in a perfusion fluid 20.
  • the organ chamber 10 has a closure 22 in which the organ connector 18 is supported.
  • the closure 22 also supports a filtered vent 24, an oxygen and temperature probe 26 and a pH probe 28.
  • the chamber outlet 12 is connected to a pump inlet 30 of a pump 32 for circulating the perfusion fluid 20.
  • the pump 32 may be any commercially available medical circulation pump.
  • the pump also has a pump outlet 34.
  • the pump outlet 34 connects via a two-way valve 36 to a heat exchanger 38 for cooling the perfusion fluid 20.
  • the heat exchanger 38 has a hx inlet 40, a hx outlet 42 and a hx bypass 44, the function of which will be described in further detail below.
  • a further component in the fluid circuit is an oxygenator 46 for oxygenation of the perfusion fluid.
  • the oxygenator 46 has an oxygenation chamber 48 having a threaded cap 50 hermetically sealed thereto.
  • the oxygenator 46 also comprises a number of ports for connection tn ⁇ e fluid circuit 2 and to an oxygen source 52.
  • an oxygenator inlet port 54 is connected in fluid communication with the hx outlet 42 of the heat exchanger 38 and an overflow port 56 is connected to the organ chamber inlet 12.
  • an oxygen inlet 58 and an oxygen outlet 60 are provided at a lower part of the oxygenation chamber 48.
  • the oxygen inlet 58 and oxygen outlet 60 are connected together internally of the oxygenation chamber 48 by an oxygen permeable member 62 as will be described in further detail below.
  • the oxygen inlet 58 is connected to the oxygen source 52, the oxygen outlet 60 connects to a vent 64 Also, at the lower part of the oxygenation chamber 48, there is provided an oxygenator outlet port 66.
  • the oxygenator outlet port 66 is connected in fluid communication to the organ connector 18 on the organ chamber closure 22.
  • the oxygenator 46 is also provided with a filtered vent 68 for equalizing pressure within the oxygenation chamber 48.
  • the filtered vent 68 is connected through the threaded cap 50.
  • an oxygen saturation probe 70 is provided in the oxygenator outlet port 66.
  • the entire perfusion fluid circuit 2 is contained in an insulated housing 72.
  • the oxygen source 52 is exterior to the housing 72.
  • a control unit 74 and alarm system 76 are located exterior of the housing 72.
  • Control unit 74 comprises a display 78 and a number of input keys 80. It is connected to the alarm system 76 for generation of appropriate alarms to medical personnel in the event of malfunction etc. of the organ perfusion device 1.
  • Figures 2 to 4 show a number of views of an organ chamber 10 according to a preferred embodiment of the invention for use in the perfusion and transport of a heart.
  • the organ chamber 10 comprises a generally cylindrical body 81 having a removable secondary lid 82 in which the access opening 21 is provided.
  • the closure 22 is retained in a closed position by a pair of fastening elements 84 of the quarter turn locking fastener type.
  • the fastening elements 84 engage through the closure 22 into locking recesses 86.
  • seals 88, 90 are located respectively between the organ chamber 10 and the secondary lid 82 and between the secondary Hd 82 and the closure 22.
  • Hold-down clamps 92 retain the secondary lid 82 in position and also serve to immobilize the organ chamber 10 during transport.
  • FIG 4 also illustrates the construction of the organ connector 18.
  • the organ connector 2 comprises an organ portion 94 and a closure portion 96.
  • the organ portion 94 may be connected to the organ by the surgeon by means of sutures. In the present case this is attached to the aorta, distal to the coronary artery for perfusion of the coronary vasculature.
  • the closure portion 96 is connected through the closure 22. It is understood however that the closure portion 96 could also be integrally formed as part of the closure 22.
  • the organ portion 94 and closure portion 96 are embodied as mating quick-connect connectors allowing a harvested organ 16 to be attached to the closure in an efficient fluid-tight manner. Any suitable medical grade quick-connect system e.g. luer lock, may be used for the organ connector.
  • FIGs 5 to 10 show a number of views of the oxygenator 46 according to the preferred embodiment of the invention.
  • the oxygenator 46 has a generally cylindrical oxygenation chamber 48 having a base 100 and threaded cap 50 hermetically sealed thereto.
  • a seal 98 is arranged between the oxygenation chamber 48 and the cap 50.
  • the connection between the cap 50 and the filtered vent 68 is also visible in Figure 10.
  • FIGs 6 and 7 clearly show the location of the oxygenator inlet port 54 and overflow port 56 at the upper portion of the oxygenation chamber 48 and also the oxygenator outlet port 66 located centrally in the base 100.
  • the oxygenator outlet port 66 is in the form of a standard Y-connector 1 12.
  • the oxygen saturation probe 70 is inserted into a side branch 114 of the Y-connector 112.
  • the oxygen inlet 58 and oxygen outlet 60 enter the oxygenation chamber 48 adjacent to the base.
  • the form of the oxygen inlet 58 is shown in further detail in Figures 8 and 9.
  • the oxvgen o ⁇ tW 60 is essentially identical to the oxygen inlet 58 and will not be further described.
  • the oxygen inlet 58 comprises a threaded plug 102 that can be secured hermetically into a mating socket in the wall of the oxygenation chamber 48.
  • the plug 102 has a stub connector 104 for reception of tubing 106 leading to the oxygen source 52.
  • a plurality of small bores 108 - in this case 8 - pass through the plug 102. Each bore 108 receives an end of a section of silastic tubing 1 10.
  • the silastic tubing 110 is preferably .07" diameter medical grade tubing and has been found to be particularly suitable as an oxygen permeable member 62.
  • the silastic tubing 110 is potted into the stub connector 104 using a suitable potting compound. As can be seen in Figure 7, the silastic tubing 110 extends from the oxygen inlet 58 to the oxygen outlet 60.
  • Figures 11 to 15 illustrate the configuration of the organ perfusion device 1 according to the preferred embodiment.
  • insulated housing 72 is partially cut-away to reveal the organ chamber 10, oxygenator 46 and heat exchanger 38. These components are connected together by standard 3/16" internal diameter medical grade tubing (not shown) to form the fluid circuit 2 as described above.
  • the tubing is color coded to ensure correct connection of the fluid circuit 2.
  • a preferred material for the housing is polystyrene although other plastics materials or combinations of material offering good thermal insulation and the necessary rigidity may also be used.
  • Figure 11 also shows a frame 1 12 providing additional rigidity to the structure and also serving as a mounting for the attachment of various components.
  • the insulated housing 72 is omitted for the sake of clarity.
  • the hold-down clamps 92 are attached at their lower ends 1 14 to a base plate 1 16 to prevent movement of the organ chamber 10.
  • the oxygenator 46 is also supported from the base plate 116 by a pair of stands 118. Stands 118 maintain the oxygenator 46 at the correct height above the organ chamber 10. This height is adjustable by appropriate connections between the oxygenator 46 and the stands 118. Although not shown, it is understood that automatic height adjustment could also be provided.
  • FIGs 13, 14 and 15 show respectively a side view, plan view and angled view of the organ perfusion device 1.
  • the location of the oxygen source 52 on the rear face of the frame 1 12 is shown.
  • the pump drive 120 is located externally of the insulated housing 72 and communicates with the pump 32 (not shown) located inside the insulated housing 72 and forming part of the fluid circuit 2.
  • the pump drive 120 is located externally of the insulated housing 72 and communicates with the pump 32 (not shown) located inside the insulated housing 72 and forming part of the fluid circuit 2.
  • the organ perfusion device 1 Prior to use, the organ perfusion device 1 is prepared for receipt of an organ: the organ chamber 10 is partially filled with a quantity of perfusion fluid 20, cooled to around 40 C; ice packs are inserted into the heat exchanger 38; the battery 122 is fully charged; and a fresh source of oxygen 52 is connected. The device 1 may then be primed by operation of the pump 32 for circulation of the perfusion fluid 20 around the fluid circuit 2 to remove any unwanted air that may be present.
  • An organ 16 is removed from a donor according to the applicable protocol.
  • the present example will be given in relation to a heart but it is to be understood that the principles of the procedure may be adapted for the ex vivo perfusion of any organ.
  • the harvested organ 16 is then attached to the organ portion 94 of the organ connector 18 by suturing of the aorta such that the interior of the organ portion 94 communicates with the entry to the coronary artery.
  • the fastening elements 84 are unlocked and the closure 22 is removed.
  • the organ 16 may then be lowered into the organ chamber 10 and the two parts of the organ connector 18 are joined together.
  • a further quantity of perfusion fluid 20 may be added if necessary to bring the level in the organ chamber 10 up to the required point such that the organ 16 is effectively immersed in the fluid 20.
  • the closure 22 is then firmly and hermetically closed and the fastening elements 84 locked into position.
  • the overseeing surgeon or medical technician initiates operation of the organ perfusion device 1.
  • the device is set to an "INITIATE PERFUSION" mode.
  • the pump 32 commences to circulate perfusion fluid 20 from the organ chamber 10 via the organ chamber outlet 14 to the heat exchanger 38.
  • the two-way valve 36 is initially set to direct the flow through the heat exchanger 38. Here it is rapidly cooled by heat exchange to tne ice packs contained in the heat exchanger.
  • the cooled perfusion fluid 20 leaves the heat exchanger 38 via the hx outlet 42 and is directed to the oxygenator 46 via the oxygenator inlet port 54.
  • oxygenator 46 it is to be understood that this component is in fact a combined oxygenator and pressure head device. These distinct functions could also be separately provided in two different items.
  • Perfusion fluid 20 entering the oxygenator 46 causes the level of fluid in the oxygenation chamber 48 to rise above the level of the overflow outlet 56. As a consequence, flow takes place through the overflow outlet 56 back to the organ chamber via the organ chamber inlet 12.
  • perfusion fluid 20 also passes through the oxygenator outlet 66 to the organ connector 18 and into the organ 16.
  • the perfusion fluid 20 enters the 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 20 exits from the cardiac system via the coronary vein and/or vena cava directly into the interior of the organ chamber 10.
  • the flow rate of perfusion fluid 20 through the coronary system is determined by the pressure at the inlet to the coronary artery (with respect to the outlet). This pressure is determined effectively by the difference in height H between the fluid level in the oxygenator 46 and the fluid level in the organ chamber.
  • a substantially constant coronary flow is achieved.
  • the height H is set to 12.6" which equates to a pressure across the coronary system of around 3100 N/m2. This pressure has been found substantially adequate for maintaining an ideal perfusion flow of 7-9 ml/min per 100 grams of weight.
  • the control unit 74 monitors the temperature of the perfusion fluid 20 using the oxygen and temperature probe 26. Initially, this temperature will have risen on immersion of the freshly harvested warm heart in the organ chamber. As perfusion of chilled fluid through the coronary system takes place, the temperature measured by the oxygen and temperature probe 26 drops. Once the temperature reaches 4° C (or another desired value) the control unit 74 controls the two-way valve 36 to direct flow of the perfusion fluid 20 via the hx bypass 44. During steady-state operation of the device, the control unit 74 intermittently controls the two-way valve 36 to alternately direct flow through the hx inlet 40 or through the hx bypass. In this way temperature control of the perfusion fluid 20 and the organ 16 is achieved. It is of course clear that other control methods could also be adopted e.g. by using a mixer valve instead of two-way valve 36.
  • Oxygenation of the perfusion fluid 20 takes place in the oxygenator 46.
  • the oxygenation chamber 48 contains an oxygen permeable member 62 comprising a number of lengths of silastic tubing 110.
  • control unit 74 controls the oxygen source 52 to supply oxygen gas to the oxygen inlet 58.
  • the oxygen supply is regulated at the oxygen inlet 58.
  • the oxygen passes via the oxygen inlet 58 and is distributed to the eight lengths of silastic tubing 1 10. Because of the permeable nature of the silastic material and the driving pressure difference between the interior of the tubing 1 10 and the oxygenation chamber 48, oxygen can permeate through the wall of the tubing 110 into the perfusion fluid 20. Residual oxygen gas exits from the silastic tubing 110 via the oxygen outlet 60 to the vent 64.
  • the arrangement of the silastic tubing 110 in the base of the oxygenation chamber 48 ensures that all of the perfusion fluid 20 passing to the oxygenation outlet 66 comes into close contact therewith.
  • the perfusion fluid 20 supplied to the organ 16 via the organ connector 18 is thus rich in oxygen.
  • the oxygen saturation level is measured on exit from the oxygenator 46 by the oxygen saturation probe 70.
  • the control unit 74 controls the oxygen supply 52 to ensure the perfusion fluid is saturated.
  • the control unit 74 also determines the oxygen saturation level as measured by the probe 26. By analyzing both values, the oxygen uptake across the heart may be determined and recorded, providing an indication of the level of metabolic activity in the tissue of the heart.
  • the probe 26 is located in the organ chamber 10, it is also contemplated that such sensors may be located directly at the exit from the coronary vein in order to more closely determine the characteristics of the perfusion fluid 20 on exit from the organ 16.
  • the perfusion fluid must be carefully selected to optimize organ survival.
  • solutions described in the literature and in patents are for "preservation" of organs; wherein the organ is immersed in the solution passively
  • the solution described below is for perfusion of the organ.
  • this solution was developed principally for heart perfusion, it represents a significant advantage particularly for the perfusion of kidneys, and also liver, lung and other organs.
  • the perfusion fluid in stable form prior to use, may comprise physiologically acceptable concentrations of NaCl, CaCl 2 * 2H 2 O, MgCl 2 , K 2 HPO 4 , L-histidine, lactobionic acid as a lactone, D-mannitol, D-glucose, sodium L-glutamate, and adenosine.
  • the perfusion fluid in stable form prior to use, may comprise about 25 mM NaCl, about 0.5 mM CaCl 2 • 2H 2 O, about 14.5 mM MgCl 2 , about 15 mM K 2 HPO 4 , about 25 mM L-histidine, about 80 mM lactobionic acid, about 30 mM D- mannitol, about 12 mM D-glucose, about 15 mM Sodium L-glutamate, and about 5 mM Adenosine.
  • the pH of the perfusion fluid is adjusted to about 7.6 at 22.5 0 C. This slightly alkaline pH neutralizes the lactic acid produced by the organ carrying out glycolysis.
  • the following unstable components may be added to the perfusion fluid immediately before use: about 1 unit/50 ml regular insulin, about 0.2 mM amiloride, about 3 mM L-glutathione (reduced), and about 5 mM D-fructose bisphosphate.
  • a principal aim during perfusion is to maintain the integrity of the cardiac cell membrane, and the integrity of the cardiac cell membrane potential.
  • the cardiac cell normally has a high concentration of potassium and a low concentration of sodium, while the extracellular fluid has a low potassium concentration and high sodium concentration.
  • the intracellular cardiac ion concentrations are maintained by pumping sodium ions out of the cell by an energetically driven process. When the heart is cooled, energy production by oxidative phosphorylation stops, and sodium ions are no longer pumped out. The intracellular sodium concentration then increases.
  • the sodium overload produced is accompanied by an abnormally high calcium influx that causes muscle cell injury and death by several different mechanisms. Therefore, the object during perfusion is to minimize the leakage of sodium ions into the heart cells, and the loss of potassium ions outward.
  • the formulation of the perfusion fluid described above confers several advantages contributing to the preservation of the organ.
  • high magnesium and low calcium keeps the heart in hyperpolarized arrest and helps preserve the heart muscle cell membrane so that membrane excitability is better restored after transplantation.
  • histidine allows a greater buffering capacity while holding the phosphate concentration down.
  • Lactobionate does not permeate the cardiac muscle cell membrane and acts to reduce swelling.
  • Mannitol is another impermeant and along with glutathione, is also a free radical scavenger.
  • Fructose bisphosphate stabilizes heart muscle cell membranes, reduced oxygen free radical formation, reduces lipid peroxidation, and reduces damage to the coronary artery epithelium.
  • Glutamate helps functional recovery after transplantation.
  • Adenosine prevents peripheral vasoconstriction in the coronary circulation during long term perfusion; it increases the store of high energy phosphates in heart muscle; there is better recovery of the heart after transplantation.
  • Glucose is a nutrient energy source. Its use preserves the cardiac muscle glycogen. While glucose has often been used in Krebs- Henseleit perfusion solution for Langendorff perfusions, it has not been used in "preservation” solutions. This solution uses a higher glucose concentration than in plasma, which is protective. See e.g. Saupe, K., et al. J. Molec. Cell. Cardiol. 2001, 33:261-269. Insulin enhances the uptake of glucose into heart muscle cells, and promotes glucose utilization, lnsuiin also inhibits programmed cell death (apoptosis).
  • Amiloride is an inhibitor of the sodium-hydrogen ion-exchanger (NHE), a membrane transporter involved in the movement of sodium ions into the cardiac muscle cell in exchange for hydrogen ions moving outward.
  • NHE sodium-hydrogen ion-exchanger
  • Six isoforms of NHE are known; NHE-I is the principal isoform in cardiac muscle cells. Normally NHE acts as a protective mechanism against acidosis. At 4° C, however, muscle cells survive only by glycolysis that produces lactic acid. Outward movement of these hydrogen ions is accompanied by a large influx of sodium ions that is detrimental to heart cells. Inhibition of NHE-I reduces sodium influx; the hydrogen ions then diffuse out of the cells without the influx of sodium ions.
  • NHE-I inhibition reduces damage from anoxia, and the damage from reperfusion injury after transplantation.
  • Three more powerful and more specific NHE-I inhibitors, eniporide, cariporide,and zoniporide, may be also be used for the perfusion solution.

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Abstract

L'invention concerne un dispositif de perfusion d'organe portatif comportant une chambre à organes destinée à supporter un organe immergé dans un fluide de perfusion. Une pompe fait circuler le fluide de perfusion autour d'un circuit contenant une pompe, un échangeur thermique destiné à refroidir le fluide de perfusion, un oxygénateur destiné à oxygéner le fluide de perfusion, et un chargeur de pression destiné à assurer une alimentation constante de la tête vers le système vasculaire de l'organe. Un canal de dérivation forme une connexion fluidique à partir du flux en amont de l'oxygénateur vers la chambre à organes permettant à l'excès de fluide de contourner l'organe. Le dispositif comprend également une source d'oxygène, des capteurs, une source de puissance et une unité de commande destinée à recevoir des informations provenant des capteurs et à fournir des instructions de commande aux éléments de commande.
PCT/US2006/016163 2005-04-29 2006-04-28 Procede et dispositif destines a la perfusion d'organe WO2006118990A2 (fr)

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WO2017134192A1 (fr) * 2016-02-04 2017-08-10 Xvivo Perfusion Ab Simulateur pulmonaire ex vivo
CN106754355A (zh) * 2016-11-23 2017-05-31 厦门大学 一种器官体外培养系统
CN110122474A (zh) * 2019-04-26 2019-08-16 浙江机电职业技术学院 一种基于非接触传感控制灌注技术的人体断肢保护箱
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