Perfusion loop assembly for an ex-vivo liver perfusion and a liver chamber assembly

Abstract

The present invention relates to a perfusion loop assembly for an ex vivo liver perfusion including: a pump for providing a fluid flow of a perfusion fluid through a first branch line and a second branch line; the first branch line being configured to provide a first portion of the perfusion fluid to the hepatic artery of the liver; the first branch line being coupled with a first gas exchanger, the second branch line being configured to provide a second portion of the perfusion fluid to the portal vein of the liver; the second branch line further including a first valve for controlling the flow of the perfusion fluid into the portal vein of the liver, a liver chamber assembly configured to hold the liver ex vivo, a liver outlet line attached to the vena cava of the ex vivo liver, at least one reservoir connected to the liver outlet and upstream from the pump.

Claims

1. A perfusion loop assembly for an ex vivo liver perfusion comprising: only one pump for providing a flow of a perfusion liquid through a first branch line and a second branch line, wherein the perfusion flow is split downstream of the one pump into the first branch line and the second branch line at a branching point; the first branch line being configured to provide a first portion of the perfusion liquid to the hepatic artery of the liver, wherein at least one gas exchanger is arranged in the first branch line downstream of the branching point; the second branch line being configured to provide a second portion of the perfusion liquid to the portal vein of the liver, the second branch line further comprising at least one first valve for controlling the flow of the perfusion liquid into the portal vein of the liver; a liver chamber assembly configured to hold the liver ex vivo; a liver outlet line attached to the vena cava of the ex vivo liver, wherein the liver outlet line comprises at least one valve; and at least one reservoir connected to the liver outlet line and upstream from the one pump, wherein the first branch line, the second branch line and/or the liver outlet line comprise an interface configured to be inserted into the hepatic artery of the liver, the portal vein and/or the vena cava respectively; wherein the first branch line, the second branch line and/or liver outlet line comprise at least one flow rate sensor and/or at least one pressure sensor; wherein a bypass with a valve is established between the first branch line and the second branch line, wherein the valve of said bypass is operative for controlling a flow of the perfusion liquid between the first branch line and the second branch line; and wherein a flow throttling in the at least one first valve of the second branch line, in the valve in the bypass, and in the valve in the liver outlet line is accomplished over one or multiple stages, wherein each of the one or multiple stages includes a manually adjustable constriction, an automatically adjustable constriction, or both a manually and an automatically adjustable constriction.

2. The perfusion loop assembly according to claim 1, further comprising: at least one third gas exchanger downstream of the one pump; and downstream from the at least one third gas exchanger the perfusion liquid flow being split into the first branch line and the second branch line.

3. The perfusion loop assembly according to claim 1, wherein data from each sensor is transmitted to a control system for monitoring and/or controlling the perfusion loop assembly and/or manipulating devices depending on the measured sensor data.

4. The perfusion loop assembly according to claim 1, wherein the second branch line comprises at least one second gas exchanger.

5. The perfusion loop assembly according to claim 1, wherein the at least one first valve in the second branch line is a proportional pinch valve.

6. The perfusion loop assembly according to claim 1, wherein the at least one reservoir is a hard shell or soft shell reservoir close to a liver outlet.

7. The perfusion loop assembly according to claim 1, wherein a height of the at least one reservoir relative to the ex vivo liver is controlled by a linear motor for adjusting a liquid head.

8. The perfusion loop assembly according to claim 1, wherein a control system effects a desired pressure variation in the vena cava liver outlet branch, wherein the control system comprises at least one pinch valve in the vena cava line and/or an alternatingly adjusting of a height of the reservoir.

9. The perfusion loop assembly according to claim 1, wherein the perfusion loop assembly comprises at least one port for medication and/or liquid retrieval for analysis.

10. The perfusion loop assembly according to claim 1, comprising a dialysis machine to remove toxins and desired substances from the perfusion media.

11. The perfusion loop assembly according to claim 10, wherein the dialysis machine is connected to the liver chamber and the liver outlet line.

12. The perfusion loop assembly according to claim 1, comprising at least one monitoring, controlling, and/or processing device for bile produced by the ex vivo liver.

13. The perfusion loop assembly according to claim 12, wherein the monitoring, controlling and/or processing device uses measurements of the produced mass of the bile, optical parameters of the bile and/or the flow rate of the bile.

14. The perfusion loop assembly according to claim 1, wherein the temperature in the loop is in the range of 2° C. and normothermic conditions.

15. The perfusion loop assembly according to claim 1, comprising the second branch line including at least one second gas exchanger.

16. The perfusion loop assembly according to claim 1, comprising at least one monitoring, controlling, and/or processing device for ascites produced by the ex vivo liver.

17. The perfusion loop assembly according claim 16, wherein the monitoring, controlling and/or processing device uses measurements of the produced mass of the ascites, optical parameters of the ascites and/or the flow rate of the ascites.

18. The perfusion loop assembly according to claim 16, comprising at least one dialysis machine for removing toxins and urea from the ascites.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1a a first embodiment of a perfusion loop assembly;

(2) FIG. 1b a diagram showing the simulated and measured performance of the perfusion loop assembly of FIG. 1;

(3) FIG. 2 a second embodiment of a perfusion loop assembly;

(4) FIG. 3 a third embodiment of a perfusion loop assembly;

(5) FIG. 4 a fourth embodiment of a perfusion loop assembly

(6) FIG. 5 a fifth embodiment of a perfusion loop assembly;

(7) FIG. 6 a sectional cut through a first embodiment of a liver chamber assembly;

(8) FIG. 7 a first embodiment of a compression means;

(9) FIG. 8 a second embodiment of a compression means;

(10) FIG. 9 a third embodiment of a compression means;

(11) FIG. 10 a schematic cross-sectional view of a bypass with constrictions.

DESCRIPTION OF THE INVENTION

(12) FIG. 1 a shows a first embodiment of the perfusion loop assembly comprising a pump 101 for keeping the perfusion medium flowing. Downstream from the pump 101 the line branches into a first branch line 110 and second branch line 120. The branching point 102 (e.g. a divider) can be a mechanical device or a split in the line coming from the pump.

(13) The first branch line 110 provides a first portion of the perfusion fluid to the hepatic artery (arteria hepatica propria or arteria hepatica communis) 111 of the liver which is here housed in a liver chamber assembly 130.

(14) Here a gas exchanger 112, an oxygenator is arranged solely in the first branch line 110, i.e. hepatic artery branch. A flow sensor 114 is here measuring the fluid flow in the first branch line 110 upstream from the gas exchanger 112.

(15) The second branch line 120 is configured to provide a second portion of the perfusion fluid to the portal vein (vena portae hepatis) 121 of the liver in the liver chamber assembly 130. The second branch line 120 is also comprising at least one valve 122 for controlling the flow of the perfusion fluid into the portal vein 121 of the liver in the liver chamber assembly 130.

(16) The valve 122 is here a proportional pinch valve (Resolution Air, MPPV-8) to adjust the flow into the portal vein 121. The proportional pinch valve 122 can be varied from fully open to almost or fully closed (up to a flow rate of 2.0 l/min in the portal vein 121). Upstream from the valve 122 a flow rate sensor 124 measures the perfusion medium flow in the second branch line 120.

(17) Pressure sensors 113, 123 measure the fluid pressure under ex vivo perfusion conditions in first branch line 110 (the hepatic artery 111 branch) and the second branch line (the portal vein 121 branch). The pressure sensors 113, 123 can be located in or close to the cannulation (not shown here) of the hepatic artery 111 and/or the portal vein 121.

(18) Different embodiments of the liver chamber 130 will be described below.

(19) The perfusion medium is collected through the liver outlet line 140 attached to the vena cava (vena cava inferior) 142 of the liver. A pressure sensor 141 measures the pressure under perfusion circulation, which can be located in or close to the cannulation (not shown here) of the vena cava inferior 142.

(20) The outflow of the liver chamber assembly 130, i.e. the output of the vena cava 142 is directed to a reservoir 150 connected to the liver outlet line 140 and upstream from the pump 101. Therefore it is possible to generate a closed perfusion loop. It is possible to have additional flow lines into the system (e.g. to make up for fluid losses) and out of the system (e.g. as purge streams).

(21) The connections of the lines 110, 120, 140 to the respective blood vessels 111, 121, 142 (hepatic artery, portal vein, vena cava) are made through cannulation, i.e. the ends of the lines 110, 120, 140 are constricted and inserted into the blood vessels 111, 121, 142. The cannulation is sealed by using surgical suture.

(22) For the hepatic artery 111 liver inlet branch, 3/16″ (0.00476 m, inner diameter) or ¼″ tubes are used. For the portal vein 121 liver inlet branch, ¼″ (0.00635 m, inner diameter) or ⅜″ tubes are used. For the remaining tubes of the perfusion loop, ⅜″ (0.00952 m, inner diameter) or ½″ tubes are used. Different sized connectors are used to connect the individual branches of the loop.

(23) The (reservoir 150 is attached to the vena cava 142 liver outlet branch line 140 and can impose atmospheric pressure on the enclosed perfusion medium. The reservoir 150 is attached at roughly the same height as the liver storage chamber, with an adjustable height setting (+/−50 cm). This can be adjusted (not shown here) by mechanical means to control the liquid head at the outlet of the liver (vena cava).

(24) All tubings are kept as short as possible in order to minimize foreign surfaces. Moreover, the number of bendings and connectors in the perfusion loop should be minimized. Flow transition from laminar to turbulent in the perfusion loop should be avoided (acceleration and deceleration) to minimize hemolysis. The individual tube section lengths are in the range of 5 to 100 cm.

(25) The length of the lines in the perfusion loop should be kept to a minimum in order to minimize the external surface in contact with the perfusion media.

(26) The reservoir 150 (Eurosets, Variable Venous Reservoir 1800) is added after the inferior vena cava 142 in order to have atmospheric pressure (reference pressure). A pump 101 (Thoratec, Centrimag) with almost linear pressure-flow characteristics was used to circulate the perfusion fluid.

(27) Flow rate sensors 114, 124, 143 (Sonotec, sonoflow CO0.56) and pressure sensors 113, 123, 141 (Edwards Lifesciences, TrueWave) are integrated in the perfusion loop. The perfusion medium flow rates and pressures are measured in all liver line branches 110, 120, 140 (hepatic artery, portal vein, vena cava).

(28) The control of the perfusion loop assembly is effected by a control system 30 which is only shown schematically in FIG. 1 a. The control system 30 can be connected or coupled with relevant measurement points (e.g. pressure, flow rate, composition, optical measurement) and the relevant control elements (e.g. valves, pump motor, medication dosing, fluid head adjustment through reservoir 150 position). Measurement variables and manipulated variables will be described below.

(29) The embodiment shown in FIG. 1a is an example of a perfusion loop assembly. Other embodiments might have e.g. a different arrangement of sensors, additional lines and other units as will be shown in connection with FIGS. 2 to 5 below.

(30) A numerical hydraulic analogy model verifies the flow characteristics of the perfusion loop. The liver is simulated by a constant pressure drop. An experimental validation of the numerical model was carried out by simulating the liver pressure drop by adjustable gate clamps. Results are shown in the diagram of FIG. 1b and explained in detail further below.

(31) By progressively closing the proportional pinch valve 122, it could be shown, that a constant total flow rate in the system could be maintained. The pressure in the hepatic artery inlet branch 110 could be varied over a large range by progressively closing the proportional pinch valve and increasing the flow rate through this branch 110, thus reaching physiological values.

(32) The pressure in the portal vein inlet branch 120 always remained in physiological ranges, even while the flow rate decreased through this branch 120. The numerical and experimental results fit reasonably well.

(33) When closing the pinch valve 122, the overall resistance in the hydraulic circuit increases and as a consequence, the pump has to provide more power by increasing its rotation speed.

(34) The pressure in the system (i.e. the perfusion loop assembly) ranges from −300 mmHg to 300 mmHg with respect to atmospheric pressure. The pressure differences in the system are overcome by the pump, with the lowest pressure of the system at the pump inlet and the highest pressure of the system at the pump outlet.

(35) The temperature of the perfusion medium is controlled by the built in heat exchanger of the oxygenator which is connected to an external recirculation chiller (not shown in FIG. 1a). The perfusion loop assembly is optimized to provide normothermic perfusion, which is at 37° C. for humans. In principle the temperature range of the fluid in the perfusion fluid device is between 2° and normothermic conditions. The temperature is e.g. controlled through the chiller.

(36) An insulation layer around the reservoir 150 or heating of the reservoir 150 may help to compensate for heat losses within the perfusion loop assembly, mostly originating from the exposed tubes.

(37) The experimental validation of the model was done and the results are shown in the diagram of FIG. 1b. A constant flow rate of 1.8 l/min was adjusted using a controller for the pump 101. Water was used as a flow medium at room temperature (density p=10000 kg/m.sup.3 and dynamic viscosity μ=0.001 Pas). The flows in the hepatic artery 111 (Sonotec, sonoflow CO.55, 3/16″), portal vein 121 (Sonotec, sonoflow CO.56, ¼″) and vena cava 142 (Em-tec, 3/16″) were recorded with ultrasonic sensors. A pressure monitoring set (Edwards Lifesciences, TrueWave (3 cc)/12 in (30 cm)) was used to measure the individual pressures. In order to calibrate the resistance of the liver through the hepatic artery 111 and portal vein 121 (adjustable gate clamps), the following steps were performed to reach conditions with the proportional pinch control valve 122 fully open:

(38) 1. Fully close the hepatic artery and adjust the flow rate to 1.5 l/min.

(39) 2. Tune the clamp (resistance of the liver) on the hepatic artery side until a pressure drop (p1-p3) of 88.5 mmHg is reached.

(40) 3. Open up the hepatic artery, fully close the portal vein and adjust the flow rate to 0.3 l/min.

(41) 4. Tune the clamp (resistance of the liver) on the portal vein side until a pressure drop (p2-p3) of 6 mmHg is reached.

(42) The numerical results of the model (solid line) as well as the experimental validation (dashed line) are shown in the diagram of FIG. 1b. For both cases, the pinch valve on the portal vein side was first fully opened and then closed until a flow rate of 0.5 l/min was obtained in the hepatic artery.

(43) The model predicts the pressure in the portal vein 121 very well for the entire flow range. However, there is a non-linear behavior during the experiment, contrary to the theoretical assumptions and expectations. The pressure drop in the hepatic artery 111 started to deviate from the model as the flow rate increased and the experimental validations showed higher differences. This could be explained due to the tighter closed clamp in the hepatic artery 111, which promotes turbulences at higher discharges, resulting in an increased pressure drop.

(44) An advantage of the described embodiment of the perfusion loop assembly is that there is always a positive pressure at the outlet of the vena cava 142 due to the reservoir 150. There is the possibility that the pressure becomes slightly negative for a short period.

(45) The reservoir has to be placed very close to the exit of the liver in order not to have an overpressure in the vena cava 142. Care must be taken as the height relative to the liver of the reservoir 150 has a very narrow range since the liver outlet is very sensible in terms of over- and underpressure with respect to atmospheric pressure.

(46) Two further experiments were performed on the same setup with a higher (2.5 l/min) and lower (1 l/min) flow rate. The main result is that the flow rate in the portal vein can be regulated by changing the pump speed and adapting the position of the pinch valve. For example, if the same pressure and flow conditions at the hepatic artery shall be reached (e.g. a specific point in FIG. 1b), but a lower flow rate is desired through the portal vein, then the pumping speed must be decreased and the pinch valve has to be closed further. The opposite procedure has to be applied when a higher flow rate through the portal vein is desired. In this case, the pump has to deliver more flow (increase the power) and the pinch valve has to be opened in order to lower the pressure and decrease the flow in front of the hepatic artery.

(47) The impact of the hepatic artery, oxygenator and pinch valve resistances (derived from the hydraulic analogy model) are very high. These components have the greatest influence on the perfusion loop and generate the highest pressure drops in the system. Therefore, it is also expected that they have a major effect on hemolysis.

(48) FIG. 2 shows a second embodiment of the perfusion loop assembly wherein in addition to the first embodiment shown in FIG. 1a a second oxygenator 125 is provided in the second branch line 120 (portal vein branch) downstream of the pump 101 and the flow divider 102 and upstream of the pinch valve 122. Pressure and flow rate are measured downstream of the flow divider.

(49) For reasons of clarity some details shown in FIG. 1 a are not depicted in FIG. 2, but the basic functionality is the same so that reference can be made to the embodiment of FIG. 1 a.

(50) In addition to the setup shown in FIG. 1a a further pinch valve 141a is arranged downstream of the vena cava outlet 142 in the vena cava outlet line 140. The pinch valve 141a allows to adjust the pressure at the vena cava outlet such that physiological pressure values resp. variations are generated in the vena cava as created e.g. by breathing. For example, during one breath sequence the pressure in the vena cava varies between +15 and −10 mmHg when inhaling and exhaling. However, it is also possible to keep the pressure in the vena cava constant on the physiological level when using the pinch valve.

(51) FIG. 3 shows a third embodiment of the perfusion loop wherein in addition to the first embodiment of FIG. 1a a bypass 160 (with a valve 161) is provided from the first branch line 111 (hepatic artery branch) to the branch line to the vena cava 142. Therefore, the liver chamber assembly 130 is bypassed by this line. Said bypass 160 will have no influence on the above described perfusion loop assembly, besides a higher flow rate through the pump 101.

(52) The pressure drop over the bypass 160 can be accomplished over one or multiple stages, which are each made up of individual constrictions 200 not shown here, but in FIG. 10. Multiple constrictions allow a more gentle pressure expansion which minimizes hemolytic contributions in the perfusion system by minimizing pressure gradients in the perfusion medium. The proportional pinch valve 161 controls the flow rate through the bypass 160 based on the oxygen saturation in the perfusion medium. The bypass 160 allows for obtaining physiological oxygenation the (second) portal vein branch line 120 (90-100% oxygen saturation) and portal vein 121 (70-80% oxygen saturation). For reasons of clarity other units shown in FIG. 1a are not depicted in FIG. 3, but the basic functionality is the same so that reference can be made to the embodiment of FIG. 1a.

(53) In another embodiment the flowsheet would be like in FIG. 3 only that the bypass 165 would be between the first branch line 110 an the second branch line 120,

(54) The embodiment of the perfusion loop illustrated in FIG. 4 differs from the embodiment in FIG. 1a in that an oxygenator 170 is located in front or upstream of the divider 102 that splits the perfusion loop into the first branch line 110 (hepatic artery branch) and second branch line 120 (portal vein branch). In this case only one oxygenator 170 is used to oxidize both liver branch lines 111, 121. This means that there is less foreign surface in the perfusion loop (oxygenators have very large foreign surfaces due to the membrane oxygenation) what in turn causes fewer hemolytic contributors in the perfusion loop. For reasons of clarity other units shown in FIG. 1a are not depicted in FIG. 4, but the basic functionality is the same so that reference can be made to the embodiment of FIG. 1a.

(55) The embodiment of FIG. 5 is a variation of the embodiment shown in FIG. 3 with the additional features of a bypass 180 or branch passing from the liver chamber assembly 130 via a pump 182 to the vena cava branch 140 for collecting ascites from the liver surface. The ascites are collected in a reservoir 181 and may be guided through a dialysis machine (not shown) for removing toxins and urea so that the ascites can be circulated back into the perfusion loop.

(56) A further additional feature (which can be alternatively used with any embodiment) is the constant measurement or monitoring of bile 190 production.

(57) For this purpose a suitable device (such as a spectrophotometer) is connected to the liver and the liver flow is captured and monitored. The color of human bile 190 (i.e. liver bile) is representative of the properties. Deviation e.g. from the normal golden-yellow or light-brown color can indicate a deviation of the function of the perfused liver in the liver chamber assembly 130. This deviation can be used in a control loop (not shown here) to adjust e.g. the rate of the pump 101 and/or the gas exchange or given infusions and medications. In addition or alternative to the color, physical properties (e.g. viscosity), the composition of the bile and/or the pH value can be monitored or used in a control loop.

(58) Another measureable parameter which can be used alone or in combination with other is hemoglobin (or another blood related value) in the bile. If that value increase above a certain threshold, it might be an indication that the ex vivo liver is not performing.

(59) FIG. 6 shows a schematic, sectional cut through of an embodiment of the present liver chamber assembly 10 illustrating the principle features thereof. The chamber 11 can be a rigid box or a more flexible bag and is configured to hold the liver 13. The chamber 11 is designed to keep sterility and control the desired inside conditions for the liver perfusion process (such as temperature, humidity, gas composition, pressure). The humidity within the chamber 11 may be adjusted using an evaporation unit 12. The chamber 11 has several sealed ducts for electric lines 14a, tubings 14b for fluids, lines 14c for hepatic artery (HA), portal vein (PV), vena cava (VC), bile outflow, ascites (AZ) outflow and sensor lines 14d connected to the liver 13 or connected to inner parts of the liver chamber assembly 10. Ascites and bile are continuously removed from the liver 13 and monitored. The data can be used in the control of the perfusion loop assembly (e.g. embodiments shown in FIGS. 1a, 2, 3, 4, and 5) and/or the liver chamber assembly 10.

(60) The liver 13 is positioned on a liver support structure 15 that fixes and stores the liver 13. The support structure 15 may comprise a flexible material such as a cushion filled with a fluid. Lines and tubing 14a-c pass through the support structure 15. Alternatively the support structure 15 can comprise a plastic sheet material, a membrane and/or a set of rigid elements which can be individually moved.

(61) An inner layer 16 made of a biocompatible material (e.g. membrane or foil) is placed around the liver 13 to keep sterility, humidity, temperature and collect the ascites fluids or fluid losses secreted from the surface of the liver 13. Lines for electrodes (e.g. for electrical stimulation) connected to the surface of the liver 13 or sensor and monitoring lines 14d can also pass through (sealed) the inner layer 16.

(62) Compression means 17 is for inducing compression and decompression (respectively some kind of massage) of the perfused liver 13. This can be made to mimic the physiological liver motion. The liver 13 can be mechanically and/or electrically stimulated.

(63) Different embodiments of compression means 17 are illustrated in FIGS. 7 to 9, respectively. Since the basic functionality is described in FIG. 6, reference can be made to that description. Compression in this context means e.g. any kind of pressure exacted onto the surface of the liver 13 or a part of the surface of the liver 13 which is different from the mere pressure on the liver, in particular on the non-moving (stationary) liver, by gravitational force. A compression can be performed by moving a liver periodically against a rigid part (in particular stiffer than the liver tissue), such as a plate. In this case, the direction of the acting, periodic force would be the sum of the weight force and the pressing force against the rigid part. This would be one embodiment of a dynamic compression force.

(64) In another embodiment of a dynamic compression the direction of the pressure (i.e. the force distributed over a certain area of the liver surface) would generally deviate from the direction of the gravitational force, i.e. the direction of the pressure on the liver 13 under its own weight. It should be noted that this dynamic compression would be something like a massage. That means that different parts of the liver surface are subjected to different pressures (i.e. the location, the amount of the applied force and/or the direction direction) at different times. This could also include the some movement of the force over the liver surface, like in a stroking movement.

(65) This would also enable compression patterns which are different from the physiological pressure regime.

(66) The dynamic compression would e.g. allow the directed increase of perfusion in certain parts of the liver. This could e.g. be effected or enhanced by an electrostimulation. It is also possible that the compression, in particular the dynamic compression can be controlled in dependence of the color of the liver surface. An imaging system could detect discolorations in the liver surface and change the compression, in particular the directional dynamics compression in those areas. In another embodiment, a control system 30 (e.g. a computer, a microprocessor) of the compression means 17 (shown schematically in FIGS. 7 to 9) would take those measurements and adjust the actors of the compression means 17 (e.g. cushions 17a, drum 17b, nozzles 20) according to the measurements.

(67) The first embodiment of a compression means 17 shown in FIG. 7 comprises multiple deflateable and inflatable cushions 17a that are separately controllable. The cushions 17a are made of a flexible and thin material. The cushions 17a are placed around the liver 13 and help to position and fix the liver 13. The deflation and inflation process is controlled by pumping a fluid into the cushions 17a and out of the cushions 17a with certain frequency (for example 0.5 Hz). By doing so the liver 13 is massaged according to a provided protocol. Lines and tubing 14a-c connected to the liver 13 pass through the cushions 17a. Additionally, lines for electrodes (electrical stimulation) connected to the surface of the liver 13 or sensor and monitoring lines 14d can also pass through.

(68) The second embodiment of a compression means shown in FIG. 8 comprises a rotation mechanism in form of a drum 17b filled optionally with a suitable fluid (e.g. isotonic water, Ringer solution). Here the liver 13 is fixed and positioned inside the support structure 15 and optionally covered by the inner layer 16. This system is placed in the drum 17b. The drum 17b rotates around the axis X. The direction of rotation changes in an alternating manner or stays the same. The rotation continuously changes liver 13 position/orientation with respect to the direction of the gravitational forces acting on the liver 13. Therefore, the forces acting on the surface of the liver 13 are continuously changing that enables the massage of the liver 13 surface over time. The liver 13 is compressed and decompressed (massaged) by its own weight.

(69) The third embodiment of the compression means shown in FIG. 9 comprises the storage of the liver 13 in a storage vessel 18 filled with a storage fluid 19. The storage vessel 18 is made of a box or bag with the required stiffness and stability to store a certain volume of the storage fluid 19. The storage fluid 19 may be an aqueous salt solution, water, oil, glycerin or any other liquid.

(70) The liver 13 is placed in the inner layer 16 that covers the whole liver 13 and optionally also in the support structure 15. This inner layer is finally closed and sealed to form a storage bag that is placed inside the storage vessel 18 filled with storage fluid 19.

(71) Inside the storage vessel 18, said bag is hold in place by a positioning device. This storage bag has to be tight that storage fluid cannot enter. Lines and tubing 14a-c pass through the inner layer 16, and optionally also through the support structure 15

(72) Several nozzles 20 surround the storage bag (inner layer 16) respectively optionally the support structure 15 to massage and move the liver 13. Every nozzle 20 is controlled individually with respect to mass flow over time. Storage fluid 19 is fed to the multi-nozzle-system by a pump (e.g. centrifugal pump) in order to have an elevated pressure inside the multi-nozzle-system. By opening and closing nozzles individually, fluid jets impinge on the surface of the storage bag respectively optionally on the surface of the support structure 15. This impingement results in a local massage respectively deformation on the liver surface.

(73) The compression means and the details for operating the compression means, as described above in the context of FIGS. 7 to 9, in particular the dynamic compression with a time-pendent direction of the compression force, can be used with all embodiments described above.

(74) In the following some more details of the control system 30 of the perfusion loop assembly (schematically shown in FIG. 1a) and the liver chamber assembly 130 are given.

(75) Typical measurement signals comprise the flow rates, pressures, temperatures, humidity, ascites data (e.g. flow rate), bile data (e.g. flow rate, composition), pump speed and valve position (e.g. proportional pinch valve position) and parameters of liver tissue and blood analysis. The signal processing units transmit their data e.g. to an embedded microprocessor. Signals from blood gas analysis and/or chemical analysis can also be transmitted to the microprocessor.

(76) The microprocessor of the control system 30 can e.g. control the perfusion loop assembly by manipulating the following items: flow and/or pressure in first branch line 110 (hepatic artery) flow and/or pressure in the second branch line 120 (portal vein) flow rate through one bypass (e.g. bypass 160 from hepatic artery 111 to vena cava 142) pressure in the vena cava 142 temperature of the perfusion medium humidity in the liver chamber assembly 130 gas supply to a gas exchanger, e.g. oxygenator 112, 125, 170 return of ascites liquid dosing of at least one medication

(77) With these controlled and manipulated variables an automatic control of the perfusion loop assembly and/or the liver chamber assembly 130 can be performed. Setpoints could be changed any time.

(78) The input and output data can be visualized dynamically to monitor the progress. The data is recorded within the control system. Since this involves potentially sensitive medical data, the data is encrypted. The data processing can be performed centrally for a distributed network of perfusion loop assemblies and/or liver chamber assemblies.

(79) In FIG. 10 a schematic view of a bypass, as e.g. used in the embodiment shown in FIG. 3 is shown. The perfusion fluid F flows from left to right, passing through five constrictions 200, i.e. means for lowering the cross-section of the bypass. The constrictions 200 can be manually or automatically changed to control the pressure expansion in the bypass.

REFERENCE NUMBERS

(80) 11 chamber of liver chamber assembly 12 evaporation unit 13 liver 14a electric lines 14b tubings for fluid 14c lines for blood vessels (hepatic artery, portal vein, vena cava), bile, ascites 14d sensor lines 15 liver support structure 16 inner layer 17 compression means 17a cushions 17b drum 18 storage vessel 19 storage fluid 20 nozzle 30 control system 101 pump 102 flow divider 110 first branch line (hepatic artery) 111 hepatic artery vessel 112 first oxygenator, gas exchanger 113 first pressure sensor 114 first flow rate sensor 120 second branch line (portal vein) 121 portal vein vessel 122 first valve 123 second pressure sensor 124 second flow rate sensor 125 second oxygenator, gas exchanger 10, 130 liver chamber assembly 140 outlet line 141 third pressure sensor 141a vena cava pinch valve 142 vena cava vessel 143 third flow rate sensor 150 reservoir 160 bypass from hepatic artery branch to vena cava branch 161 fourth valve 170 third oxygenator, gas exchanger 180 bypass for ascites 181 reservoir 182 ascites pump 200 constriction