Ex vivo organ management system

Abstract

To provide systems, methods, and devices that facilitate ex-vivo organ care for the liver under physiologic or near-physiologic conditions.SOLUTION: An organ care system comprises: a pump configured to supply perfusion circuit fluid into a perfusion circuit; a gas exchanger; a hepatic artery interface configured to supply the perfusion circuit fluid to the hepatic artery of an ex-vivo liver; a portal vein interface configured to supply the perfusion circuit fluid to the portal vein of the ex-vivo liver; and a pressure sensor configured to measure the pressure of the perfusion circuit fluid. The organ care system is configured to: examine the ex-vivo liver and create examination results; and modify the characteristics of the organ care system in response to the examination results.SELECTED DRAWING: None

Description

Technical Field

[0001] Reference to Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 006,871, filed Jun. 2, 2014, entitled “Ex-Vivo Organ Management System,” and U.S. Provisional Patent Application No. 62 / 006,878, filed Jun. 2, 2014, entitled “Ex-Vivo Organ Management System,” the entire subject matter of which is hereby incorporated by reference.

[0002] Technical Field The present invention relates generally to systems, methods, and devices for ex-vivo organ management. More specifically, in various embodiments, the present invention relates to managing organs ex-vivo in a physiological or near-physiological state.

Background Art

[0003] Current organ preservation techniques typically involve cryopreserving organs in ice with chemical perfusion solutions. In the case of liver transplantation, using hypothermia techniques to preserve the liver ex vivo can lead to tissue damage due to ischemia. The severity of such damage increases as a function of the length of time the organ is maintained ex vivo. For example, continuing with the liver example, a liver typically becomes unusable for transplantation after only about 7 hours ex vivo. Such a relatively short time limits the number of recipients that can reach a given donor location, and consequently, the pool of recipients for the extracted liver. Even within this time limit, the liver can be severely damaged. A major problem is that there may be no visible signs of damage. This can lead to the transplantation of suboptimal organs, resulting in post-transplant organ failure or other damage. Therefore, it is desirable to develop techniques that can extend the time that organs such as the liver can be preserved ex vivo in a healthy state and that allow for the use of evaluation functions. Such techniques would reduce the risk of transplant failure and increase the pool of potential donors and recipients. [Overview of the Initiative]

[0004] The following summary is illustrative and not limiting. Other embodiments of the disclosed subject matter are also possible.

[0005] Embodiments of the disclosed subject matter can provide techniques for portable ex vivo organ management, such as ex vivo liver organ management. In some embodiments, the liver management system can maintain the liver in a normal physiological state, or close to a normal physiological state. For this purpose, the system can circulate an oxygenated, nutrient-rich perfusion fluid to the liver at physiological temperature, pressure, and flow rate, or at a temperature, pressure, or flow rate close to physiological temperature, pressure, or flow rate. In some embodiments, the system utilizes a blood product-based perfusion fluid to more accurately mimic a normal physiological state. In some embodiments, the system uses a synthetic blood substitute solution, while in other embodiments, the solution may contain a blood product in combination with a blood substitute.

[0006] Several embodiments of the disclosed subject matter relate to methods using lactate ester and liver enzyme measurements to assess i) the overall perfusion status of an excised liver, ii) the metabolic status of an excised liver, and / or iii) the overall vascular patency of an excised donor liver. This aspect of the disclosed subject matter is based on the ability of liver cells to produce / generate lactate ester when oxygen is deficient in the liver cells / the ability of liver cells to metabolize / utilize lactate ester for energy production when the liver cells are perfused with sufficient oxygen.

[0007] Some embodiments of the organ management system may include a module with a chassis and an organ chamber assembly mounted on the chassis and adapted to house a liver during perfusion. The organ management system may include a fluid conduit having a first interface for connecting to the hepatic artery of the liver, a second interface for connecting to the portal vein, a third interface for connecting to the inferior vena cava, and a fourth interface for connecting to the bile duct. The organ management system may include a lactate sensor for sensing lactate in fluids supplied to and / or flowing from the liver. The organ management system may also include sensors for measuring pressure and flow rate in the hepatic artery, portal vein, and / or inferior vena cava.

[0008] Several embodiments may be methods for determining the hepatic perfusion state. For example, a method for evaluating the hepatic perfusion state may include the steps of: placing the liver in a protective chamber of an organ management system; pumping perfusion fluid into the liver; supplying the flow of perfusion fluid away from the liver; measuring the lactate ester value of the fluid moving away from the liver; measuring the amount of bile produced by the liver; and evaluating the state of the liver using the measured lactate ester value, oxygen saturation level, and / or the amount and quality of bile produced.

[0009] Several embodiments may be methods for supplying physiological flow rates and physiological pressures to both the hepatic artery and the portal vein. In some embodiments, this flow is supplied from a single pump. In particular, the system may include a mechanism for the user to manually split a single perfusion fluid source into the hepatic artery and the portal vein and to adjust the splitting of physiological flow rates and pressures. In other embodiments, the system automatically splits the flow from the single perfusion fluid source into the hepatic artery and the portal vein, for example, using an automatic control algorithm, to obtain physiological flow pressures and flow rates.

[0010] Some embodiments of the organ management system may include a nutrient subsystem that injects a maintenance solution supply into the perfusion fluid as the perfusion fluid flows through the system, and in some embodiments, when it is in a reservoir. According to one feature, the maintenance solution contains nutrients. According to another feature, the maintenance solution includes the supply of therapeutic agents and / or additives (e.g., vasodilators, heparin, bile salts, etc.) to support long-term preservation to reduce ischemia and / or other reperfusion-related injuries.

[0011] In some embodiments, the perfusion fluid includes blood collected from a donor through a bloodletting process during hepatectomy. Initially, this donor blood is introduced into the reservoir, and the cannula position in the organ chamber assembly is bypassed through a bypass conduit, enabling a normal flow mode of the perfusion fluid through the system in the absence of the kidney, also known as the “priming tube.” Before cannulation of the extracted liver, the system can be primed by circulating the bloodletted donor blood through the system to warm, oxygenate, and / or filter it. During priming, nutrients, preservatives, and / or other therapeutic agents may also be provided through the infusion pump of the nutrient subsystem. During priming, various parameters may be initialized and calibrated through the operator interface. Once primed and functioning correctly, the pump flow can be reduced or removed from the cycle, the bypass conduit can be removed from the organ chamber assembly, and the liver can be inserted into the organ chamber assembly. Depending on the circumstances, the flow from the pump can be restored or increased.

[0012] Depending on the embodiment, the system may include a plurality of distensible chambers. The distensible chambers are effectively small, series-type fluid accumulators with flexible, elastic walls for simulating the distensibility of human blood vessels. Thus, these chambers can assist the system in more accurately mimicking human blood flow, for example, by filtering / reducing fluid pressure spikes caused by flow rate changes. In one configuration, the distensible chambers are located within the perfusion fluid pathway to the portal vein and on the output side of the perfusion fluid pump. According to one embodiment, the distensible chambers are located next to clamps used to regulate pressure to achieve physiological hepatic artery flow and portal vein flow.

[0013] In some embodiments, the organ chamber assembly includes a pad or sack assembly of a size and shape that fits into the bottom surface of the housing. Preferably, the pad assembly includes a pad formed from a material sufficiently elastic to cushion the organ from mechanical vibrations and shocks during transport. If the organ chamber assembly is configured to house a liver, one feature is that the pad of the present invention includes a mechanism for fitting the pad to such a liver in order to restrain organs of different sizes and shapes from the effects of shocks and vibrations during transport.

[0014] Some embodiments of the organ management system are divided into a multi-use module and a single-use module. The single-use module is sized and shaped to connect to the portable chassis of the multi-use module in order to interact with it electrically, mechanically, gaseously, and fluidly. In one embodiment, the multi-use and single-use modules can communicate with each other through an optical interface, which automatically optically aligns when the single-use module is placed inside the portable multi-use module. Another feature is that the portable multi-use module can supply power to the single-use module via a spring-loaded connection, which also automatically connects when the single-use module is placed inside the portable multi-use module. Another feature is that the optical interface and spring-loaded connection ensure that the connection between the single-use and multi-use modules is not lost due to collisions, such as during transport on rough ground.

[0015] In some embodiments, the disposable, one-time module includes a plurality of ports for sampling fluid from the perfusion pathway. The ports can be interlocked such that if fluid is being sampled from the first of the plurality of ports, simultaneous sampling of fluid from a second of the plurality of ports is prohibited. This safety feature reduces the possibility of fluid samples mixing or the ports being accidentally opened. In one embodiment, the one-time module includes ports for sampling from one or more of the hepatic artery, portal vein, and / or IVC interface.

[0016] Some embodiments of the disclosed subject matter relate to methods for treating the liver. An exemplary method may include the steps of: placing the liver in a protective chamber of a portable organ management system; pumping a perfusion fluid into the liver via the hepatic artery and portal vein; supplying the flow of the perfusion fluid away from the liver via the aorta; operating a flow controller to alter the flow of the perfusion fluid so that the perfusion fluid is pumped into the liver via the hepatic artery and portal vein and flows out of the liver via the aorta; and treating the liver. The treatment may include, for example, administering one or more immunosuppressive treatments, chemotherapy, gene therapy, and radiotherapy to the liver. Other treatments may include surgical applications, including split transplantation and cancer resection.

[0017] In some embodiments, the disclosed subject matter may include a perfusion circuit for ex-vivo perfusion of the liver, the perfusion circuit including a single pump supplying a pulsatile fluid flow of perfusion fluid into the circuit, a gas exchanger, and a divider configured to divide the flow of perfusion fluid into a first branch and a second branch, the first branch configured to supply a first portion of the perfusion fluid to the hepatic artery of the liver at high pressure and low flow rate, the first branch being in fluid pressure communication with the pump, the second branch configured to supply the remaining portion of the perfusion fluid to the portal vein of the liver at relatively low pressure and high flow rate, the second branch being in fluid pressure communication with the pump, and the second branch selectively controlling the flow rate of perfusion fluid to the portal vein. Therefore, the perfusion circuit further includes a clamp positioned between the divider and the liver, the second branch further includes an expandable chamber between the divider and the liver configured to reduce the pulsatile flow characteristics of the perfusion fluid from the pump to the portal vein, the pump is configured to communicate fluid pressure to the liver via the first and second branch, and the perfusion circuit includes a drain configured to receive perfusion fluid from the cannulated inferior aorta of the liver, and a reservoir positioned entirely below the liver and between the drain and the pump, configured to receive the perfusion fluid from the drain and to store a certain amount of fluid. Further embodiments are also possible.

[0018] In some embodiments, the disclosed subject includes a solution pump comprising a stepping motor in contact with a threaded rod; a carriage connected to the rod and configured to move along a linear axis as the rod rotates, configured to compress the plunger of a syringe when moved in a first direction and to retract the plunger of the syringe when moved in a second direction; a clamp configured to connect to the plunger; a connection assembly comprising a port configured to be coupled to the tip of the syringe; a first one-way valve configured to allow fluid to flow into the syringe through the port when the syringe is retracted; a second one-way valve configured to allow fluid to flow away from the syringe through the port when the syringe is compressed; a pressure sensor coupled to the connection assembly for calculating the pressure of the fluid in the connection assembly; a controller configured to control the operation of the stepping motor; and a sensor configured to determine when the syringe is fully retracted. Further embodiments are also possible.

[0019] In some embodiments, the disclosed subject includes the steps of: rotating a rod to move a carriage connected to the rod along the linear axis of the rod; compressing the plunger of a syringe as the carriage moves in a first direction along the linear axis; discharging fluid from the syringe into a port of a connection assembly via a first one-way valve as the plunger is compressed; retracting the plunger of the syringe as the carriage moves in a second direction along the linear axis; discharging fluid into the syringe via a second one-way valve and the port of the connection assembly as the plunger is retracted; sensing the pressure of the fluid in the connection assembly; and sensing the position of the plunger when the syringe is retracted. Further embodiments are also possible.

[0020] Some embodiments can include an ex-vivo perfusion fluid for mechanically perfusing a donor liver, the perfusion fluid including an energy-rich component, a bile salt, an electrolyte, and a buffering component. The perfusion fluid can include a blood product. The energy-rich component can be one or more compounds selected from the group consisting of a carbohydrate, a pyruvate, flavin adenine dinucleotide (FAD), beta-nicotinamide adenine dinucleotide (NAD), beta-nicotinamide adenine dinucleotide phosphate (NADPH), a phosphate derivative of a nucleoside, a coenzyme, and their metabolites and precursors. The perfusion fluid can further include one or more compounds selected from the group consisting of an anticoagulant, a lipid, cholesterol, a fatty acid, oxygen, an amino acid, a hormone, a vitamin, and a steroid. The perfusion fluid is substantially free of carbon dioxide. Further embodiments are possible.

[0021] These and other embodiments of the disclosed subject matter should be more fully understood by reference to the following drawings and detailed description.

Brief Description of the Drawings

[0022] The following drawings are intended to show non-limiting examples of the disclosed subject matter. Further embodiments are possible. [Figure 1] FIG. 1 is an exemplary view of a liver. [Figure 2] FIG. 2 is a photograph of an exemplary priming module. [Figure 3] FIGS. 3A-3I show various views of an exemplary organ management system and its components. [Figure 4] FIG. 4 shows an exemplary system that can be used within an embodiment of an organ management system. [Figure 5] FIG. 5 shows an exemplary system that can be used within an embodiment of an organ management system. [Figure 6] FIGS. 6A-6E show exemplary pump configurations that can be used within an embodiment of an organ management system. [Figure 7] Figures 7A-7Q show exemplary solution infusion pumps that can be used within an embodiment of an organ management system. [Figure 8] Figure 8 shows an exemplary system that can be used within an embodiment of an organ management system. [Figure 9] Figure 9 shows an exemplary system that can be used within an embodiment of an organ management system. [Figure 10] Figure 10 shows an exemplary system that can be used within an embodiment of an organ management system. [Figure 11] Figure 11 shows an exemplary system that can be used within an embodiment of an organ management system. [Figure 12] Figures 12A-12G show an exemplary graphical user interface that can be used within an embodiment of an organ management system. Figure 12H shows an exemplary system that can be used within an embodiment of an organ management system. [Figure 13] Figures 13A-13R show exemplary embodiments of a purge module and its components that can be used within an embodiment of an organ management system. [Figure 14] Figures 14A-14S show exemplary embodiments of an organ chamber and its components that can be used within an embodiment of an organ management system. [Figure 15] Figures 15A-15D show exemplary embodiments of a support structure that can be used within an embodiment of an organ management system. [Figure 16] Figures 16A-16J show an exemplary pad and its components and a support surface of a flexible material that can be used within an embodiment of an organ management system. [Figure 17] Figure 17 shows an exemplary system that can be used within an embodiment of an organ management system. [Figure 18] Figures 18A-18G show an exemplary heater assembly and its components that can be used within an embodiment of an organ management system. [Figure 19] Figures 19A-19C show an exemplary sensor system that can be used within an embodiment of an organ management system. [Figure 20]Figures 20A-20C show exemplary systems that can be used within embodiments of an organ management system. [Figure 21] Figures 21A-21K show exemplary hepatic artery cannulas that can be used in an embodiment of an organ management system. [Figure 22] Figures 22A–22G show exemplary portal vein cannulas that can be used in an embodiment of an organ management system. [Figure 23] Figures 23A-23N show exemplary connectors that can be used in embodiments of the organ management system. [Figure 24] Figures 24A-24L show exemplary connectors that can be used within an embodiment of an organ management system. [Figure 25] Figures 25A-25D show exemplary clamps that can be used in embodiments of the organ management system. [Figure 26-27] Figures 26-27 show exemplary processes that can be used within an embodiment of an organ management system. [Figure 28] Figure 28 shows exemplary test results from an embodiment of the organ management system. [Figure 29] Figure 29 shows an exemplary process that can be used within an embodiment of the organ management system. [Figure 30] Figure 30 shows an exemplary system that can be used in an embodiment of an organ management system. [Figure 31] Figure 31 shows the trend of hepatic artery flow (HAF) throughout the entire 8-hour storage period in OCS. [Figure 32] Figure 32 shows the trend of portal venous pressure (PVF) throughout the entire 8-hour period of storage in OCS. [Figure 33] Figure 33 shows a graph of portal venous pressure relative to hepatic artery pressure throughout the entire 8-hour OCS-liver perfusion period. [Figure 34] Figure 34 is a graph of arterial lactate levels during OCS liver perfusion over 8 hours. [Figure 35] Figure 35 is a graph of total bile production over 8 hours of OCS liver perfusion. [Figure 36]Figure 36 shows a graph of AST levels during OCS liver perfusion over 8 hours. [Figure 37] Figure 37 shows a graph of ACT levels during OCS liver perfusion over 8 hours. [Figure 38] Figure 38 is a graph of the expansion pressure over the entire 8-hour storage period in OCS. [Figure 39] Figure 39 is a graph of sodium bicarbonate levels over 8 hours of OCS liver perfusion. [Figure 40] Figure 40 is a graph of the pH levels detected throughout the entire 8-hour storage period in OCS. [Figure 41] Figure 41 shows images of tissue samples taken from stage I, group A. [Figure 42] Figure 42 shows the hepatic artery flow during 12 hours of OCS liver perfusion. [Figure 43] Figure 43 shows portal venous flow during 12 hours of OCS liver perfusion. [Figure 44] Figure 44 shows a graph of portal venous pressure relative to hepatic artery pressure during 12 hours of OCS-liver perfusion. [Figure 45] Figure 45 shows the arterial lactate levels after 12 hours of OCS-liver perfusion. [Figure 46] Figure 46 shows bile production during 12 hours of OCS-liver perfusion. [Figure 47] Figure 47 shows the AST levels after 12 hours of OCS-liver perfusion. [Figure 48] Figure 48 shows the ACT levels during 12 hours of OCS-liver perfusion. [Figure 49] Figure 49 shows the hepatic artery flow in the hypothermia control group of simulated transplants compared to the OCS-liver preservation group of simulated transplants. [Figure 50] Figure 50 shows portal venous flow in the hypothermally preserved control group of simulated transplants compared to the OCS-liver preservation group. [Figure 51] Figure 51 shows hepatic artery pressure and portal vein pressure in the hypothermia control group of simulated transplants compared to the OCS-liver preservation group of simulated transplants. [Figure 52]Figure 52 shows arterial lactate levels in the hypothermia-preserved group of simulated transplants compared to the OCS-preserved group of simulated transplants. [Figure 53] Figure 53 shows bile production in the hypothermia-preserved control group of simulated transplants compared to the OCS-preserved liver group of simulated transplants. [Figure 54] Figure 54 shows the AST levels of the hypothermia control group in simulated transplantation compared to the OCS-liver preservation group in simulated transplantation. [Figure 55] Figure 55 shows the ACT levels of the hypothermia control group in simulated transplantation compared to the OCS-liver preservation group in simulated transplantation. [Figure 56] Figure 56 shows the inflation pressure of the hypothermia control group in simulated transplantation compared to the OCS-liver preservation group in simulated transplantation. [Figure 57] Figure 57 shows the sodium bicarbonate levels in the hypothermic control group of simulated transplants compared to the OCS liver preservation group. [Figure 58] Figure 58 shows the pH levels of the hypothermia control group in simulated transplantation compared to the OCS-liver preservation group in simulated transplantation. [Figure 59] Figure 59 shows images of tissue samples taken from stage I, group A. [Figure 60] Figure 60 shows images of tissue samples taken from stage I, group A. [Figure 61] Figure 61 shows the location of samples taken from a pig's liver. [Figure 62] Figure 62 shows the trend of hepatic artery pressure (HAP) during 24-hour OCS perfusion in OCS. [Figure 63] Figure 63 shows the portal venous pressure of the cryopreservation control group compared to the OCS-liver preservation group. [Figure 64] Figure 64 shows hepatic artery flow in the cryopreservation control group compared to the OCS-liver preservation group. [Figure 65] Figure 65 shows portal venous flow in the cryopreservation control group compared to the OCS-liver preservation group. [Figure 66] Figure 66 shows the arterial lactate levels of the cryopreservation control group compared to the OCS-liver preservation group. [Figure 67] Figure 67 shows the AST levels of the cryopreservation control group compared to the OCS-liver preservation group. [Figure 68] Figure 68 shows the ALT levels of the cryopreservation control group compared to the OCS-liver preservation group. [Figure 69] Figure 69 shows the GGT levels of the cryopreservation control group compared to the OCS liver preservation group. [Figure 70] Figure 70 shows the pH levels of the cryopreservation control group compared to the OCS liver preservation group. [Figure 71] Figure 71 shows the HCO3 levels of the cryopreservation control group compared to the OCS-liver preservation group. [Figure 72] Figure 72 shows bile production in the cryopreservation control group compared to the OCS-liver preservation group. Figure 72 demonstrates that both groups maintained a bile production rate of over 10 ml / hour. [Modes for carrying out the invention]

[0023] The following descriptions use headings, which are included solely for the convenience of the reader. These headings are not intended to be restrictive or limit the subject matter of this specification. For example, a component described in one section of this description may be included additionally or alternatively in another section. The embodiments described herein are illustrative only, and the disclosed embodiments and various features are interchangeable within the scope of this disclosure.

[0024] I. Introduction A. Overview Embodiments of the disclosed subject matter can provide techniques for maintaining the liver ex vivo during transplantation procedures. The system can maintain the liver in a state that mimics that of the human body. For example, the system can supply surrogate blood to the ex vivo liver in a manner that simulates the blood flow provided by the human body. More specifically, the system can supply surrogate blood flow with fluid and pressure characteristics similar to those of the human body to the hepatic artery and portal vein of the liver. In some embodiments, the desired flow can be achieved using a pump system with a single pump. The system can also warm the surrogate blood to a normal temperature that simulates that of the human body, and can further supply nutrients to the surrogate blood to maintain the liver and promote normal bile production by the liver. By performing these techniques, the time the liver can be maintained outside the human body can be extended, making the geographical distance between the donor and recipient less important than before. Furthermore, the state of the liver before transplantation can be assessed using some of the embodiments disclosed herein used for maintaining the liver ex vivo. In some embodiments, the techniques described herein allow for the treatment of damaged and / or diseased livers ex vivo using procedures that would be harmful to the human body if performed in vivo. Other embodiments also fall within the scope of the disclosed subject matter.

[0025] While this disclosure focuses on embodiments intended for maintaining or treating the liver, it is not limited thereto. For example, the techniques described herein, either in use or adapted thereto, can also be used on organs such as the lungs, heart, intestines, pancreas, kidneys, spleen, bladder, gallbladder, stomach, skin, and brain.

[0026] II. The liver compared to other organs The liver is one of many organs in the human body, but maintaining and transporting it ex vivo presents unique challenges not found in other organs such as the heart or lungs. Some of the most representative differences and problems are described below.

[0027] A. The liver utilizes two inflow and outflow sources of perfusion fluid. Importantly, the liver uses two unique input pathways, compared to other organs which use only one perfusion pathway. Hepatic circulation is unique in that it features a dual-vascular blood supply, each with different flow characteristics. Referring to Figure 1, an illustrative conceptual diagram of the liver, the liver utilizes two blood supplies: the portal vein and the hepatic artery. In particular, the hepatic artery delivers blood to the liver at high pressure and pulsatile flow, but at a relatively low flow rate. Hepatic blood flow typically accounts for about one-third of total liver blood flow. In particular, the portal vein delivers blood to the liver at low pressure and with minimal pulsatile flow, but at a larger flow rate. Portal blood flow typically accounts for about two-thirds of total blood flow to the liver.

[0028] When the liver is in an ex vivo system, the expected dual blood supply from this organ can pose problems when attempting to artificially supply physiological blood flow to it. This problem can be difficult even with a dual-pump design, but it can be even more difficult with a single-pump design. Several embodiments of the subject disclosed herein can address these problems.

[0029] B. Assistance in blood drainage In vivo, the liver is located below the diaphragm. This position means that hepatic blood flow and venous drainage via the inferior vena cava are typically facilitated by diaphragmatic contraction, which results in pressurizing the liver. When air is drawn in and expelled by the lungs, the diaphragm moves with the lungs, and this movement of the diaphragm acts on the liver by applying pressure, thereby pushing blood out of the tissue. This phenomenon can be mimicked in the ex vivo liver to promote blood outflow from the liver and help prevent blood accumulation within the organ.

[0030] C. Inflation pressure To minimize edema formation in the ex-vivo liver, the perfusion fluid, for example, dextran, 25% albumin, and / or fresh frozen plasma, should have a high inflation pressure. In some embodiments, the inflation pressure of the circulating perfusion fluid is maintained in the range of 5–35 mmHg, more specifically in the range of 15–25 mmHg. Possible inflation pressures are 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25 mmHg or any range demarcated by the values ​​shown herein.

[0031] D. Metabolism and CO2 levels The liver is the center of the body's metabolism and is constantly in a metabolic state. Most compounds absorbed by the intestines first pass through the liver, which then regulates the levels of many metabolites in the blood. For example, the conversion of sugars into fats and other stored energy (e.g., gluconeogenesis and glycolysis) produces CO2. The liver consumes about 20% of the body's total oxygen. As a result, the liver produces higher levels of CO2 than most other organs. In vivo, this organ can autoregulate itself to remove excess carbon dioxide. However, in order to maintain physiological levels of oxygen and carbon dioxide and thereby pH, it is sometimes desirable to remove excess carbon dioxide from this organ. The system described herein can facilitate the achievement of blood chemical equilibrium suitable for organ preservation ex vivo.

[0032] E. Bile production The liver is an organ that produces waste products. These waste products, bile, are normally produced and excreted by the organ in vivo. Bile is produced within the liver by hepatocytes. In vivo, the liver uses bile salts to produce bile, which are then recirculated and reused in the liver via the enterohepatic circulation. These bile salts then stimulate hepatocytes to produce even more bile. Ex vivo, bile salts are not recirculated to the liver. As a result, it may be desirable to supplement the perfusion fluid with bile salts to help the organ produce bile. Furthermore, in some cases, the bile produced by the liver can provide indicators of the organ's suitability for transplantation (e.g., volume, color, and viscosity).

[0033] F. Liver support The liver is the largest solid organ in the body, yet it is delicate and fragile. Within the human body, it is protected by the rib cage and other organs. Unlike many other organs, the liver lacks protective elements and is not surrounded by a robust structure. Therefore, when the liver is removed from the body and maintained ex vivo, it should be handled more delicately than other organs. For example, it may be desirable to properly support the liver, place it on a low-friction surface, and / or cover the organ with plastic wrap to protect it during transport and ex vivo maintenance.

[0034] G. Perfusion fluid Given the wide range of biological functions of the liver compared to other organs (e.g., detoxification, protein synthesis, glycogen storage, and production of biochemicals necessary for digestion), the perfusion fluid used in the organ management system described herein can be specifically designed to maintain a state close to its physiological state in order to maintain the liver's normal function. For example, since the liver is in a state of constant metabolism that consumes energy, the oxygen content in the perfusion fluid can be maintained at or above physiological levels to meet the liver's high demands as a metabolic warehouse. Similarly, the perfusion fluid can also be designed to contain energy-rich components such as sugars and electrolytes at concentrations sufficient to provide the liver with the energy source necessary to perform its functions.

[0035] Furthermore, the flow rate of this perfusion fluid can be appropriately adjusted to ensure that oxygen and nutrients are delivered to the ex vivo liver in appropriate amounts. Additionally, the carbon dioxide content in the perfusion fluid may be lower than that of a physiologically functioning liver, thus further promoting the equilibrium of the liver's biological responses to metabolism and oxidation. In some embodiments, the perfusion fluid used herein contains no significant amount of carbon dioxide, or none at all. In some embodiments, the perfusion fluid used herein also contains sufficient amounts of bile salts to maintain the liver's need to produce bile. Thus, the perfusion fluids for organ management systems described herein can be designed to maintain the normal cellular functions of the liver in order to keep the liver viable.

[0036] Category: Description of typical system components. A. General configuration Figure 3 shows an exemplary organ management system 600 that can be used to preserve organs such as the liver when they are ex vivo, for example, during transplant surgery or medical procedures. At a general level, the organ management system 600 is configured to recreate in vivo conditions for the ex vivo organ that mimic the conditions in which the organ is placed when it is in vivo. For example, in the case of the liver, the organ management system 600 can flow perfusion fluid through the organ in a manner that mimics blood flow in the human body (e.g., flow, pressure, and temperature) and achieves similar environmental characteristics (e.g., temperature).

[0037] In some embodiments, the organ management system 600 can be divided into two parts: a disposable, single-use portion (e.g., 634) and a non-disposable, multiple-use portion (e.g., 650) (also referred to herein as the single-use module and the multiple-use module). As the names suggest, the single-use portion is replaced after the liver has been transported, while the multiple-use portion is reusable. At a general level, although not a requirement, the single-use portion includes parts of the system that come into direct contact with biological material, while the multiple-use portion includes components that do not come into direct contact with biological material. In some embodiments, all components of the single-use portion are sterilized before use, while components of the multiple-use portion are not sterilized. Each of these parts will be described in detail later. This configuration allows for an operation method in which, after use, the single-use module 634 can be discarded and replaced with a new single-use module. This makes the system 600 reusable after a short time.

[0038] Typically, single-use and multi-use parts can be configured to be detachably connected to each other via a mechanical interface. Furthermore, the single-use and multi-use parts include mechanical, gaseous, optical, and / or electrical connection parts, and these two parts can interact with each other. In some embodiments, the connections between these parts are designed to be connected / disconnected from each other in a modular manner.

[0039] The disposable module 634 and the reusable module 650 are formed, at least partially, from lightweight yet durable materials such as polycarbonate plastic, carbon fiber epoxy composite, polycarbonate-ABS plastic mixture, glass fiber reinforced nylon, acetal, plain ABS, aluminum, and / or magnesium. In some embodiments, the total weight of the system 600 is less than 100 pounds, including the reusable module, organs, battery, gas tank, and priming, nutrients, preservatives, and perfusion fluid, and less than approximately 50 pounds excluding such parts. In some embodiments, the weight of the disposable module 634 is less than 12 pounds excluding any solutions. In some embodiments, the reusable module, excluding all fluids, battery, and gas supply units, weighs less than 50 pounds.

[0040] With the cover removed and the front panel open, the operator can easily access many of the components of the disposable module 634 and the reusable module 650. For example, the operator can access various components of the single-use and reusable modules, and can also attach and / or detach the single-use module from the reusable module.

[0041] Although some components are described as being located within the single-use or multiple-use portion of System 600, this is merely illustrative. That is, components described herein as being located within the single-use portion may also be located within the multiple-use portion, and vice versa.

[0042] B. Exemplary Multiple-Use Module Referring to Figure 3A-3I, the multi-use module may include several components, including a housing, cart, battery, gas supply unit, perfusion fluid pump, injection pump (at least a portion thereof), and a control system.

[0043] 1. Cart / Housing Referring to Figure 3A-3I, an exemplary embodiment of the organ management system is shown, and the organ management system 600 may include a housing 602 and a cart 604. The cart 604 may include a platform and wheels for transporting the system 600 from one location to another. A latch 603 can secure the housing 602 to the cart 604. To further enhance portability, the system 600 may include a handle hinged to the left side of the housing 602, in conjunction with two rigidly attached handles 612a and 612b attached to the left and right sides of the housing 602. The housing 602 further includes a front panel 615 hinged to a removable top cover (not shown) and a lower panel by hinges 616a and 616b. This cover may include a handle to assist in removal.

[0044] System 600 may include an AC power cable 618, along with a frame for securing the power cable, both of which are located on the lower left side of the housing 602. A power switch 622, also located on the lower left side, allows the operator to restart the system software and electronic components.

[0045] Figure 3G shows a front perspective view of the multi-use module 650 with the single-use module 634 removed. As illustrated, the multi-use module 650 may include the cart 604 and housing 602, along with all components mounted on or inside them. The multi-use module 650 also includes a bracket assembly 638 for receiving and locking the single-use module 634 into place. An exemplary bracket assembly 638 is shown in Figure 3H.

[0046] In some embodiments, the housing 602 includes a fluid-tight reservoir configured to capture any perfusion fluid and / or other fluids that might accidentally leak from the upper portion of the housing 602 and prevent them from reaching the lower portion of the housing 602. Thus, in some embodiments, this reservoir can shield the electronic components of the system 600 from leaked fluid. In some embodiments, the reservoir 652 can be sized to accommodate the entire volume of fluid used in the system 600 at any given time.

[0047] The system 600 may further include an operator interface module 146, along with a pedestal 623 for holding the operator interface module 146. The operator interface module 146 may include a display device 624 for displaying information to the operator. The operator interface module 146 may further include a rotatable and pressable knob 626 for selecting from a number of parameters, and a display screen. The knob 626 can also be used to set parameters for automatic control of the system 600 or to manually control the operation of the system 600. In some embodiments, the operator interface module 146 may also include its own battery 368 and may be detached from the pedestal 623 for use in wireless mode. When located in the pedestal 623, the operator interface module 146 can be charged by connecting to a power source. This operator interface module may also include control buttons for controlling pumps, stopping or disabling alarms, entering or exiting standby mode, and starting a perfusion clock to begin displaying data obtained during organ management.

[0048] See also Figure 5, the system 600 further includes a plurality of interconnected circuit boards to facilitate power distribution and data transmission to and from the system 600. For example, the multiple-use module 650 includes a front-end interface circuit board 636 that is optically and electromechanically connected to the front-end circuit board 637 of the one-time-use module 650. The system 600 further includes a main board 718, a power circuit board 720, and a battery interface board 711, which are located on the multiple-use module 650. The main board 718, by its configuration, can make the system 600 fault-tolerant in that, in the event of a failure in the operation of a circuit board, the main board 718 stores one or more parameters (e.g., pumping parameters) in non-volatile memory. When the system 600 reboots, it can recapture such parameters and continue operation according to them. Furthermore, the system 600 can divide critical functions among multiple processors, so that if one processor fails, the remaining critical functions can continue to be executed by other processors.

[0049] 2. Power System Referring to Figure 4, the multi-use portion of system 600 may include a power subsystem 148 configured to supply power to system 600. The power subsystem 148 can supply power to system 600 using a replaceable battery and / or an external power source. In some embodiments, the power subsystem 148 can switch between external power and the onboard battery without interrupting the operation of the system. Furthermore, the power subsystem 148 can be configured to automatically distribute the externally supplied power between powering system 600, charging the battery, and charging the internal battery of the operator interface module 146. The battery of this power system can be used as a primary power source and / or as a backup power source in case the external power source fails or becomes insufficient. Furthermore, the power subsystem 148 can be configured to be compatible with a variety of external power sources. For example, this power system can be configured to accept a variety of input voltages (e.g., 100V-230V), a variety of frequencies (e.g., 50-60 Hz), single-phase power, three-phase power, AC, and / or DC power. Furthermore, in some embodiments, the operator interface module 146 may also include its own battery 368.

[0050] The housing 602 may include a battery bay 628 configured to hold one or more batteries 352. In embodiments with multiple batteries, the battery bay 628 may include a lockout mechanism 632 configured to prevent two or more batteries from being removed from the battery bay 628 at any point while the system 600 is operating. This feature can provide an additional level of fault tolerance that helps ensure that the power supply is always reliably available. The system 600 may also include a tank bay 630 that can be configured to house one or more gas tanks.

[0051] Referring to the conceptual diagram in Figure 5, the cable wiring 731 can carry power (e.g., AC power 351) from the power supply 350 to the power circuit board 720 via connectors 744 and 730. The power supply unit 350 converts the AC power to DC power and distributes this DC power as described above. The power circuit board 720 can connect DC power and data signals 358 to the corresponding connectors 713 and 715 on the front end interface circuit board 636 via connectors 726 and 728 through cables 727 and 729. Cable 729 can carry power and data signals to the front end interface board 636. Cable 727 can carry power to the heater 110 via the front end interface board 636. Connectors 713 and 715 can mate with the corresponding connectors 712 and 714 on the front end circuit board 637 of the auxiliary module 634 to supply power to this auxiliary module 634.

[0052] The power circuit board 720 can further supply DC power 358 and data signals from connectors 732 and 734 of the power circuit board 720 to the corresponding connectors 736 and 738 of the main circuit board 718 via cables 733 and 735. Cable 737 can connect DC power 358 and data signals from connector 740 of the main circuit board 718 to the operator interface module 146 via connector 742 of the operator interface module base 623. Furthermore, the power circuit board 720 can also supply DC power 358 and data signals from connectors 745 and 747 to connectors 749 and 751 of the battery interface board 711 via cables 741 and 743. Cable 741 can carry DC power signals, and cable 743 can carry data signals. The battery interface board 711 can distribute DC power and data to one or more batteries 352 (352a, 352b, and 352c in Figure 5), and these batteries have built-in electronic circuits that enable communication of their respective charge states, so the controller 150 can monitor and control the charging and discharging of one or more batteries 352.

[0053] 3. Perfusion fluid pump The system 600 may include a pump 106 configured to pump a perfusion fluid into its organ management system. This perfusion fluid utilizes a blood product-based perfusion fluid that can mimic a normal physiological state. In some embodiments, this perfusion fluid may be an artificial blood substitute solution, and / or this perfusion fluid may be a blood product combined with a blood substitute. In embodiments where this perfusion fluid is blood product-based, it typically contains red blood cells (e.g., oxygen-carrying cells). This perfusion fluid will be described in more detail later.

[0054] In some embodiments, the pump 106 may have a systolic phase and an diastolic phase. The amount of perfusion fluid pumped by the pump 106 can be changed by changing one or more characteristics of the pump itself. For example, the desired flow rate and pressure characteristics can be achieved by changing the number of strokes per minute and / or stroke displacement. In some embodiments, the pump 106 may be configured to use a stroke rate of 1–150 strokes / min and a displacement of 0.1–1.5 inches. More specifically, a nominal stroke rate of 60 strokes / min ± 5 strokes / min can be used in combination with a displacement of 0.5 inches. These values ​​are illustrative only, and values ​​outside these ranges can also be used. By changing the characteristics of the pump 106, flow rates between 0.0 L / min and 10 L / min can be achieved.

[0055] In some embodiments, the perfusion fluid pump 106 is divided into two separable parts: a pump drive unit located in the multi-use section 650 and a pump interface assembly in the single-use section 634. This interface assembly in the single-use section can isolate the pump drive unit of the multi-use section from direct biological contact with blood.

[0056] Figures 6A-6D show exemplary embodiments of the pump 106. Figures 6A-6C show various views of the pump interface assembly 300 according to an exemplary embodiment. Figure 6D is a perspective view of an exemplary pump drive unit 107 of the perfusion fluid pump 106. Figure 6E is a perspective view of the pump interface assembly 300 engaged with the pump drive unit 107 of the perfusion fluid pump assembly 300 according to an exemplary embodiment.

[0057] The pump interface assembly 300 includes a housing 302 with an outer side 304 and an inner side 306. The interface assembly 300 includes an inlet 308 and a discharge port 310. The pump interface assembly 300 may further include inner 312 and outer 314 O-ring seals, two deformable membranes 316 and 318, a donut-shaped bracket 320, and half-rings 319a and 319b that fit between the O-rings 314 and the bracket 320. The half-rings 319a and 319b may be made from foam, plastic or other suitable material.

[0058] The inner O-ring 312 can be fitted into an annular raceway along the periphery of the inner side surface 306. The first deformable membrane 316 is mounted to the inner O-ring 312 in a fluid-tight interconnection with the inner side surface 306 of the housing 302, thereby forming a chamber between the inner side surface of the first deformable membrane 316 and the inner side surface 306 of the housing 302. The second deformable membrane 318 is mounted on top of the first deformable membrane 316 to provide fault tolerance in case the first deformable membrane 316 ruptures or tears. For example, the deformable membranes 316 and 318 can be formed from a thin polyurethane film (about 0.002 inches thick). However, any suitable material of any suitable thickness may be used. Referring to Figures 6A and 6B, the bracket 320 can be mounted on the second deformable membrane 318, and the rings 319a and 319b can be secured to the housing 302 along the periphery of the inner side surface 306. Threaded fasteners 322a-322i can be used to attach the bracket 320 to the housing 302 through the threaded openings 324a-324i of the bracket 320. The outer O-ring 314 can be fitted into an annular groove of the bracket 320 to provide fluid sealing with the pump assembly 106. Before inserting the O-ring 314 into the annular groove of the bracket 320, the half-rings 319a and 319b are typically positioned in the groove. The O-ring 314 can then be compressed and positioned in the annular groove of the bracket 320. After being positioned in the annular groove, the O-ring 314 expands within the groove to secure itself and the half-rings 319a and 319b in place.

[0059] The pump interface assembly 300 may further include heat-crimping points 321a-321c protruding from its outer side surface 304. These points 321a-321c are receptacle for heat-bonding material, allowing the pump interface assembly 300 to be heat-crimped to the C-bracket 656 of the auxiliary portion of the system 300.

[0060] As shown in Figure 6C, the fluid outlet 310 includes an outlet housing 310a, an outlet pipe fitting 310b, a fluid flow regulating ball 310c, and an outlet port 310d. The ball 310c is sized to fit within the outlet port 310d but not to pass through the inner opening 326 of the outlet 310. The pipe fitting 310b is bonded to the outlet port 310d (for example, with epoxy or another adhesive) to trap the ball 310c between the inner opening 326 and the pipe fitting 310b. The outlet housing 310a is similarly bonded to the pipe fitting 310b.

[0061] During operation, the pump interface assembly 300 is configured and positioned to receive pumping force from the pump drive unit 334 of the perfusion pump assembly 106 and translate this pumping force to the perfusion fluid 108, thereby circulating the perfusion fluid 108 to the organ chamber assembly 104. In this exemplary embodiment, the perfusion pump assembly 106 includes a pulsatile pump having a drive unit 334 that can contact the membrane 318. The fluid intake 308 can draw the perfusion fluid 108 from a reservoir 160 or the like in response to the pump drive unit moving away from the deformable membranes 316 and 318, and supply this fluid to a chamber formed between the inner membrane 316 and the inner side surface 306 of the housing 302, thereby causing the membranes 316 and 318 to deform in the same direction.

[0062] As the pump drive unit moves away from the deformable membranes 316 and 318, the pressure head of the fluid 108 in the reservoir 160 causes the perfusion fluid 108 to flow from the reservoir 160 into the pump assembly 106. At this time, the pump assembly 106, the inlet valve 191, and the reservoir 160 are oriented to naturally supply the perfusion fluid 108 to the pump assembly 106. Simultaneously, the fluid flow control ball 310c is pulled toward the opening 326, preventing the perfusion fluid 108 from being drawn into the chamber through the discharge port 310. Note that the discharge valve 310 and the inlet valve 191 are one-way valves in the illustrated embodiment, but in alternative embodiments, these valves 310 and / or 191 are two-way valves. In response to the pump drive unit 334 moving toward the deformable membranes 316 and 318, the fluid flow control ball 310c moves toward the pipe fitting 310b, opening the inner opening 326, so that the discharge port 310 can discharge the perfusion fluid 108 out of the chamber formed between the inner side surface 306 of the housing 302 and the inner side surface of the deformable membrane 316. Another one-way suction valve 191, shown in Figure 1 between the reservoir 160 and the suction port 308, prevents the fluid from being discharged from the suction port 308 and returning to the reservoir 160.

[0063] In an embodiment of the system 600 divided into a disposable module 634 and a multi-use module 650, the pump assembly 107 can be securely attached to the multi-use module 650, and the pump interface assembly 300 can be securely attached to the disposable module 634. The pump assembly 106 and the pump interface assembly 300 may have corresponding coupling connections that interlock to form a fluid seal between the two assemblies 107 and 300.

[0064] More specifically, as shown in the perspective view of Figure 6D, the perfusion pump assembly 107 may include a pump drive housing 338 having a top surface 340 and a pump drive unit 334 housed within a cylinder 336 of the housing 338. The pump drive housing 338 may further include a coupling port 342 which may include a slot 332 sized and shaped to engage with a flange 328 protruding from the pump interface assembly 300. The top surface 338 of the pump drive housing 338 is mounted on a bracket 346 on a non-disposable, multiple-use module 650. The bracket 346 may include features 344a and 344b which abut against tapered projections 323a and 323b of the pump interface assembly 300, respectively. The bracket 346 may further include a notch 330 sized and shaped to align with the coupling port 342 and slot 332 of the pump drive housing 338.

[0065] In operation, the seal between the pump interface assembly 300 and the fluid pump assembly 107 can be formed in two steps, as illustrated with reference to Figures 6D and 6E. In the first step, the flange 328 is positioned within the coupling port 342, with the tapered projections 323a and 323b positioned on the clockwise sides adjacent to the corresponding features 344a and 344b on the bracket 346. In the second step, the flange 328 is slid into the slot 332 of the coupling port 342 by rotating the pump interface assembly 300 and the fluid pump assembly 106 in opposite directions (for example, rotating the pump interface assembly 300 counterclockwise while keeping the pump assembly 106 fixed), as indicated by arrows 345, 347, and 349. Simultaneously, the tapered projections 323a and 323b slide beneath the bracket features 344a and 344b, respectively, engaging the inner surfaces of the bracket features 344a and 344b with the tapered outer surfaces of the tapered projections 323a and 323b, thereby pulling the inner side surface 306 of the pump interface assembly 300 toward the pump drive unit 334, and interlocking the flange 328 to the coupling port 342 and the tapered projections 323a and 323b to the bracket features 344a and 344b, thereby forming a fluid seal between the two assemblies 300 and 106.

[0066] In some embodiments, the system 100 may be configured such that the flow characteristics, including the pressure and flow rate of the perfusion fluid supplied to the hepatic artery and portal vein, are directly controlled by the pump 106 and are under the pressure generated by the pump 106 (for example, so that the hepatic artery and portal vein can communicate with the pump 106 under fluid pressure). This embodiment differs from embodiments in which the pump supplies the perfusion fluid to a reservoir (for example, a reservoir located above the liver) and gravity is used to apply fluid pressure to the liver.

[0067] 4. Solution injection pump The system 600 may also include a solution pump 631 that can be configured to inject one or more solutions into the perfusion module circuit. In some embodiments of the organ management system 600, the solution pump 631 may be a commercially available pump such as the MedSystem III from CareFusion Corporation, San Diego, California, and / or a solution pump described later with respect to Figures 7A-7P. The injectable solutions supplied by the solution pump 631 can be used to perform continuous management of organs, such as inotropic support, glucose control, and pH control. Furthermore, although the solution pump 631 is generally considered to be part of a multi-use module 650, some parts of the solution pump 631 can be replaced each time the system is used on an ad-hoc basis.

[0068] The solution pump 631 can be configured to supply one or more solutions simultaneously (also referred to as having one or more channels). In some embodiments, the solution pump 631 can supply three solutions: a maintenance solution, a bile salt, and a vasodilator such as epoprostenol sodium. Each of these solutions will be described in detail later. The solution pump 631 can support a number of infusion rates (faster / slower rates are also possible, e.g., 1–200 ml / hour). The infusion rate can be adjustable in time increments (faster / slower rates are also possible, e.g., 1 ml / hour increments), and while the change in infusion rate typically takes effect within 5 seconds, this is not a requirement. At infusion rates of 10 ml / hour or less, the amount injected can be accurate within + / - 10% of the infusion rate setpoint, but this is not a requirement. At infusion rates greater than 10 ml / hour, the amount injected can be accurate within + / - 5% of the infusion rate setpoint, but this is not a requirement.

[0069] This solution pump can be configured to maintain any required accuracy with input pressures (static pressure relative to this solution pump line connection) of 0 to -50 mmHg on the solution side and 0 to +220 mmHg on the organ side. Preferably, the infusion should not experience flow discontinuities exceeding 3 seconds. After the solution pump has degassed, bubbles larger than 50 μL are typically not injected into the perfusion module. In some embodiments, the line portion between the solution pump 631 and the organ includes valves (e.g., pinch valves) to further control the flow of solution to the organ. The solution pump 631 can provide status information for each channel, such as infusion status and errors.

[0070] The solution pump 631 can be used in combination with one or more disposable cartridges for supplying the solution. For example, the line portion between the solution source and the solution pump 631 may include a spike for connecting to an infusion bag. In embodiments that include a disposable cartridge for supplying the solution, this cartridge should be capable of operating for at least 24 hours.

[0071] The solution pump 631 can be configured to be controlled via one or more communication ports. For example, the solution pump 631 can be controlled via commands that can be received via a serial port, a network (e.g., Ethernet®, WiFi), and / or cellular communication. Various aspects of the solution pump 631, such as the initial available solution volume and infusion status (e.g., infusion or stopped) for each channel, can be controlled. The general and / or warning status of each channel can be accessed via this communication port. The status of each channel may include whether a disposable cartridge is present, whether an initial volume is available, the infusion status, the infusion rate, the time remaining until empty, and an indication of the total volume injected. Furthermore, the solution pump 631 can be configured so that each channel has a fault mode infusion rate that can be written / read via the communication port. In some embodiments, sensors located throughout the organ management system 600 can be connected (directly or indirectly via the controller 150) to facilitate automatic control of the solution pump 631 by the controller 150 using open or closed feedback loops.

[0072] The solution pump 631 can be configured to indicate when a fault occurs. For example, when a fault or blockage is detected, the solution pump 631 can illuminate a fault indicator associated with the faulty channel and / or send a notification via the communication port. The solution pump 631 can be configured to temporarily suspend injection in the faulty channel and resume injection after the fault or blockage is resolved. In embodiments where the injection rate is set via the communication port, if a signal to / from the communication port is lost, the solution pump 631 can be configured to set the injection rate to a pre-programmed fault mode injection rate.

[0073] The solution pump 631 may include one or more fault detection algorithms / mechanisms. For example, if a hardware failure is detected, the solution pump 631 may warn a device connected to the communication port that the hardware failure has occurred. If a blockage on the solution and / or organ side is detected, the solution pump 631 may warn a connected device via the communication port that the blockage has occurred. The solution pump 631 may be configured to perform self-diagnostic tests, including post-power-on self-diagnosis and background self-diagnosis. The results of the self-diagnosis can be displayed on the solution pump 631 itself and / or communicated via the communication port.

[0074] As mentioned above, this solution pump may be a commercially available solution pump and / or a custom-designed pump. Referring to Figures 7A-7P, an exemplary embodiment of a custom-designed solution pump 631 is illustrated and described.

[0075] Some embodiments of the solution pump described herein can use a syringe connected to a motor to control the delivery of the injected solution. By increasing the diameter of the syringe, the syringe's fluid capacity can be increased. Increasing the fluid capacity thus reduces the frequency of changing the syringe with a new pre-filled syringe. However, with a larger diameter syringe, the amount of solution delivered when the plunger is pushed down by one unit increases with the increase in diameter, which can lead to a loss of accuracy in solution delivery. Another exemplary embodiment of the solution pump uses a relatively small-diameter syringe, which can improve the accuracy of solution delivery. However, because the syringe has a small fluid capacity, the solution may run out quickly. Changing the syringe with a new pre-filled syringe can lead to problems such as the introduction of air bubbles, interruption of solution delivery, inconvenience to the user, and access problems. Therefore, in some embodiments, a relatively small-diameter syringe can be connected to an external fluid solution source and perfusion circuit via a fluid line and a series of one-way valves. In these embodiments, when the syringe is pushed down, the solution flows through a one-way valve and enters the perfusion circuit. When the syringe is withdrawn, the solution enters the syringe from an external fluid source through another one-way valve, refilling the syringe with solution. Thus, some embodiments of this design allow for highly precise control of solution delivery (e.g., by using smaller diameter syringes) while eliminating the need to replace a pre-filled syringe with another.

[0076] Referring to Figures 7A-7P, exemplary embodiments of the solution pump 9000 are illustrated. In this embodiment, the solution pump 9000 can supply the injection solution using a removable / replaceable cassette 9020. Figures 7C and 7D are exploded views of the solution pump 9000 and the injection cassette 9020, respectively. In this embodiment, the solution pump 9000 includes three channels and is configured to supply up to three different solutions. Other embodiments may include more or fewer channels.

[0077] The solution pump 9000 may be a syringe pump driven by stepping motors 9002a, 9002b, and 9002c. Each stepping motor 9002 can rotate a lead screw 9005. A carriage 9042 with a carriage cover communicates with the lead screw 9005 and can move back and forth along the screw 9005. The interior of the carriage 9042 can also be threaded with matching threads to facilitate movement along the lead screw 9005 in conjunction with its rotation. Furthermore, the carriage 9042 can also move along a straight rail 9041 to facilitate back and forth movement along the lead screw 9005. A pin 9003 is attached to the carriage cover 9004 and a carrier 9036 configured to hold the syringe plunger 9017, so that the plunger can be pushed in and pulled out as the carriage 9042 moves back and forth along the lead screw 9005. Pin 9003 may be threaded to facilitate attachment to carrier 9036, but this is not a requirement. In the embodiments shown in Figures 7E, 7F, 7G, and 7H, carrier 9036 can be molded to fit around plunger 9017 and hold it. Carrier 9036 can clamp syringe plunger by press fitting using projection 9045 and fitting via thread and / or other optional fasteners.

[0078] In some embodiments, the stepping motor 9002 can be configured to operate at different speeds depending on whether the syringe is extended or compressed. For example, when the syringe is compressed (e.g., during injection), the motor can move at a slow speed such as 4 steps per second, while when the syringe is extended (e.g., during refilling), the motor can move at a high speed such as 16,000 steps per second. Other speeds are also possible. Furthermore, each stepping motor 9002 may include an optical encoder on the motor shaft enclosed internally (or elsewhere) that can be used to track the position and / or speed of the motor 9002. Thus, the position of the syringe plunger can be calculated.

[0079] In the embodiment shown in Figure 7C, the stepping motors 9002a, 9002b, and 9002c are arranged in parallel with each other, but this is not a requirement. Pin 9003 passes through slot 9008 in the upper cover 9001 and can be attached to the carrier 9036, which connects to the plunger 9017 of the syringe 9016. The syringe can be pushed in and pulled out using the connection between the carriage 9042 and the plunger 9017 via pin 9003 and the carrier 9036, thereby allowing the syringe to supply or replenish fluid if properly connected. For example, when the stepping motor 9002 rotates the lead screw 9005 clockwise, the carriage 9042 and carriage cover 9004, connected by pin 9003 to the carrier 9036 and the plunger 9017, can move in the direction of pushing the plunger 9017 and releasing the fluid solution from the syringe 9016. When the stepping motor rotates counterclockwise, the carriage 9042 can move in the opposite direction, retracting the plunger 9017 so that the syringe 9016 can be refilled with fluid from a fluid source such as an external infusion bag.

[0080] The solution pump 9000 may include an optical switch 9007 that can be used to detect when the syringe is in the "home position" or another position. In some embodiments, this home position may be the position when the syringe 9016 is extended and filled with solution, but other home positions are also possible. The optical switch 9007 may be U-shaped and further configured to transmit a light beam between the two upper parts of this U-shape (for example, by providing a transmitter on one side and a receiver on the other). In some embodiments, when the carriage 9042 is in the home position, a flag 9006 on the carriage cover 9004 may block the light beam from the optical switch 9007 to provide information about the syringe's position. The flag 9006 may be made of any material that blocks this light beam, such as translucent plastic and / or metal. In some examples, the solution pump 9000 may lose track of the position of the carriage 9042, for example due to malfunction. When this occurs, the carriage 9042 can return to its home position, refill the syringe 9016, and leave the plunger 9017 extended. This allows the pump 9000 to recognize the syringe position again without accidentally supplying additional solution. In some embodiments of the solution pump 9000, an additional optical switch 9007 may be included to determine when the syringe is nearly or completely empty.

[0081] The solution pump 9000 may include a pressure sensor 9009 for detecting blockages in the delivery line 9010 or output line 9011. An alarm may indicate that the pressure sensor 9009 has detected a blockage by sensing a pressure above or below a predetermined threshold. This pressure sensor may be any commercially available sensor suitable for this purpose. In one embodiment, this sensor may be a MEMSCAP SP854 transducer comprising a working fluid and a diaphragm. The pressure sensor 9009 can pass through an opening 9012 in the upper cover 9001.

[0082] The stepping motor 9002, the straight rail 9041, and the pressure sensor 9009 can be mounted on the structural plate 9013. The printed circuit board ("PCB") 9015 can be mounted on the opposite side of the structural plate 9013 and may contain electronic components used to operate the solution pump 9000. The plate 9013 may be made of aluminum or any other suitable material and may include a flange 9014 to increase rigidity. The plate may also include a series of mounting holes to provide connection points to the top cover and bottom cover.

[0083] The upper cover 9001 can engage with the bottom cover 9018 to surround the solution pump 9000. These two parts can engage along their edges and be secured with screws or other fasteners. The mounting plate 9019 can be attached to the bottom cover 9018 (numbered as 9015 in some figures) and can also be attached to the inner wall of the system 600, for example. The upper cover 9001 may also include an opening 9025 for connector cables that connect to other parts of the system 600, such as the controller 150.

[0084] The solution pump 9000 can engage with the injection cassette 9020 that holds the syringe 9016. In one embodiment, the upper cover 9001 may include a pinned boss 9023. As shown in Figures 7A and 7B, a tab 9021 on the injection cassette 9020 engages with a pin on the boss 9023 to connect the solution pump 9000 and the injection cassette 9020. Furthermore, the solution pump 9000 can engage with the injection cassette 9020 via a surrounding groove for a pressure sensor 9009 that can be housed in a pinch release portion 9022 of the injection cassette 9020.

[0085] The infusion cassette 9020 may include at one end a delivery line 9010 equipped with an infusion bag spike 9024, which can be connected to an infusion bag or another external solution source. The other end of the delivery line 9010 can be connected to a one-way check valve 9026 designed to allow fluid to flow only in the direction away from the infusion bag towards the syringe 9016. The one-way check valve 9026 can be connected to a connector 9027. The output line 9011 can be connected to a second one-way check valve 9032 designed to allow fluid to flow only in the direction away from the syringe 9016 and towards the port 9034. The one-way check valve 9032 can also be connected to a connector 9027. The output line 9011 may include a filter 9033 for filtering particles and air from the solution. The filter 9033 may be any hydrophobic filter suitable for this purpose. The output line 9011 can further be coupled to a port 9034 that connects to a perfusion module. Port 9034 may include a Luer fitting. The output line 9011 may further include a roller clamp 9035 that can close the output line 9011. When in use, the roller clamp 9035 can remain open to allow fluid to pass through the output line 9011.

[0086] Referring to Figure 7I-7K, connector 9027 may be, for example, a Y-connector. Connector 9027 may include connectors 9043 and 9044. Connector 9043 can be connected to the discharge line 9010, and connector 9044 can be connected to the output line 9011. Connector 9027 may also include a vertical injection line. This vertical injection line can be connected to the connector mount. Connector 9027 may also include an alignment tab 9028.

[0087] Referring to Figure 7L-7P, an exemplary connector mount 9029 is illustrated. The connector mount 9029 may include a connection port 9031 that can be coupled to a connector 9027 and a syringe mount 9030 that can be coupled to a syringe 9016. A pressure membrane (not shown) can be placed on the connector mount 9029 to monitor the pressure in the fluid circuit between the syringe 9016, the delivery line 9010, and the output line 9011 (e.g., using a pressure sensor 9009). The pressure membrane can be mounted on the connector mount 9029 opposite the connection port 9031. The cassette 9020 can also be detachably mounted to the top cover 9001 using a snap connector via the connector mount 9029. For example, a wing 9055 can pass through an opening in the top cover 9037. By tightening the wing 9055, the bottom portion 9056 can be bent outward, freeing it from, for example, the corresponding connector portion of the pressure sensor 9009.

[0088] In one embodiment, the syringe 9016 can deliver fluid as the plunger 9017 is compressed by the movement of the carriage 9042 along the lead screw 9005 by the stepping motor 9002. The fluid from the syringe enters this vertical infusion line, passes through the one-way check valve 9032, enters the output line 9011, and flows into the perfusion fluid circulating in the system 600 via the filter 9033. When the plunger 9017 is compressed almost or completely so that almost no fluid is delivered from the syringe 9016, the syringe is retracted, and the fluid can pass from the infusion bag (not shown) through the delivery line 9010, past the one-way check valve 9026, enter the vertical infusion line, and enter the syringe 9016, thus refilling the syringe.

[0089] The injection cassette may include an upper cover 9037 that can engage with the bottom cover 9038 to surround the syringe 9016. A gasket 9039 can seal around the slot 9008 of the upper cover 9001 to prevent fluid from entering the solution pump 9000 through the slot 9008. This gasket can be manufactured from any suitable sealing material, including foam. A shipping lock 9040 holds the plunger 9017 and carrier in a fully retracted position so that the carriage 9042 can engage in the home position. The purpose of the shipping lock 9040 is to ensure that the hole 9092 in the carrier 9036 is in the correct position so that the drive pin 9003 can protrude into the hole 9092 when the user installs the cassette 9020. The shipping lock 9040 can be removed before use.

[0090] It should be understood that the type and configuration of syringes used in cassette 9020 can affect how the system is controlled. For example, a larger syringe diameter reduces the distance the plunger needs to travel to deliver a predetermined amount of solution. Furthermore, multiple syringes can have different capacities, which can affect how often they need to be refilled. Therefore, it can be advantageous for the solution pump 9000 to be aware of what type of syringe is loaded into cassette 9020. Thus, in some embodiments, the system 9000 includes a mechanism that can determine what type of syringe is contained in cassette 9020. For example, in embodiments where the solution pump 9000 is configured to operate with two different types of syringes, the pump may include a magnet and a Hall effect sensor that can be configured to determine which of the two types of syringes is being used. For example, cassette 9020 may include a magnet with N and S poles. This magnet can be oriented so that only one of its two poles interacts with the Hall effect sensor. When using the first type of syringe, the north pole can be configured to interact with the Hall effect sensor, and similarly, when using the second type of syringe, the south pole can be configured to interact with the Hall effect sensor. By determining which of the two types of syringes is interacting with the Hall effect sensor, the solution pump 9000 can determine which type of syringe is being used in the cassette 9020. This sensor configuration is for illustrative purposes only, and other sensors can be used to determine which type of syringe is being used in the cassette 9020.

[0091] The solution pump 9000 can be controlled by one or more control systems. For example, the solution pump 9000 can be controlled by a controller 150 and / or may include an internal control system. Wherever the controller is located, it can be configured to know how many partial or complete rotations of the stepping motor 9002 are needed to supply the required amount of solution and / or to refill the syringe. For example, the controller knows that 40 steps of the stepping motor can supply 1 mL of solution. In some embodiments, the amount of solution supplied by the solution pump 9000 can be controlled manually and / or automatically by the controller 150.

[0092] The solution pump 631 can be configured to supply a solution flow rate that varies between 0.5 and 200 mL / hour, although other flow rates are also possible.

[0093] Some embodiments of the solution pump 631 may include a priming cycle that can be used to prime the pump 631 and remove air from its lines. For example, a user can assemble a complete line set in a dry state and run it until the air is removed. Each priming cycle may, for example, use a special fast-forward / high-speed refill operation to deliver 3 mL of air (or solution) forward. In some embodiments, this priming cycle may be under user control and / or run automatically.

[0094] In some embodiments, when the motor 9002 is operating at high speed (e.g., during refilling and / or priming), this high-speed cycle may include rise and fall periods when entering and exiting high-speed operation. These rise and fall periods can be used to overcome the rotational inertia of the motor 9002. This function can be implemented by firmware and / or a controller that controls the pump 631 using a lookup table calculated to adjust the pulse rate of the motor 9002 for constant acceleration and / or deceleration. These rise and fall periods can also be used during low-speed operation.

[0095] In some embodiments, the solution pump 631 can be configured to compensate for inherent backlash that may occur when the direction of movement of the syringe is reversed. For example, the fluid flow may be particularly affected by the inherent backlash of the motor 9002 and lead screw 9005. Errors caused by backlash may affect the resumption of injection flow after a replenishment cycle. To compensate for these possible errors, the firmware and / or controller in the pump can capture the pressure in the syringe chamber at the end of every injection stroke. A fast replenishment cycle can then be performed, and this firmware and / or controller can advance the plunger at a medium to high speed until the pressure in the syringe chamber equals the pressure captured during the last injection stroke. Once that pressure is reached, all system backlash is typically resolved, and the pump can continue injection at the desired speed.

[0096] Stepping motors typically provide maximum torque for a given motor size and are easy to drive, but they can consume a lot of power and generate significant mechanical noise. Therefore, in some embodiments of the pump 631, the firmware and / or controller can include a dynamic torque function that can operate the motor 9002 with the minimum torque required for a given time. This can be achieved using a digital-to-analog converter that controls the current limit of each stepping motor drive, thereby controlling the torque supplied by the motor. Thus, the torque of the stepping motor can be adjusted to efficiently achieve the desired operation. When stopped, a small current can be supplied to the motor to maintain its stationary position without slipping. At the start of each forward injection stroke, the stepping motor can be operated at a selected injection speed with a predetermined minimum torque. If the encoder indicates that the stepping is not moving as desired, the torque can be increased until the appropriate operation is achieved. In this way, the forward injection stroke can be performed with the minimum torque required to perform its work.

[0097] The solution pump 631 can be configured to compensate for the amount of slip between the actual position of the syringe plunger and the desired position. For example, if the firmware and / or controller determines that the syringe position (e.g., given by an encoder) is lagging behind the desired profile, the speed can be doubled until the syringe position catches up. This process of slip, torque increase, and / or speed doubling can be performed fast enough to achieve continuous injection at the selected speed.

[0098] Figure 7Q shows an exemplary embodiment of a microcontroller architecture that may be included in the solution pump 631, but this is not a requirement and other configurations are possible. In this embodiment, the microcontroller architecture includes, for example, a controller 150, a pressure input sensor, motor current and diagnostic voltage sensors, a Hall magnetic sensor, a photointerrupter, and / or a processor (e.g., a PIC 18F8722 processor) that receives input from the encoder input section. The processor can use the information it receives to provide feedback to the controller 150 and / or control the stepping motor drive to actuate the syringe on each channel.

[0099] 5. Gas system including variable discharge rate control The multi-use module 650 may include onboard gas cylinders, such as one or more common gas cylinders, that can be fitted into the gas tank bay 630 and / or the oxygen concentrator. The gas supply system may include (i) one or more regulators that reduce the pressure of the gas supplied by one or more gas cylinders, (ii) pressure sensors configured to measure the pressure of the gas supply, and (ii) gas pressure gauges that can visually indicate the sufficiency of the gas supply. Each of these components may be manually controlled and / or connected to a controller 150 for automatic control. For example, the controller 150 can automatically control the gas flow to the gas exchanger 114. The gas supplied by the gas supplied from the gas source may vary, but in some embodiments the gas supply may be 85% O2, 1% CO2, and the remainder N2, with a mixing process accuracy of 0.030%, while in other embodiments the gas supply may be 50% O2 and 95% O2 with the remainder N2 and / or Ar. In some embodiments, multiple gases can be pre-mixed and supplied from a single cylinder, or supplied from multiple gas cylinders and mixed within the system 600. In some embodiments, the gases can be supplied from a portable oxygen concentrator, such as an Oxus portable oxygen concentrator available from Oxus, Inc. in Rochester Hills, Michigan, or a Freestyle series portable oxygen concentrator available from Airsep or Buffalo, New York.

[0100] In some embodiments, the system 600 can support gas flow rates of 0–1000 mL / min and have a setpoint resolution of 50 mL / min with a gas flow delivery accuracy of ±20% in the range of 200–1000 mL / min. The system 600 and gas supply source 172 can be configured to supply gas flow in the event of a circulation pump failure. The ranges described above are illustrative, and values ​​other than those specifically stated may be used. Finally, in some embodiments, the system 600 and gas supply 172 can be configured to display the pressure of the gas supply source 172 via a number of interfaces (e.g., via the gauges of the gas supply source 172 and / or the operator interface module 146).

[0101] 6. Controllers and User Interfaces System 600 may include a control system (e.g., Controller 150) that controls the overall operation of System 600 and the components used therein. At a general level, this control system may include an onboard computer system connected to one or more components of System 600 and one or more sensors, network connections, and / or user inputs. Using the information obtained from these sensors, network connections, and / or user inputs, this control system can control various components within System 600. For example, this control system can be used to implement one or more open or closed feedback systems for controlling the operation of System 600. This control system may be a general-purpose commercial computer and / or a specially designed computer system. Although System 600 has been conceptually described with reference to a single controller, control of System 600 can be distributed across multiple controllers or processors. For example, any or all of the subsystems described may include their own dedicated processors / controllers. Optionally, these dedicated processors / controllers of the various subsystems can communicate with and through a central controller / processor. For example, in some embodiments, a single controller located within a multiple-use module 650 can control the entire system 600; in another embodiment, a single controller located within a single-use module 634 can control the entire system 600; and in yet another embodiment, this controller can be divided between the single-use module 634 and the multiple-use module 650.

[0102] In another example, the controller 150 can be located on the main circuit board 718 and can perform all the control and processing required by the system 600. However, in other embodiments, the controller 150 can be distributed, with some processing functions located on the front-end interface circuit board 636, some on the power circuit board 720, and / or some on the operator interface module 146. Depending on whether the controller 150 is distributed within the system 600 and the degree of such distribution, suitable cabling can be arranged between the various circuit boards.

[0103] Figure 8 shows a typical block diagram of an exemplary control scheme for system 600. For example, system 600 may include a controller 150 that controls the operation of system 600. As shown, the controller 150 can interact with several subsystems: an operator interface 146 that assists the operator in monitoring and controlling system 600 and monitoring the state of organs; a data acquisition subsystem 147 that may include various sensors that obtain data about organs and system 600 and carry this data to the controller 150; a power management subsystem 148 that supplies fault-tolerant power to system 600; a heating subsystem 149 that supplies controlled energy to a heater 110 that heats the perfusion fluid 108; a data management subsystem 151 that stores and maintains data about the operation of system 600 and the liver; and a pumping subsystem 153 that controls the pumping of the perfusion fluid 108 through system 600.

[0104] Exemplary embodiments of the data acquisition subsystem 147 are described below with reference to Figure 9. In this embodiment, the data acquisition subsystem 147 includes sensors for obtaining information about how the system 100 and the liver are functioning. The data acquisition subsystem 147 can provide this information to the controller 150 for processing. For example, the data acquisition subsystem 147 can be connected to the following sensors: namely, temperature sensors 120, 122 and 124; pressure sensors 126, 128 and 130 (which may be pressure sensors 130a and 130b as described elsewhere in this specification); flow sensors 134, 136 and 138; oxygenation / hematocrit / temperature sensor 140; Hall effect sensor 388; shaft encoder 390; battery sensors 362a, 362b and 362c; external power availability sensor 354; operator interface module battery sensor 370; and gas pressure sensor 132. The following describes how the system 600 uses the information from the data acquisition subsystem 147, with reference to the heating 149, power management 148, pump injection 153, data management 151, and operator interface 146 subsystems.

[0105] Referring to Figure 10, this figure shows an exemplary block diagram of a power management system 148 that provides fault-tolerant power to system 600. System 600 may be powered by one of several power sources, such as an external power supply (e.g., 60 Hz, AC 120V in North America, or 50 Hz, AC 230V in Europe), or by one or more batteries 352. The remainder of this description will refer to the AC power supply as an external power supply, but it should be understood that a DC power supply can also be used. Controller 150 may receive data from an AC line voltage availability sensor 354 indicating whether the AC voltage 351 is available to and / or sufficient for use by system 600.

[0106] In response to the controller 150 detecting that external power is unavailable, the controller 150 sends a signal to the power switching circuit system 356 to supply system power from one or more batteries 352. After the controller 150 determines from the battery charge sensor 362 which of the one or more batteries 352 is most sufficiently charged, it switches through the switching network 356 to activate that battery. This system can be designed so that the operation of the system 600 is not interrupted when the power is switched from one power source to another.

[0107] Alternatively, when the controller 150 detects that an external power source is available, it can determine whether to use this external power source to provide system power, power the user interface module 146, charge one or more batteries 352, and / or charge the internal battery of the user interface module 146, which has its own internal charger and charge controller. To use an available external power source (e.g., AC power 141), the controller 150 can draw the external power into the power management system 148 by sending a signal through the switching system 164. If the external power source is AC, the power management system 148 can receive the external AC power, convert it to DC, and supply power to the system 600. The power management system 148 is general-purpose and can operate on any line frequency or line voltage commonly used worldwide. In the exemplary embodiment, the controller 150 can further direct power through the switching network 364 and charging circuit 366 to a suitable battery in response to one or more battery sensors 362 indicating a low battery power. When the controller 150 receives a battery power signal from the sensor 370 (which can monitor the battery of the user interface module 146), it can respond to this by, or alternatively, directing a charging voltage 367 to the user interface battery 368. In some embodiments, the power management subsystem 148 can select the battery to power the system 600 using an algorithm to optimize battery life, which may include other factors such as selecting the least charged battery first or the minimum number of charging cycles. If the battery currently used to power the system 600 is removed by the user, the power management subsystem 148 can automatically switch to the next battery according to the algorithm to continue powering the system 600.

[0108] Referring to Figure 11, an exemplary embodiment of the heating subsystem 149 is illustrated. The heating subsystem 149 can control the temperature of the perfusion fluid 108 in the system 600, for example, through a dual feedback loop method. In the first loop 251 (perfusion fluid temperature loop), a perfusion fluid temperature thermistor sensor 124 provides two (fault-tolerant) signals 125 and 127 to the controller 150. These signals 125 and 127 typically indicate the temperature of the perfusion fluid 108 as it exits the heater assembly 110. The controller 150 can adjust drive signals 285 and 287 to the drive units 247 and 249, respectively. The drive units 247 and 249 can convert the corresponding digital level signals 285 and 287 from the controller 150 into heater drive signals 281 and 283, respectively, which have current levels sufficient to drive the first 246 and second 248 heaters to heat the perfusion fluid 108 to a desired temperature range. In response to the controller 150 detecting that the perfusion fluid temperatures 125 and 127 are below the desired temperature range, it can set the drive signals 281 and 283 for the first 246 and second 248 heaters, respectively, to a level sufficient to continue heating the perfusion fluid 108. Conversely, in response to the controller 150 detecting that the perfusion fluid temperatures 125 and 127 exceed the desired temperature range, it can reduce the drive signals 281 and 283 for the first 246 and second 248 heaters, respectively. In response to detecting that the temperature of the perfusion fluid 108 is within the desired temperature range, the controller 150 can maintain the drive signals 281 and 283 at a constant or substantially constant level. This temperature control system can control the heating of the perfusion fluid to a temperature range of 0-50°C, more specifically to a temperature range of 32-42°C, and even more specifically to a temperature range of 32-37°C. These ranges are for illustrative purposes only, and this temperature control system can be controlled to heat the perfusion fluid to any temperature range within 0-50°C. This desired temperature can be user-selected and / or automatically controlled by the controller 150. As used herein and in claims, “normal temperature” is defined as a temperature between 34-37°C.

[0109] In some embodiments, the controller 150 can modify the drive signals 281 and 283 that control the first and second heaters in substantially the same manner. However, this is not a requirement. For example, each heater 246 and 248 may respond differently to a particular current or voltage level of drive signal. In such cases, the controller 150 can drive each heater 246 and 248 at slightly different levels to obtain the same temperature from each. In some embodiments, each heater 246 and 248 may have associated calibration coefficients, which the controller 150 stores and uses when determining the level of a particular drive signal to provide to a particular heater in an attempt to achieve a particular temperature result. In some configurations, the controller 150 can set one of the thermistors of the dual sensor 124 as a default thermistor, and will use the temperature reading from this default thermistor if the thermistor gives two different readings. In some embodiments, if the temperature readings are within a predetermined range, the controller 150 can use the higher of the two readings. The drive units 247 and 249 apply heater drive signals 281 and 283 to the corresponding drive lead wires 282a and 282b of the heater assembly 110.

[0110] In the second loop 253 (heater temperature loop), the heater temperature sensors 120 and 122 can provide the controller 150 with signals 121 and 123 indicating the temperatures of the heaters 246 and 248, respectively. In the illustrated embodiment, an upper temperature limit may be set for the heaters 246 and 248, above which their temperatures are not permitted to rise (for example, by default, by operator selection, or automatically by the controller 150). When the temperatures of the heaters 246 and 248 rise and approach this upper temperature limit, the sensors 121 and 123 can indicate this to the controller 150, which can then reduce the drive signals 281 and 283 to the heaters 246 and 248, thereby reducing or stopping the power supply to the heaters 246 and 248. Thus, a low-temperature signal 125 or 127 from the perfusion fluid temperature sensor 124 allows the controller 150 to increase power to the heaters 246 and 248, while the heater temperature sensors 120 and 122 ensure that the heaters 246 and 248 are not driven to the point where their respective heater plates 250 and 252 become so hot that they damage the perfusion fluid 108.

[0111] In some embodiments, the controller 150 can be configured to maintain the perfusion fluid temperature between 0 and 50°C. In some embodiments, the perfusion fluid is maintained within a temperature range of 32–42°C, or in more specific embodiments, within a range of 35–37°C. In some embodiments, the controller can be configured to limit the temperatures of the heater plates 250 and 252 to approximately 38°C, 39°C, 40°C, 41°C, or 42°C. All ranges and figures described above are illustrative, and values ​​outside these ranges may also be used. Finally, where a claim uses the term "substantially" in relation to a specific temperature value or range, this means that the temperature is within the operating temperature range of the heater / control system used. For example, if the temperature described in a claim is "substantially 32°C" and the heater / control system used in the allegedly infringed product maintains a temperature within ±5% of the desired value, then any temperature that is ±5% of 32°C is "substantially 32°C".

[0112] As shown in the figure, the second loop 253 can be configured to override the first loop 251, if necessary, so that temperature readings from temperature sensors 120 and 122 indicating that heaters 246 and 248 are approaching their maximum allowable temperature override the action of any low-temperature signals from the perfusion fluid temperature sensor 124. In this view, subsystem 149 can ensure that the temperatures of heater plates 250 and 252 do not rise above the maximum allowable temperature even if the temperature of the perfusion fluid 108 has not reached a desired temperature value. This override function can be particularly important in the event of failure. For example, if both perfusion fluid temperature sensors 124 fail, the second loop 253 can prevent the heater assembly 110 from overheating or damaging the perfusion fluid 108 by switching control to only the heater temperature sensors 120 and 122 and lowering the temperature setpoint to a lower value. In some embodiments, the controller 150 may take into account two time constants specified for delays related to temperature measurements from the heaters 246 and 248 and the perfusion fluid 108 in order to optimize the dynamic response of temperature control.

[0113] In some embodiments, the user may be provided with the option to disable the blood warming function of the system 600. In this embodiment, the system can more efficiently support the cooling of the liver during cryogenic treatment after storage. In some embodiments, the heater assembly 110 (or another device such as a gas exchanger with an integrated cooling interface) can function as a chiller for cooling the temperature of the perfusion fluid.

[0114] Returning to the operator interface subsystem 146, 12A–12G show examples of various display screens of the operator interface subsystem 146. These display screens allow the operator to receive information from system 600 and issue commands to system 100. Figure 12A shows an exemplary top-level “home” screen 400. Typically, from this display screen 400, the operator can access all or almost all of the data available from the data acquisition subsystem 147 and typically issue any desired command to the controller 150. For example, the user can monitor and adjust the pumping subsystem 153 via screen 400. As further detailed with reference to Figures 12B–12G, screen 400 also allows the operator to access more detailed display screens to obtain information, issue commands, and set operator-selectable parameters.

[0115] In this exemplary embodiment, screen 400 includes various sections, each displaying different information and / or accepting different inputs. However, screen 400 is for illustrative purposes only, and the information displayed on screen 400 can be customized by the user (for example, using the dialog 590 described later in Figure 12F). The values ​​displayed on screen 400 can be updated at regular intervals, for example, every second. In this example, screen 400 includes the following sections: • Section 402 displays the hepatic artery flow rate. This value can be the flow rate reading from the flow sensor 138b. • Section 404 displays portal vein flow rate. This value can be the flow indication from the flow sensor 138a. For example, section 406 displays the oxygen saturation (SvO2) of the perfusion fluid leaving the liver, as measured by sensor 140. For example, section 408 displays the hematocrit (HCT) level of the perfusion fluid leaving the liver, as measured by sensor 140. • A section 410 displays the desired and measured temperatures of the perfusion fluid. In this embodiment, the larger upper number represents the measured temperature, while the smaller number shown below it represents the set temperature at which the desired perfusion fluid temperature is obtained. This temperature can be measured from one or more locations, such as the output of the heater assembly 110, using temperature sensors 120 and 122 and, in some embodiments, sensor 140. • Section 412 displays the flow rate measured by the flow sensor 136. Section 414 displays the systolic / diastolic blood pressure of the hepatic artery. The numbers in parentheses below the systolic / diastolic blood pressure are the arithmetic mean of the pressure waveform. This systolic / diastolic / mean blood pressure of the hepatic artery can be measured by pressure sensor 130a. Section 416 displays the waveform of hepatic artery pressure over time. Section 418 displays portal vein systolic / diastolic blood pressure. The numbers in parentheses below the systolic / diastolic blood pressure are the arithmetic mean of these two values. Portal vein systolic / diastolic blood pressure can be measured by pressure sensor 130a. • Section 420 displays the waveform of portal vein pressure over time. Section 422 displays the hepatic artery pressure averaged over time (e.g., 2 minutes). Section 424 displays the average hepatic arterial flow rate over time (e.g., 2 minutes). Section 426 graphs the values ​​from sections 422 and 424 over time. In this embodiment, this graph represents a 3.5-hour time period. In some embodiments, section 426 can be controlled by the user to represent different time periods. Section 428 displays an icon indicating that the perfusion fluid pump is operating. • Part 429 (not illuminated in this example) can display an organ type indicator showing which organs are being perfused and which operating mode is being used. For example, "M" can be used to indicate that system 600 is in maintenance mode. • Section 430 displays the status of the storage medium (e.g., SD card) included in the system 600. • Section 432 displays the flow rate from the onboard gas supply source. This section can also display the remaining time until the onboard gas supply source is depleted. • A section 434 that displays the status of the power supply system. In this embodiment, the system 600 includes three batteries, each battery having a corresponding status indicator that shows the degree of charge of the battery. This section also indicates whether the system 600 is connected to an external power source (by displaying a plug icon). In some embodiments, this section may also include a numerical indication of how much time the batteries can power the system 600 in the current operating mode. • A section 436 in the operator interface module 146 that displays the battery status and remaining charge. This section may also include an indication of the remaining time the battery of the operator interface module 146 can support it in wireless operation mode. • Section 438 displays the status of the network and / or cellular connection. This section can determine whether the operator interface module 146 is operating wirelessly, along with a graph showing the strength of the wireless connection between the operator interface module 146 and the rest of the system 600. • Additional features may include indicators to show when one or more alarms and / or parts of System 600 have been disabled by the user.

[0116] As can be seen from Figures 12A-12G, some sections may also include alarm range indicators (e.g., indicator 440) that show where the current value is within the acceptable range. Each section may also include an alarm indicator (not shown) that indicates when the respective value is outside the range indicated by the corresponding range indicator. Each range indicator for each value can be associated with an alarm value set in dialog 512 or set independently by the user. Screen 400 can be implemented on a touchscreen interface. In the user input section, the user can touch a specific section and change the value within it using knob 626.

[0117] Referring to Figures 12B, 12C, and 12D, the user can choose to enter the configuration menu 484. In some embodiments of the system, the configuration menu 484 can be limited to a portion of the screen so that the user can continue to monitor the information displayed on the screen. Using this configuration menu, the user can program the desired operating parameters of the system 600. In this embodiment of the configuration menu 484, the menu comprises three tabbed pages 484a, 484b, and 484c ("Liver", "System", and "Actions").

[0118] Tabbed page 484a displays the liver tab. On this tab, the user enters the alarm dialog 512 (see Figure 12E below), selects data shown in the central graphic frame, selects data shown in the lower graphic frame, sets the desired gas flow rate, and sets the desired temperature. Changes made on tabbed page 484a may be reflected on screen 400.

[0119] Tabbed page 484b displays the System tab. This tab allows the user to adjust one or more display features of System 600. For example, the user can select the units used to display various measurements (e.g., Pascals or mmHg), restore factory defaults, remember new default settings, and restore saved default settings. From this tab, the service technician can establish a wireless connection from their work laptop to the system. Changes made on tabbed page 484b may be reflected on screen 400.

[0120] On tabbed page 484c, the Actions tab is shown. This menu allows the user to view the status of the device, view a summary of all warnings, adjust the scale of displayed measurements, and / or interact with data stored by System 600. For example, in some embodiments, the user can take a sample of perfusion fluid and perform an external test on it. The user can then manually input the values ​​obtained from the external test into a data stream maintained by System 600. In this way, System 600 can include all such data, regardless of whether the data related to the organ to be transplanted was generated outside of System 600.

[0121] Referring to Figure 12E, the alarm dialog 512 displays parameters related to the operation of the system 600. In this embodiment, there are alarms for hepatic artery flow (HAF), portal pressure (PVP), hepatic artery pressure (HAP), inferior vena cava pressure (IVCP), perfusion fluid temperature (temperature), oxygen saturation (SvO2), and hematocrit (HCT). The number of parameters included in dialog 512 may be more or less than these. Column 514 indicates the upper limit of the alarm (e.g., values ​​above this number will cause a warning), and 516 indicates the lower limit of the alarm (e.g., values ​​below this number will cause a warning). The user can enable / disable individual alarms by selecting the relevant warning icon in column 518. The icons in column 518 may indicate whether an individual alarm is enabled or disabled (e.g., in Figure 12E, the IVCP alarm is disabled). These alarm limits may be predetermined, user-configurable, and / or set by the controller 150. In some embodiments, the system 600 can be configured to automatically switch between multiple sets of alarm limits for a given fluid flow mode when that fluid flow mode is changed. Changes made in dialog 512 may be reflected on screen 400.

[0122] Figure 12F shows an exemplary user interface (dialog 590) in which the user can select what is displayed in different parts of the screen 400. For example, in Figure 12F, the user can choose to display real-time waveforms of hepatic artery pressure, portal vein pressure, or inferior vena cava pressure, or to display trend graphs of those or other measurement parameters in a part of the screen 400. The controller 150 can also calculate and display other waveforms.

[0123] Figure 12G shows an exemplary user interface (dialog 592) in which the user can adjust the parameters of the pumping subsystem 153. In this example, the user can adjust the pump flow and turn the pump on / off.

[0124] The data management subsystem 151 can receive and store data and system information from various other subsystems. This data and other information may be downloaded to a portable storage device and configured in a database as needed by the operator. The stored data and information can be accessed by the operator and displayed through the operator interface subsystem 146. The data management system 151 can be configured to store this information in one or more locations. For example, the data management subsystem 151 can be configured to store data in storage devices located inside the system 600 (e.g., hard drives, flash drives, SD cards, compact flash cards, RAM, ROMs, CDs, DVDs) or outside the system (e.g., remote storage devices or cloud storage devices).

[0125] In embodiments using external storage devices, the data management subsystem 151 (or another part of the controller 150) can communicate with the external storage device via various communication connections, such as point-to-point network connections, intranets, and the Internet. For example, the data management subsystem 151 can communicate with remote storage devices or "clouds" (e.g., data servers and storage devices on shared and / or private networks) via Wi-Fi (e.g., 802.11), cellular connections (e.g., LTE), Bluetooth® (e.g., 802.15), infrared connections, satellite connections, and / or hardwired network connections (e.g., Ethernet®). In some embodiments, the data management subsystem can be configured to automatically detect the optimal network connection for communicating with remote storage devices and / or clouds. For example, the data management subsystem can be configured to default to a known Wi-Fi network and automatically switch to a cellular network when the known Wi-Fi network is unavailable. Remote and cloud-based embodiments will be described in detail later.

[0126] Referring to Figure 12H, the pumping subsystem 153 is described in more detail here. The controller 150 can operate the pump injection subsystem 153 by sending a drive signal 399 to the brushless three-phase pump motor 360 using Hall effect sensor feedback. This drive signal 339 causes the pump motor shaft 337 to rotate, which in turn causes the pump screw 341 to extend and retract the pump drive unit 334. In the exemplary embodiment, the drive signal 339 is controlled to change the direction and speed of rotation of the motor shaft 337, thereby causing the pump drive unit 334 to extend and retract periodically. This periodic motion injects the perfusion fluid into the system 600.

[0127] The controller 150 receives a first signal 387 from a Hall effect sensor 388 integrated within the pump motor shaft 337, which can indicate the position of the pump motor shaft 337 for the purpose of rectifying the motor winding current. The controller 150 can also receive a second, higher-resolution signal 389 from a shaft encoder sensor 390, which indicates the precise rotational position of the pump screw 341. From the current motor rectification phase position 387 and the current rotational position 389, the controller 150 calculates an appropriate drive signal 339 (both amplitude and polarity) to cause the necessary rotational change of the motor shaft 337, causing a suitable positional change of the pump screw 341, and achieving the desired pumping action. The controller 150 can change the pump speed (i.e., how often the pump injection cycle is repeated) by changing the amplitude of the drive signal 339, and the controller 150 can also change the pumping stroke amount (for example, by changing how far the pump drive unit 334 moves in a single cycle) by changing the direction of rotation. Generally speaking, the periodic pumping speed regulates the pulsating speed at which the perfusion fluid 108 is supplied to the liver, while the pumping stroke (for a given speed) regulates the amount of perfusion fluid supplied to the liver.

[0128] Both velocity and stroke length affect the flow rate of the perfusion fluid 108 to the liver, and indirectly, its pressure. As described herein, the system 600 may include three flow sensors 134, 136, and 138 and three pressure sensors 126, 128, and 130. Sensors 134, 136, and 138 can provide corresponding flow signals 135, 137, and 139 to the controller 150. Similarly, sensors 126, 128, and 130 can provide corresponding pressure signals 129, 131, and 133 to the controller 150. The controller 150 can utilize all of these signals in feedback to ensure that the commands it gives to the perfusion pump 106 have the desired effect on the system 600. In some cases, the controller 150 may generate various alarms in response to signals indicating that a particular flow rate or fluid pressure has fallen outside an acceptable range. In addition, by utilizing multiple sensors, the controller 150 can distinguish between mechanical problems in the system 600 (e.g., rupture of a conduit) and biological problems in the liver.

[0129] Although three pressure sensors are disclosed above, this is not a requirement. Many embodiments described herein use only two pressure sensors (e.g., pressure sensors 130a and 130b). In this example, the input to the third pressure sensor can be ignored. However, in some embodiments of the systems described herein, the third pressure sensor can be used to measure the pressure of the perfusion fluid flowing from the inferior vena cava (or another location in system 100). In this example, the controller 150 can process the pressure signals from the sensors described above.

[0130] The pump infusion system 153 may be configured to fine-tune the pumping speed and volume profile by controlling the position of the pump drive unit 334 at each moment of the pumping cycle. This allows the pump system 153 to deliver the perfusion fluid 108 to the liver in a desired pulsation pattern. In one exemplary embodiment, the rotational position of the shaft 337 is detected by the shaft encoder 390 and can be adjusted by the controller 150 by at least about 100 increments per rotation. In another exemplary embodiment, the rotational position of the shaft 337 is detected by the shaft encoder 390 and can be adjusted by the controller 150 by at least about 1000 increments per rotation. In a further exemplary embodiment, the rotational position of the shaft 337 is detected by the shaft encoder 390 and can be adjusted by the controller 150 by at least about 2000 increments per rotation. The position of the pump screw 341, and thus the pump drive unit 334, can be initially calibrated to a reference position of the pump screw 341.

[0131] As described above, the system 600 can be manually controlled using the controller 150. However, some or all of the control of the system 600 can be automated and performed by the controller 150. For example, the controller 150 can be configured to automatically control the perfusion fluid pump 106 flow (e.g., pressure flow rate), solution pump 631, pump 106, gas exchanger 114, heater 110, and / or flow clamp 190. Control of the system 600 can be achieved with or without user intervention. For example, the controller 150 can be programmed with one or more predetermined routines and / or implement an open or closed feedback system using information from various sensors in the system 600. For example, if the controller determines that the oxygenation level of the perfusion fluid flowing out of the IVC is too low or the CO2 level is too high, the controller 150 can adjust the gas supply to the gas exchanger 114 accordingly. In another example, the controller 150 can control the injection of one or more solutions based on sensor 140 and / or other optional sensors in system 600. As yet another example, if the controller senses that the liver is producing too much CO2, it can lower the liver temperature to 35°C (if it was being maintained at a higher temperature) and reduce the metabolic rate and CO2 production or O2 consumption accordingly. In yet another example, the controller 150 can adjust the gas flow to the gas exchanger 114 based on measurements from one or more sensors in system 600.

[0132] In some embodiments, the controller 150 can be configured to control various aspects of the system 600 as a function of the lactate ester value of the perfusion fluid. In one embodiment, a number of perfusion fluid lactate ester values ​​can be obtained over time. For example, the user can take a sample of the perfusion fluid and calculate the lactate ester value using an external blood gas analyzer, and / or the system 600 can use an onboard lactate ester sensor (e.g., a lactate ester sensor located at the measurement drain 2804). This lactate ester value can be measured at the IVC or another site and can be repeated at predetermined time intervals (e.g., every 30 minutes). The controller 150 can analyze the trend of the lactate ester value over time. If the lactate ester is decreasing or remains relatively flat, this may indicate that the liver is being properly perfused. If the lactate ester is increasing, this may indicate inadequate perfusion, and consequently the controller 150 may increase the pump flow, adjust the proportion of perfused vasodilators, and / or change the gas flow to the gas exchanger 114.

[0133] Automating this control process allows for more precise control over system parameters, resulting in numerous benefits such as improved liver health and / or reduced user burden.

[0134] In some embodiments, the system 600 may include a global positioning device that tracks the geographical location of the system.

[0135] C. Exemplary as-needed module A description of the emergency module is provided herein as an exemplary embodiment, referred to as emergency module 634, but other embodiments are possible. As described above, this portion of system 600 typically includes all system components that come into contact with various peripheral components, flow channels, sensors, and supporting electronic components used in conjunction with them, in addition to biological materials such as perfusion fluid. After transporting an organ using system 600, the emergency module can be removed from system 600 and discarded. A new (and sterilized) emergency module can be installed in system 600 for transporting a new organ. In one embodiment, module 634 does not include a processor but relies on a controller 150, which can be distributed across a front-end interface circuit board 636, a power circuit board 720, an operator interface module 146, and a main circuit board 718 for control. However, in some embodiments, the emergency module may include its own controller / processor (e.g., on the front-end circuit board 637).

[0136] Referring to Figures 13A–13H, an exemplary emergency module 634 is illustrated. Figures 13M–R show another exemplary emergency module 634 with an alternatively shaped organ chamber 104. However, in some figures, some components have been omitted for clarity (e.g., tubing connections, ports, and / or clamps).

[0137] The reusable module 634 may include a chassis 635 having upper 750a and lower 750b sections. The upper section 750a may include a platform 752 for supporting various components. The lower section 750b may support the platform 752 and may include a structure for rotatably connecting to the reusable module 650.

[0138] The lower chassis portion 750b may include a C-mount 656 for securely mounting the perfusion pump interface assembly 300 and a projection 662 for sliding into and tightly engaging with the slot 660. In some embodiments, the lower chassis portion 750b may also provide a mounting structure for a perfusion circuit, which may include the following components: a gas exchanger 114, a heater assembly 110, a reservoir 160, and perfusion flow expandable chambers 184, 186. In some embodiments, the lower chassis portion 750b may also include various sensors, such as a sensor 140, flow sensors 136, 138a, 138b, and pressure sensors 130a, 130b, via appropriate mounting hardware. The lower chassis portion 750b may also be fitted with a front end circuit board 637. This embodiment is for illustrative purposes only, and the components listed above as part of the lower chassis portion 750b can also be located elsewhere, such as in the upper portion 750a (e.g., pressure sensors 130a, 130b).

[0139] The upper chassis portion 750a may include a platform 752. The platform 752 may include handles 752a and 752b formed to assist in the installation and removal of the one-time module 634 from the multiple-use module 650, although these handles may be provided elsewhere on the one-time module 634. The platform 752 may include one or more orifices (e.g., 717) through which tubing and / or other components pass. The platform 752 may include one or more integrally molded brackets (e.g., 716) for holding components in place on the platform 752, such as fluid injection and / or sampling ports, which will be detailed later. The upper chassis portion 750a may further include a flow clamp 190 for regulating the flow of perfusion fluid to the portal vein, as will be detailed later. The organ chamber assembly 104 may be configured to be attached to the platform 752 via one or more supports 719. Referring particularly to Figure 13I, the organ chamber 104 can be mounted such that its left and right sides (relative to the main drain) are at an angle of approximately 15° to the platform 752. This can help the perfusion fluid flow out of the organ chamber 104, especially during transient conditions that may occur during transport (e.g., aircraft takeoff and landing).

[0140] 1. Organ Chamber System 600 may include organ chambers configured to hold ex vivo organs. The design of these organ chambers can be modified depending on the type of organ. For example, the design of these organ chambers can be modified depending on whether they are used for transporting, for example, the liver, heart, and / or lungs. The following description focuses on organ chamber 104 configured for transporting the liver, but this embodiment is for illustrative purposes only, and other configurations are possible. For example, other configurations of organ chamber 104 can also be used for transporting the liver.

[0141] a) Shape / Drain structure Referring to Figures 14A–14H, exemplary embodiments of the organ chamber 104 are illustrated from multiple viewpoints. In this embodiment, the organ chamber 104 includes a base 2802, a front member 2816, a removable lid 2820, and a support surface 2810 (detailed in relation to Figures 15A–15D). In some embodiments, the organ chamber 104 may include a pad 4500 for supporting the liver. The bottom of the organ chamber 104 may be configured in a semi-funnel shape, with the sides of this funnel angled approximately 15° to the platform 752, as clearly illustrated in Figure 13I.

[0142] At a typical level, the base member 2802 may include one or more drains (e.g., 2804, 2806), tubing inserted into the organ chamber 104 while the lid (e.g., 2820) is closed, one or more orifices (e.g., 2830) for connectors and / or equipment, one or more hinges (e.g., 2832), and one or more mounting brackets (e.g., 2834). In some embodiments, the mounting bracket 2834 is molded, as shown in Figure 14I. In some embodiments, the base member 2802 is configured to fit onto and support a support surface 2810 on which the liver is typically placed. The organ chamber 104 and the support surface 2810 can be formed from any suitable polymer plastic, such as polycarbonate.

[0143] The base 2802 of the chamber 2204 is molded and positioned within the system 600 to facilitate drainage of the perfusion medium from the liver 101. The organ chamber 104 may have two drains: a measuring drain 2804 and a main drain 2806 from which overflow from this measuring drain can be received. The measuring drain 2804 can drain the perfusion fluid at a flow rate of about 0.5 L / min, which is considerably less than the 1–3 L / min flow of the perfusion fluid 250 through the liver 101. The measuring drain 2804 leads to a sensor 140 capable of measuring SaO2, hematocrit value, and / or temperature, and then to a reservoir 160. The main drain 2806 may lead directly to a defoamer / filter 161 without passing through the sensor 140. In some embodiments, the sensor 140 cannot obtain accurate measurements unless the perfusion fluid 108 is substantially free of bubbles. To obtain a bubble-free perfusion column, the base 2802 is formed to collect perfusion fluid 108 that drains from the liver 101 into a pool collected on the measuring drain 2804. This perfusion pool typically allows bubbles to dissipate before the perfusion enters the drain 2804. Pool formation above the drain 2804 is facilitated by an optional wall 2808, which can partially prevent the flow of perfusion fluid from the measuring drain 2804 to the main drain 2806 until the perfusion pool is large enough to ensure that bubbles dissipate from this flow. The main drain 2806 can be lower than the measuring drain 2804, and once the perfusion fluid overflows, the perfusion fluid flows around and / or beyond the wall 2808 and is discharged from the main drain 2806.

[0144] In an alternative embodiment of this dual drain system, another system is used to collect the perfusion fluid in a pool that sends it to the measuring drain. In some embodiments, the flow from the liver is directed to a container such as a small cup 2838, from which it is sent to the measuring drain. The cup 2838 is filled with perfusion fluid, and excess blood overflows from the cup and is directed to the main drain, thus reaching this reservoir pool. In this embodiment, the cup 2838 can perform a function similar to that of the wall portion 2808 in the embodiments described above by forming a small amount of perfusion fluid from which air bubbles can dissipate before the perfusion fluid flows from the measuring drain to the oxygen sensor. In yet another embodiment of the measuring drain, a gentle recess that performs the same function as the cup described above may be formed at the bottom of the base 2802 around the measuring drain 2804.

[0145] The upper part of the organ chamber 104 can be covered with a sealable lid comprising a front member 2816, a removable lid 2820, an inner lid (not shown) with a sterile drape, and a sealing member 2818. The removable lid 2820 can be hinged and removable to the base member 2802 via a hinge portion 2832. The sealing member 2818 can seal the front member 2816 and / or the base 2802 to the lid 2820 to form a fluid and / or airtight seal. The sealing member 2818 can be manufactured from, for example, rubber and / or foam. In some embodiments, the front member 2816 and the lid 2820 are robust enough to physically protect the liver 101 from indirect or direct contact.

[0146] Exemplary embodiments of the organ chamber 104 are illustrated from multiple viewpoints in Figures 14I-S. In this embodiment, the base 2802 of the organ chamber 104 has a different shape. Figures 14I-14K ​​show a top view, Figures 14L-14O show a side view, Figures 14P-14R show a bottom view, and Figure 14S shows an exploded view of an alternative embodiment. The organ chamber 104 includes the base 2802, the organ support surface 2810, and a removable lid 2820.

[0147] For example, the top of this organ chamber can be covered with a single sealable lid 2820. The removable lid can be hinged and detachably coupled to the organ chamber base member via a hinge portion 2832. This lid is secured to the base via a series of latches 2836 or other mechanisms. The sealing member 2818 of this lid can be manufactured from rubber and / or foam, and furthermore, it can seal this lid to the base to form a fluid or airtight seal. In some embodiments, these lids and bases are robust enough to physically protect the liver from indirect or direct contact. The organ chamber includes orifices (e.g., 2830) for conduit connections of blood vessels into which cannulas, including the HA, PV, and bile duct, are inserted. The organ chamber includes a structure 2840 located above the measuring drain 2804, which holds the end of the IVC in place during organ transport. This structure directs the perfusion fluid exiting the IVC cannula towards the measuring drain.

[0148] In another embodiment (not shown), the organ chamber 104 may include a double-lid system including an inner lid and an outer lid. More specifically, in one embodiment, the organ chamber assembly may include a housing, an outer lid, and an intermediate lid. The housing includes a bottom and one or more walls for housing the organ. The intermediate lid may cover the opening of the housing to substantially enclose the organ within the housing and may further include a frame and a flexible membrane suspended within the frame. The flexible membrane may be transparent, opaque, translucent, or substantially transparent. In some embodiments, the flexible membrane includes enough excess membrane material to contact the organ housed in the chamber. This feature allows a medical operator to indirectly touch / examine the organ through the membrane while maintaining the sterility of the system and the organ. For example, the area of ​​the intermediate lid membrane may be 100-300% larger than the area defined by the intermediate lid frame or 100-300% larger than the two-dimensional area occupied by the liver. In some embodiments, this flexible membrane can be selected to allow the operator to maintain the sterility and / or environment of the chamber while performing liver ultrasound through the membrane.

[0149] In some embodiments, the intermediate lid is hinged to the housing. The intermediate lid also includes a latch for securing the intermediate lid when closed to the opening of the organ chamber. The outer lid may similarly be hinged and latched, or it may be completely removable. In some embodiments, gaskets may be provided to form a fluid and / or air seal between the intermediate lid frame and one or more organ chamber walls, and / or to form a fluid and / or air seal between the periphery of the outer lid and the intermediate lid frame. In this embodiment, the environment surrounding the liver 101 can be maintained whether the outer lid is open or not.

[0150] Covering the organ chamber 104 minimizes gas exchange between the perfusion fluid 108 and the ambient air, which can help the oxygen sensor reliably measure the desired oxygen level (e.g., the level corresponding to the perfusion fluid leaving the liver 101) and help maintain sterility. Closing the organ chamber 2204 also reduces heat loss from the liver. Because the liver has a large surface area, heat loss can be considerable. Heat loss can be a significant issue when the system 600 is in a relatively low-temperature environment, such as outdoors when transporting the liver in and out of a vehicle. Furthermore, before transplantation, the system 600 may be temporarily placed in a hospital waiting area or operating room, where the temperature is typically in the range of 15-22°C. In these ambient temperatures, it is important to minimize heat loss from the organ chamber 2204 so that the heater 230 can maintain the desired perfusion fluid and liver temperature. Sealing the liver 101 within the organ chamber 2204 can help maintain temperature uniformity throughout the liver 101.

[0151] Referring also to Figures 15A-15D, an exemplary embodiment of a support surface 2810 configured to support the liver 101 is shown. This embodiment includes a drain channel 2812, a drain 2814, and an orifice 2815. The drain channel 2812 carries the perfusion fluid discharged from the liver 101 and directs it to the drain 2814. In some embodiments, when the support surface 2810 is mounted on the base 2802, the drain 2814 is positioned above and / or near the measuring drain 2804 so that a considerable amount of perfusion fluid 108 is reliably discharged from the support surface 2810 into the measuring drain 2804. The orifice 2815 is configured to provide an auxiliary portion for discharging perfusion fluid from the support surface 2810. Furthermore, the support surface 2810 can be configured for use with a pad 4500 (described later). The support surface 2810 may include an orifice 2813 that can be used to secure the pad 4500, for example, using screws or rivets. In some embodiments, when the support surface 2810 is attached to the organ chamber 104, it is positioned at an angle of approximately 5 degrees to the horizontal, but other angles can also be used (e.g., 0-60 degrees).

[0152] Referring to Figures 16F-16J, in an alternative embodiment, the support surface 4700 is a flexible material that supports and cushions the organ, and the support surface 2810 is omitted. The material has a composition that forms a flexible and smooth surface on which sensitive liver tissue can be placed. The surface can be perforated, and the number, arrangement, and diameter of the perforations allow drainage from the liver while achieving a non-traumatic surface to the liver tissue. In this embodiment and other embodiments, the support 4700 is a multi-material layer including an upper layer 4706, a bottom layer 4708 of the flexible material 4706, and an inner layer which is a frame 4702 of a malleable metal substrate (e.g., aluminum) of the metallic material 4706. In some embodiments, the upper layer 4706 and the bottom layer 4708 can be made from polyethylene foam and / or porous silicon foam.

[0153] This assembly is supported by an organ chamber base 2802, with the support surface 4700 suspended above the bottom of the organ chamber base 2802 at a height suitable for causing displacement due to the weight of the organ. The frame 4702 of the support surface 4700 can be held in place on the organ chamber base 2802 using fasteners 4704 such as molded pins, rivets, screws, or other fittings inserted into openings 4610 in the frame 4702.

[0154] In some embodiments, the malleable metal frame 4702 extends into a projection 4712. The projection 4712 may be surrounded by an upper layer 4706 and a bottom layer 4708. These projections 4712 can be formed to surround the liver so as to stabilize its x, y, and z axis position. By bending the projections 4712, the user can selectively support the liver in a manner that mimics how it is supported within the human body. In some embodiments, some portions of the frame 4702 may be tapered and terminated at a circular portion, as shown in Figure 16G. The tapering of these portions of the frame 4702 allows i) the projection 4712 to be easily rounded, with a reduced or even eliminated possibility of creases, and ii) the weight of the support surface 4700 to be reduced. This circular portion can provide a surface that the user can easily hold. The tapered shape of this portion of frame 4702 can be specifically selected to be rounded and form a natural arc, rather than bending or kinking. The projection 4712 can be any desired shape to surround the liver. When in use, the liver is positioned on the upper layer 4706 of the support surface 4700, allowing the support surface 4700 to be pushed down. Thus, the projection 4712 can be formed to surround the liver.

[0155] b) Stabilization of the liver In some embodiments, stabilization of the liver during transport can be performed by one or more systems designed to support and hold the liver in place without applying unnecessary pressure that could damage it. For example, in some embodiments, system 600 can support the liver with a soft stabilizing liver pad (e.g., 4500) together with a wrap / tarpaulin (e.g., 4600). In some embodiments, this stabilization system can allow some movement of the liver within predetermined limits (e.g., the system can allow movement of the liver up to 2 inches in any direction). In some embodiments, the surface on which the liver rests can be a low-friction surface that helps reduce damage to the liver. The sides of the pad that contact the support surface 2810 can be a high-friction surface that helps hold the pad in place.

[0156] This pad can be designed to form a support that selectively and controllly supports the liver 101 without applying unnecessary pressure to it. In other words, if the liver 101 is placed on a surface other than the support surface 2810, the parts of the liver that come into contact with it during transport may be physically damaged. For example, this pad can be formed from a material that has sufficient elasticity to cushion the liver from mechanical vibrations and shocks during transport.

[0157] Exemplary embodiments of the stabilizing liver pad and wrap are shown as pad 4500 in Figures 16A–16E and as wrap 4600 in Figure 16D. Pad 4500 may include two layers: an upper layer 4502 and a bottom layer 4504. In some embodiments, the upper layer 4502 may be made from polyethylene foam and the bottom layer 4504 may be made from porous silicone foam. In this embodiment, the upper layer 4502 may be 6 mm thick and the bottom layer 4504 may be 3 / 16 inch thick, but other thicknesses and materials may also be used. The upper layer 4502 and the bottom layer 4504 can be bonded to each other using an adhesive such as MOMENTIVE Silicone RTV 118 Silicone. The shape of pad 4500 can be optimized for liver (for example, as shown in Figure 16A). For example, the shape of the pad 4500 may include curved corners and one or more fingers (e.g., 4506, 4508, 4510, 4512, 4514, and 4516). The pad 4500 may also include one or more holes 4520 through which the pad 4500 is fastened to the support surface 2810, for example, with rivets and / or screws. Depending on the embodiment, the pad 4500 is approximately 16 x 12 inches in size, but other sizes are also possible.

[0158] A deformable metal substrate 4518 can be sandwiched between the upper layer 4502 and the bottom layer 4504. The deformable substrate 4518 can be manufactured from a strong but flexible material such as metal, but other materials may also be used. In some embodiments, the deformable substrate 4518 is 0.04-inch thick aluminum 1100-0. The substrate 4518 can be configured to be easily handled by the user but not to be repositioned by vibration or impact of the liver. The deformable substrate 4518 may include fingers 4522, 4524, 4526, 4528, 4530, and 4532 corresponding to fingers 4506, 4508, 4510, 4512, 4514, and 4516, respectively. By bending the various fingers of the pad 4500, the user can selectively support the liver in a manner that mimics how it is supported within the human body. An exemplary embodiment of the pad 4500 with fingers in a rounded position is shown in Figure 16D. In some embodiments, each finger of the deformable base material 4518 may be formed in a tapered shape (as shown by, for example, 4534) and terminated in a circular shape. The tapered shape of these portions of the base material 4518 allows i) the fingers to bend easily, but the possibility of creases when bending is reduced or even eliminated, and ii) the weight of the pad 4700 can be reduced. This circular portion can provide a surface that the user can easily hold. The tapered shape of this portion of the finger can be specifically selected so that the pad finger rounds into a natural arc shape rather than bending or kinking.

[0159] Referring to Figures 16F-16J, in an alternative embodiment, this stabilizer may include three layers. The upper layer 4708 and the bottom layer 4504 can be manufactured from porous silicon foam. Each foam layer is 3 / 16 inch thick, but other thicknesses and materials can also be used. The inner layer is a frame 4702 of a deformable metal substrate with a narrow frame shape. The frame 4702 can be manufactured from a rigid but flexible material, but other materials can also be used. In some embodiments, the frame 4702 is 0.04 inch thick aluminum 1100-0. The frame 4702 can be configured to be easily handled by the user but not to be altered in position by vibration or impact to the liver.

[0160] The upper layer 4706 and the bottom layer 4708 can be bonded to each other using an adhesive such as MOMENTIVE Silicone RTV 118 Silicone. By covering the inner extent of the frame 4702, the upper and bottom layers 4706 and 4708 can form a flexible support surface 4700 in which the liver can be positioned for transport. The shape of the support surface 4700 can be optimized for the liver. For example, the shape of the support surface 4700 may include curved corners to restrict liver movement during transport and one or more protrusions 4712. In some embodiments, a wrap 4600 can be placed over the liver to hold it in place and retain moisture within the liver during transport. For example, as shown in Figure 16D, the wrap 4600 can be attached to a pad on one side (e.g., the right side in Figure 16D) and the rest of the wrap can be left draped over the liver. In other embodiments, the wrap may be secured at multiple edges or all edges. The wrap 4600 may be used in conjunction with the flexible support surface 4700. In some embodiments, the wrap 4600 can perform one or more functions, such as fixing the liver during transplantation, helping to maintain sterility, and retaining moisture within the liver by acting as a vapor barrier. The wrap can be made of polyethylene sheet and can be translucent or transparent to facilitate visual inspection of the liver. The size of the wrap 4600 can vary. For example, it can be between 0.5 and 24 inches in length and between 0.5 and 24 inches in width.

[0161] 2. Overview of the perfusion circuit As mentioned above, the liver has two blood sources, the hepatic artery and the portal vein, which supply roughly one-third and two-thirds of its blood, respectively. Typically, comparing the blood supply from the hepatic artery and the portal vein, the hepatic artery supplies blood at a high but low flow rate, while the portal vein supplies blood at a low but high flow rate. Furthermore, typically, the hepatic artery supplies pulsatile flow to the liver, while the portal vein does not.

[0162] System 600 can be configured to supply a perfusion solution to the liver using a single pump in a manner that simulates the human body (e.g., appropriate pressure, volume, and pulsatile flow). For example, in normal flow mode, System 600 can circulate the perfusion fluid to the liver in the same manner as blood circulates in the human body. More specifically, the perfusion fluid enters the liver via the hepatic artery and portal vein and exits the liver via the IVC. In normal flow mode, System 100 pumps the perfusion fluid into the liver 102 at a rate close to the physiological rate of approximately 1 L / min to approximately 3 L / min, although in some embodiments this range may be 1.1–1.75 L / min (however, the system may be configured to provide flow rates outside this range, such as 0–10 L / min). Each of the above figures represents the total flow rate per minute supplied to the hepatic artery and portal vein.

[0163] Referring to Figure 17, an exemplary embodiment of the perfusion set 100 is illustrated. The perfusion set 100 may include a reservoir 160, a one-way valve 191, a pump 106, a one-way valve 310, expandable chambers 184, 186, a gas exchanger 114, a heater 110, flow meters 136, 138a, 138b, a divider 105, a flow clamp 190, pressure sensors 130a, 130b, an organ chamber 104, a sensor 140, a defoamer / filter 161, and tubing / interfaces connecting them. The liver may also be connected to a bag 187 for collecting the bile produced therefrom. In some embodiments, the perfusion set 100 is entirely contained within a one-off module 634, but this is not required. In some embodiments, the inferior vena cava (IVC) is cannula-inserted, and the flow from the IVC can be directed to a conduit that can measure IVC pressure, flow, and oxygen saturation. In other embodiments, the IVC is cannula-inserted, and the perfusion fluid flows freely from the IVC into the organ chamber 104 (and eventually into one or more drains in the organ chamber 104).

[0164] In one embodiment, the perfusion fluid flows from the reservoir 160 to the valve 191, and then to the pump 106. After the pump 106, the perfusion can flow to the one-way valve 310 and the expandable chamber 184. After the expandable chamber 184, the perfusion fluid can flow to the gas exchanger 114 and then to the heater 110. After the heater 110, the perfusion fluid flows to a configured flow meter 136, where the flow rate in that portion of the perfusion circuit is measured. After the flow meter 136, the perfusion fluid flows to a divider 105, which divides the perfusion fluid flow into branch tubes 313 and 315. In some embodiments, the divider 105 divides the flow into the hepatic artery and the portal vein in a ratio between 1:2 and 1:3. The branch tube 313 eventually leads to the portal vein of the liver, and the branch tube 315 eventually leads to the hepatic artery of the liver. The branch tube 313 may include a flow meter 138a and an expandable chamber 186 that supplies perfusion fluid to a flow clamp 190. From the flow clamp 190, the perfusion fluid can flow to a pressure sensor 130a before flowing into the portal vein of the liver. The branch tube 315 may include a flow meter 138b that supplies perfusion fluid to a pressure sensor 130b before supplying it to the hepatic artery of the liver. As the perfusion fluid leaves the liver, a portion of it is collected by a measuring drain 2804 and the remainder by a main drain 2806. The perfusion fluid collected by the measuring drain 2804 can be supplied to a sensor 140. The perfusion fluid leaving the sensor 140 can be supplied to a defoaming agent / filter 161. The perfusion fluid collected by drain 2806 can be supplied directly to the defoaming agent / filter 161. The perfusion fluid leaving the defoaming agent / filter 161 can be supplied to a reservoir 160. Furthermore, bile produced in the liver can be collected in bag 187.

[0165] In some embodiments, the system 100 contains at least 1.6 L of perfusion fluid (or other fluid) internally during operation.

[0166] 3. Reservoir The ad-hoc module 634 may include a perfusion reservoir 160 mounted below the organ chamber 104. The reservoir 160 may be configured to store and filter the perfusion fluid 108 as it circulates through the perfusion set 100. The reservoir 160 may include one or more one-way valves (not shown) to prevent the perfusion fluid from flowing in the wrong direction. In some embodiments, the reservoir 160 has a minimum capacity of 2 L, but smaller capacities may also be used. In some embodiments, the reservoir 160 may include a filter (shown separately in Figure 17 as a defoamer / filter 161) designed to capture particles in the perfusion fluid 108. In some embodiments, this filter may be configured to capture particles larger than 20 microns in the perfusion fluid 108. In some embodiments, the reservoir 160 includes a defoamer (shown separately in Figure 17 as a defoamer / filter 161) to reduce and / or remove foam generated from the perfusion fluid 108. In some embodiments, the reservoir 160 may be made of a transparent material and may include a water level indicator so that the user can estimate the amount of perfusion fluid in the reservoir 160. In some embodiments, the reservoir 160 may be configured to allow a minimum fluid inflow of 4.5 L / min from the organ chamber 104, but other flow rates are also possible. In some embodiments, the reservoir 160 includes a vent to the atmosphere, which includes a sterile barrier (not shown).

[0167] The reservoir 160 can be positioned in various locations within the system 600. For example, the reservoir 160 can be positioned above the liver, completely below the liver, partially below the liver, next to the liver, etc. Thus, one potential advantage of some of the embodiments described herein is that the reservoir can be positioned below the liver, since gravity-induced pressure head of the perfusion fluid is not required.

[0168] 4. Valve In some embodiments, valves 191 and 310 are one-way valves configured to ensure that the perfusate of system 100 flows in the correct direction within system 100. Exemplary embodiments of valves 191 and 310 are described above in relation to pump 106.

[0169] 5. Perfusion fluid pump Exemplary embodiments of the pump 106 have been described in more detail with reference to Figures 6A-6E. As described above, in some embodiments, the pump is divided between a multi-use module 650 and a single-use module 634. For example, the single-use module 634 may include a pump interface assembly, while the multi-use module 650 includes a pump drive unit. 6. Extendable Chamber

[0170] Pump 106 provides a general pulsating output, while the characteristics of this flow are typically adapted to match the flow typically supplied from the human body to the liver. For example, when the liver is in vivo, the portal vein typically supplies a pulsating flow of blood to the liver. Therefore, in some embodiments, one or more stretchable chambers can be used to reduce the pulsating flow generated by pump 106 in order to provide a non-pulsating flow of perfusion fluid to the portal vein of the liver. In some embodiments, these stretchable chambers are substantially small series fluid accumulators with flexible and elastic walls to simulate the extensibility of human blood vessels. The stretchable chambers can assist system 600 in more accurately mimicking human blood flow by, for example, filtering / reducing fluid pressure spikes caused by the flow profile from pump 106. In embodiments of system 600 described herein, two stretchable chambers 184 and 186 are used. The desired results can be obtained by varying the various characteristics of these stretchable chambers. For example, the combination of i) the relationship between pressure and volume and ii) the overall volume of the expandable chamber may affect the performance of the expandable chamber. Preferably, the desired result can be obtained by selecting the characteristics of each expandable chamber.

[0171] In some embodiments, the expandable chamber 184 is located between the valve 310 and the gas exchanger 114 and operates to partially smooth the pulsating output of the pump 106. For example, the expandable chamber 184 can be configured so that the flow of perfusion fluid ultimately supplied to the hepatic artery of the liver mimics that of the human body. In some embodiments, the expandable chamber 184 can be omitted if the output of the pump 106 is such that the flow of perfusion fluid into the hepatic artery accurately mimics the flow into the hepatic artery of the human body.

[0172] In some embodiments, the expandable chamber 184 is positioned between the divider 105 and the flow clamp 190. The expandable chamber 184 can operate to substantially reduce or even eliminate the pulsatile nature of the perfusion fluid flow ultimately supplied to the portal vein. Furthermore, although the expandable chamber 184 is positioned before the flow clamp 190 in the branch 313, this is not a requirement. For example, the flow clamp 190 can be positioned before the expandable chamber 186. However, in this embodiment, it may be desirable to adjust the parameters of the expandable chamber 186.

[0173] 7. Gas exchanger The system 600 may also include, for example, a gas exchanger 114 (also called an oxygen adduct) configured to remove CO2 from the perfusion fluid and add O2. The gas exchanger 114 can receive input gas from an external or onboard source 172 (e.g., a gas supply source 172 or an oxygen concentrator) through a gas regulator and / or gas flow chamber, which may be a pulse-width adjustable solenoid valve that controls the gas flow, or other gas control device that allows for precise control of the gas flow rate. In some embodiments, the gas exchanger 114 may be a standard membrane ventilator, such as an interventional lung support membrane oxygen adduct from NOVALUNG or a Quadrox series product from Maquette, Jersey. In an exemplary embodiment, the gas contains a mixture of oxygen, carbon dioxide, and nitrogen. The exemplary mixture of gases contains 80% O2, 0.1% CO2, and the remainder N2, with a mixing process accuracy of 0.030%. In some embodiments, the operation of the gas exchanger, regulator, and / or gas flow chamber can be controlled by the controller 150 using the output of the sensor 140.

[0174] In some embodiments, the oxygen adductor 141 may have an oxygen transfer rate of 27.5 mLpm / LPM at a blood flow rate of 500 mLpm under standard conditions. The oxygen adductor 141 may also have a carbon dioxide transfer rate of 20 mLpm at a blood flow rate of 500 mLpm under standard conditions. Standard conditions, for example, are as follows: gas = 100% O2, blood temperature = 37.0 ± 0.5℃, hemoglobin = 12 ± 1 mg%, SvO2 = 65 ± 5%, pCO2 = 45 ± 5 mmHg, and a gas-to-blood ratio of 1:1). Vapor values ​​are for illustrative purposes only and are not limiting. Higher and / or lower transfer rates than those described above may also be used.

[0175] 8. Heater / cooler The perfusion set 100 may include one or more heaters configured to maintain the temperature of the perfusion fluid 108 at a desired level. By warming the perfusion fluid and circulating this warmed liquid into the liver, the liver itself can be warmed. The heater can warm the perfusion fluid to a wide range of temperatures (e.g., 0-50°C), but typically, the heater warms the perfusion fluid to a temperature of 30-37°C. In some embodiments, the heater can be configured to warm to 34-37°C, 35-37°C, or any range within 0-50°C. In some embodiments, the range described herein can be extended to 42°C.

[0176] Referring to Figures 18A-18G, exemplary embodiments of the heater assembly 110 are illustrated. Figures 18A-18F show various views of the perfusion fluid heater assembly 110. The heater assembly 110 may include a housing 234 with an inlet 110a and an outlet 110b. As shown in both the longitudinal and transverse cross-sectional views, the heater assembly 110 may include a flow path 240 extending between the inlet 110a and the outlet 110b. The heater assembly 110 may be conceptualized as having symmetrical halves, an upper 236 and a lower 238. Thus, only the upper half is shown in the exploded view of Figure 18F.

[0177] A channel 240 can be formed between the first 242 and the second 244 channel plates. An inlet 110a can allow the perfusion fluid to flow into the channel 240, and an outlet 110b can allow the perfusion fluid to exit the heater 110. The first 242 and the second 244 channel plates may have substantially bioinert perfusion fluid 108 contact surfaces that enable direct contact with the perfusion fluid flowing through the channel 240. These fluid contact surfaces may be formed by processing or coating the plates, or they may be the plate surfaces themselves. The heater assembly 110 may include first and second electric heaters 246 and 248, respectively. The first heater 246 can be positioned adjacent to the first heater plate 250 and can transfer heat to this plate. The first heater plate 250 can then transfer this heat to the first channel plate 242. Similarly, the second heater 248 can be positioned adjacent to the second heater plate 252 and can transfer heat to this plate. The second heater plate 252 can transfer heat to the second flow channel plate 244. In the exemplary embodiment, the first 250 and second 252 heater plates can be formed from a material such as aluminum that conducts and disperses heat from the first 246 and second 248 electric heaters relatively uniformly. The uniform heat distribution by the heater plates 250 and 252 allows the flow channel plates to be formed from a bioinert material such as titanium, mitigating concerns regarding their heat distribution properties. The heater assembly 110 may further include O-rings 254 and 256 for fluid sealing the flow channel plates 242 and 244 to the housing 234 to form the flow channels 240. In some embodiments, the functions of the heater plates and flow channel plates are combined into a single plate.

[0178] The heater assembly 110 may further include first assembly brackets 258 and 260. The assembly bracket 258 is mounted on the upper side 236 of the heater assembly 110, around the electric heater 246, so that the heater 246, heater plate 250, and flow path plate 242 can be sandwiched between the assembly bracket 258 and the housing 234. Bolts 262a-262j can be fitted into corresponding through holes in the bracket 258, electric heater 246, heater plate 250, and flow path plate 242 and screwed into corresponding nuts 264a-264j to secure all of these components to the housing 234. The assembly bracket 260 may be mounted on the bottom surface 238 of the heater assembly 110 in a similar manner to how the heater 248, heater plate 252, and flow path plate 244 are secured to the housing 234. An elastic pad 268 can be fitted around the bracket 258. Similarly, the elastic pad 270 can be fitted around the bracket 268. The bracket 272 can be fitted onto the pad 268. Bolts 278a-278f can be fitted into holes 276a-276f in the bracket 272 and screwed onto nuts 280a-280f, thereby compressing the elastic pad 268 toward the heater 246 and providing more efficient heat transfer to the heater plate 250. The elastic pad 270 can be compressed toward the heater 248 by bracket 274 in a similar manner.

[0179] The illustrated heater assembly 110 may include temperature sensors 120 and 122 and a dual sensor 124. The dual sensor 124 may actually include a dual thermistor that provides fault tolerance and can measure the temperature of the perfusion fluid 108 exiting the heater assembly 110 and provide these temperatures to the controller 150. As will be further detailed with respect to the heating subsystem 149, the temperatures of heaters 256 and 248 can be controlled by using the signals from sensors 120, 122 and 124 in a feedback loop to control the drive signals to the first 246 and / or second 248 heaters. In addition, the illustrated heater assembly 110 may further include temperature sensors / leads 120 and 122 that monitor the temperatures of heaters 246 and 248 and provide these temperatures to the controller 150, respectively, so that the heater plates 250 and 252, and consequently the blood contact surfaces 242 and 244 of the heater plates 250 and 252, do not reach temperatures that could damage the perfusion fluid. In practice, the sensors attached to sensor / lead wires 120 and 122 can be RTD (Resistance Temperature Device) based. The maximum temperature of heater plates 250 and 252 can be limited by using the signals from the sensors attached to sensor / lead wires 120 and 122 in a feedback loop to further control the drive signals to the first 246 and / or second 248 heaters. As a protection against failure, sensors can be provided on both heaters 246 and 248 so that the system can operate at the temperature of the other sensor if one fails.

[0180] The heater 246 of the heater assembly 110 can receive drive signals 281a and 283b (collectively 283) from the controller 150 via the corresponding drive lead 282b. Similarly, the heater 248 receives drive signals 283a and 283b (collectively 283) from the controller 150 via the drive lead 282b. The drive signals 281 and 283 control the current to each heater 246 and 248, and thus control the heat generated by each heater 246 and 248. More specifically, as shown in Figure 18G, the drive lead 282a includes a high pair and a low pair connected to the resistive element 286 of the heater 246. The greater the current supplied through the resistive element 286, the hotter the resistive element 286 becomes. The heater 248 operates in the same manner with respect to the drive lead 282b. In the illustrated embodiment, the element 286 has a resistance of approximately 5 ohms. However, in other exemplary embodiments, the element may have a resistance between approximately 3 ohms and approximately 10 ohms. Heaters 246 and 248 can be controlled individually by the processor 150.

[0181] The heater assembly 110, which houses the components, can be formed from molded plastic such as polycarbonate and can weigh less than approximately 1 pound. More specifically, the housing 234 and brackets 258, 260, 272, and 274 can all be formed from molded plastic such as polycarbonate. Another feature is that the heater assembly may be a single-use, disposable assembly.

[0182] During operation, the illustrated heater assembly 110 can use power from about 1 watt to about 200 watts and can be sized and shaped to transfer the perfusion fluid 108 flowing through the channel 240 at a flow rate of about 300 ml / min to about 5 L / min, at a temperature of less than about 30°C to at least about 37°C, in less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, or even less than about 10 minutes, without causing hemolysis of cells, denaturing proteins, or damaging any blood product portion of the perfusion fluid.

[0183] The heater assembly 110 may include housing components such as a housing 234 formed from polycarbonate and weighing less than approximately 5 pounds, as well as brackets 258, 260, 272, and 274. In some embodiments, the heater assembly may weigh less than 4 pounds. In the exemplary embodiment, the heater assembly 110 may have a length 288 of approximately 6.6 inches and a width 290 of approximately 2.7 inches, without including the inlet 110a and outlet 110b. The heater assembly 110 may have a height 292 of approximately 2.6 inches. The flow path 240 of the heater assembly 110 may have a nominal width 296 of approximately 1.5 inches, a nominal length 294 of approximately 3.5 inches, and a nominal height 298 of approximately 0.070 inches. The height 298 and width 296 may be selected so that the perfusion fluid 108 is heated uniformly as it passes through the flow path 240. The height 298 and width 296 are selected such that the cross-sectional area of ​​the flow path 240 is approximately equal to the inner cross-sectional area of ​​the fluid conduit that carries the perfusion fluid 108 into and / or out of the heater assembly 110. In one embodiment, the height 298 and width 296 are selected such that the cross-sectional area within the flow path 240 is approximately equal to the inner cross-sectional area of ​​the intake fluid conduit 792 and / or substantially equal to the inner cross-sectional area of ​​the discharge fluid conduit 794.

[0184] The protrusions 257a-257d and 259a-259d may be included in the heater assembly 110 and may be used to receive a heat-activated adhesive for bonding the heater assembly to the multi-use unit 650.

[0185] In addition to the heater 110, the system 100 may include additional heaters (not shown) placed in the organ chamber 110 to provide heat (e.g., resistance heaters). 9. Pressure / flow probe

[0186] In some embodiments, the system 600 may include pressure sensors 130a, 130b and flow sensors 138a, 138b. These probes and / or sensors are available as standard commercial products. For example, the flow sensors 136, 138a, and 138b may be ultrasonic flow sensors, such as those available from Transonic Systems, Inc. in Ithaca, New York. The hydraulic probes 130a, 130b may be conventional strain gauge pressure sensors available from MSI or GEThermometrics. Alternatively, a pre-calibrated pressure transducer chip may be embedded in the organ chamber connector and connected to the controller 150. In some embodiments, these sensors may be configured to measure average, instantaneous, and / or peak flow and / or pressure values. In embodiments where the average value is calculated, the system may be configured to calculate this average using moving average sample values. These sensors may further be configured to provide systolic and diastolic measurements. While these are separate devices in Figure 17, in some embodiments, a single device can measure both pressure and flow. In some embodiments, these sensors can be configured to measure pressure in the 0–225 mmHg range with an accuracy of ±(7% + 10 mmHg) for each transducer. In some embodiments, the flow sensor can be configured to measure flow rate in the 0–10 L / min range with an accuracy of ±12% + 0.140 L / min. In some embodiments, these pressure and flow sensors can be configured to sample pressure / flow rate within the cannula tip, within the vascular, or within the tubing prior to the cannula.

[0187] Although a single sensor 130b and a single sensor 130a are provided, these sensors may include two or more pressure sensors. For example, in some embodiments, sensor 130a may include two pressure sensors for redundancy. In some embodiments, when both sensors are operating, the controller 150 can calculate the actual pressure by averaging both outputs. In some embodiments, if one of the two pressure sensors in sensor 130a fails, the controller can ignore the malfunctioning sensor.

[0188] As will be explained in more detail with respect to Figure 23A-23K, these pressure sensors can be housed in the housing 3010 of connector 3000 (and similarly in connector 3050).

[0189] 10. Flow control System 600 can be configured to achieve a perfusion fluid flow rate that varies in the range of 0–10 L / min at the flow sensor 136 (e.g., before the divider 105). In some embodiments, the system can be configured to produce a flow rate of 0.6–4 L / min at the flow sensor 136, or more specifically, a flow rate of 1.1–1.75 L / min at the flow sensor 136. These ranges are for illustrative purposes only, and the flow rate at sensor 136 can be any range within 0–10 L / min. System 600 can be configured to achieve a perfusion fluid flow rate that varies in the range of 0–10 L / min, more specifically, in the range of 0.25–1 L / min, at the hepatic artery of the liver (e.g., measured by the flow sensor 130b). These ranges are for illustrative purposes only, and the flow rate at the hepatic artery can be any range within 0–10 L / min. The system 600 can be configured to provide a perfusion fluid flow rate to the hepatic portal vein (measured, for example, by the flow sensor 130a) ranging from 0 to 10 L / min, more specifically from 0.75 to 2 L / min. These ranges are illustrative only, and the flow rate in the portal vein can be any range from 0 to 10 L / min.

[0190] In some embodiments, the system 600 can generate a perfusion fluid flow passing through the perfusion module at a flow rate of 0.3–3.5 L / min, with at least 1.8 liters contained within. In some embodiments, the pressure applied to the hepatic artery via the branch 315 is in the range of 25–150 mmHg, more specifically 50–120 mmHg, and the pressure applied to the portal vein via the branch 313 is in the range of 1–25 mmHg, more specifically 5–15 mmHg. These ranges are for illustrative purposes only, and each pressure can be within any range of 5–150 mmHg.

[0191] 11. Perfusion fluid sensor Sensor 140 can sense one or more characteristics of the perfusion fluid flowing from the liver by measuring the amount of light absorbed or reflected by the perfusion fluid when applied at multiple wavelengths. For example, sensor 140 may be an O2 saturation, hematocrit, and / or temperature sensor. Figures 19A-19C show exemplary embodiments of sensor 140. Sensor 140 may include an in-line cuvette portion of tube 812 connected to conduit 798, which may have at least one optically transparent window from which an infrared sensor can provide infrared light. An exemplary embodiment of sensor 140 may be the BLOP4 and / or BLOP4 Plus probes available from DATAMED SRL. The cuvette 812 may be a single molded piece having connectors 801a and 801b. Connectors 801a and 801b may be configured adjacent to receiving portions 803a and 803b to which conduit ends 798a and 798b connect, respectively. Such interconnections between the cuvette 812 and the conduit ends 798a and 798b can be configured such that the transverse flow area inside the conduit 798 and cuvette 812 is substantially constant. This configuration thus reduces, and in some embodiments substantially eliminates, the discontinuity at the interfaces 814a and 814b between the cuvette 812 and the conduit 798. The reduction / elimination of discontinuity allows the blood-based perfusion fluid 108 to flow through the cuvette with less red blood cell lysis and turbulence, resulting in more accurate readings of the perfusion fluid oxygen level. This also reduces damage to the perfusion fluid 108 by the system 600, ultimately reducing damage to the transplanted organ.

[0192] The cuvette 812 can be formed from any suitable light-transmitting material such as light-transmitting glass or polymer. As shown in Figure 19A, the sensor 140 may further include an optical transceiver 816 for determining the amount of oxygen in the perfusion fluid 108 by directing light waves to the perfusion fluid 108 passing through the cuvette 812 and measuring light transmission and / or light reflectance. In some embodiments, the optical transceiver is located on one side of the cuvette 812, and a detector for measuring the light transmittance through the perfusion fluid 108 is located on the opposite side of the cuvette 812. Figure 19C shows a top cross-sectional view of the cuvette 812 and the transceiver 816. The transceiver 816 can be fitted around the cuvette 812 such that its inner flat surfaces 811 and 813 are coupled to the flat surfaces 821 and 823 of the cuvette, respectively, while its inner convex surface 815 is coupled to the convex surface 819 of the cuvette 812. During operation, when ultraviolet light passes through the transceiver 816, it travels from the flat surface 811 through the perfusion fluid 108 in the cuvette 812 and is received by the flat surface 813. This flat surface 813 can be configured together with a detector that measures the light transmittance through the perfusion fluid 108.

[0193] In some embodiments, the sensor 140 can be configured to measure SvO2 in the range of 0-99%, although in some embodiments this can be limited to 50-99%. If the sensor 140 also measures hematocrit, the measurement range is 0-99%, but in some embodiments this can be limited to 15-50%. In some embodiments, the accuracy of these measurements by the sensor 140 can be ±5 units, and measurements can be performed at least every 10 seconds. In embodiments where the sensor 140 also measures temperature, the measurement range can be 0-50°C.

[0194] In some embodiments, the system 600 may include one or more lactate sensors (not shown) configured to measure lactate esters in the perfusion fluid. For example, the lactate sensor may be placed between the measuring drain 2804 of the branch tube 315 and / or branch tube 313 and the defoamer / filter 161. In this configuration, the system 600 may be configured to measure the lactate ester levels of the perfusion fluid before and / or after processing with liver. In some embodiments, the lactate sensor may be a series lactate analyzer probe. In some embodiments, the lactate sensor may be located outside the system 600, and a sample of the perfusion fluid taken from the sampling port may be used.

[0195] In some embodiments, the system 600 may further include one or more sensors (e.g., sensor 140 and / or other sensors such as disposable blood gas analyzer probes) for measuring pH, HCO3, pO2, pCO2, glucose, sodium, potassium, and / or lactate esters. Exemplary sensors that can be used to measure the above values ​​include commercially available probes from Sphere Medical, Cambridge, UK. As described above, this sensor can be coupled to the measuring drain 2804. Alternatively, a single tubing can be used to deliver the perfusion fluid to and from the sensor. Some embodiments of this sensor use a calibration fluid before and / or after the measurement. In embodiments using such a sensor, the system may include a valve that can be used to control the flow of the calibration fluid to the sensor. In some embodiments, this valve can be manually operated and / or automatically operated by the controller 150. In some embodiments, no calibration fluid is used, thereby allowing for continuous sampling of the perfusion fluid.

[0196] In addition to using the aforementioned sensors in the feedback loop to control System 600, some or all of these sensors can be used to determine the viability of the liver for transplantation.

[0197] In some embodiments, an external blood analyzer sensor may be used. In these embodiments, blood samples can be taken from ports provided in branch tubes 313 and 315 (these ports will be described in detail later). These blood samples can be analyzed using standard hospital equipment (e.g., a radiometer) or via point-of-care blood gas analysis (e.g., I-STAT1 available from Abbott Laboratories or Epoc available from Alere).

[0198] 12. Sampling / Injection Port System 600 may include one or more ports that can be used to sample the perfusion fluid and / or inject fluid into the perfusion fluid. In some embodiments, these ports may be configured for use with a standard syringe and / or with a controllable valve. In some embodiments, these ports may be Luer ports. Basically, System 100 may include injection / sampling ports at any location inside, and the following examples are not limiting.

[0199] Referring to Figure 17, ports 4301, 4302, 4303, 4304, 4305, 4306, 4307, and 4308 may be included. Port 4301 can be used for high-volume, instantaneous administration and / or irrigation (e.g., post-storage irrigation) to the hepatic artery. Port 4302 can be used for high-volume, instantaneous administration and / or irrigation (e.g., post-storage irrigation) to the portal vein. Ports 4303, 4304, and 4305 can be connected to the respective channels of the solution pump 631 to supply the injector to the portal vein (in the case of 4301 and 4304) and the hepatic artery (in the case of 4305). Ports 4306 and 4307 can be used to obtain samples of the perfusion fluid flowing into the hepatic artery and portal vein, respectively. Port 4308 can be used to sample the perfusion fluid from the IVC (or hepatic vein, depending on the method of hepatectomy). In some embodiments, each port may include a valve operated by the user to obtain the fluid flow from these ports.

[0200] The port configuration shown in Figure 17 is illustrative, and more or fewer ports can be used. Furthermore, ports can be located between the pump 106 or divider 105, between the organ chamber and the bile bag 187, within the bile bag 187, and between the main drain 2806 and the defoaming agent / filter 161.

[0201] The emergency module 634 may further include a tube 774 for filling the reservoir 160 with a priming solution and blood products taken from a donor or from a blood bank. The priming tube 774 can be supplied directly to the reservoir 160, and / or the priming tube can be positioned so that its end drains directly above the drain 2806 in the organ chamber 104. The emergency module 634 may further include a non-exhaust cap that replaces the exhaust cap of a selected fluid port, for example, while a sterile gas is flowing through the emergency module 634.

[0202] In some embodiments, the system 100 may include exhaust ports and / or air purge ports for removing air from the hepatic artery interface, portal vein interface, and other parts of the system 100.

[0203] In some embodiments, additional injection ports may be included for user-introduced contrast agent into the perfusion fluid to improve liver imaging. For example, an ultrasound contrast agent can be injected to perform contrast-enhanced ultrasound diagnosis.

[0204] 13. Organ support While the perfusion fluid can be naturally drained from the liver as a result of pressurizing the hepatic artery and portal vein, System 600 may also include additional features that help the perfusion fluid be drained from the liver in a manner that mimics the human body. Specifically, in the human body, the diaphragm typically pressurizes the liver when a person breathes. This pressure pushes blood out of the person's liver. System 600 may include one or more systems designed to mimic the pressure exerted on the liver by the diaphragm. Exemplary embodiments include contact and non-contact embodiments. In some embodiments, the amount of pressure exerted on the liver may be less than the pressure in the hepatic portal vein and / or hepatic artery. Schematic diagrams of exemplary embodiments of these organ assist systems are shown in Figure 30.

[0205] One embodiment of a non-contact pressure system is a system that simulates the pressure exerted on the liver by the diaphragm by varying the air pressure within an organ chamber 104. In this embodiment, the organ chamber 104 can be configured to provide a substantially airtight environment so that the air pressure within the organ chamber 104 can be maintained at a level higher (or lower) than the ambient air. As the air pressure within the organ chamber 104 increases, this can exert a pressure on the liver that simulates the pressure exerted by the diaphragm, increasing the rate at which the liver pushes out the perfusion fluid. In some embodiments, this air pressure can be varied in a manner that mimics the human respiratory rate (e.g., 12-15 breaths per minute) or at other frequencies (e.g., 0.5-50 breaths per minute). The air pressure within the organ chamber 104 can be varied by various means, for example, a dedicated air pump (not shown) and / or an onboard gas supply source 172. In some embodiments, the air pressure within the organ chamber 104 can be controlled by a controller 150. In these embodiments, the controller can be connected to a pneumatic sensor that measures the pressure within the organ chamber 104, which is used as part of a feedback control loop.

[0206] One embodiment of the contact pressure system is a system that applies pressure to the liver using a wrap and / or bladder. For example, the wrap can be placed over part or all of the liver within the organ chamber 104. The edges of the wrap can then be mechanically tightened to apply pressure to the portion of the liver covered by the wrap. In this example, one or more motors mounted at various points around the wrap can be used to tighten the edges of the wrap. Another embodiment of the contact pressure system uses a removable bladder (not shown). In this embodiment, an inflatable bladder can be placed between the liver and the upper surface (or other location) of the organ chamber 104. The bladder can then be inflated / deflated using a pump. When the bladder is inflated, it presses against the upper surface (or other location) of the organ chamber 104, thereby applying pressure to the liver inside. Similar to the non-contact pressure system described above, the pressure applied to the liver can be applied periodically to mimic the natural pressure exerted by the diaphragm. In some embodiments, the pressure applied to the liver can be varied in a manner that mimics the human respiratory rate (e.g., 12-15 breaths per minute) or at other frequencies (e.g., 0.5-50 breaths per minute). Whether the pressure applied to the liver is via a wrap or a bladder, this pressure can be controlled by the controller 150. In some embodiments, one or more sensors for measuring the pressure applied to the liver can be included in the organ chamber 104 as part of a feedback control loop. Other methods for applying contact pressure to the liver are also possible.

[0207] 14. Insertion of the cannula In use, in one embodiment, the liver can be collected from a donor and connected to the system 600 by cannula insertion. For example, interface 162 allows cannula insertion into the hepatic artery vascular tissue via a conduit located within the organ chamber assembly. Interface 166 allows cannula insertion into the portal vein vascular tissue via a conduit located within the organ chamber assembly. The liver releases perfusion fluid through the inferior vena cava (IVC). In some embodiments, the IVC is cannula inserted via interface 170 (not shown) and the flow can be directed directly into a conduit in which IVC pressure, flow rate, and oxygen saturation can be measured internally. In another embodiment, the IVC is cannula inserted via interface 170 and the flow can be directed into the organ chamber. In yet another embodiment, the IVC is not cannula inserted, and the organ chamber provides a means to direct the perfusion fluid flow to a reservoir for efficient collection.

[0208] After pulling vascular tissue onto the respective ends of interfaces 162, 166, and 170, each of these interfaces can be cannula-inserted into the liver by tying or fixing this tissue to the interface. This vascular tissue is preferably a short portion of blood vessels that remain connected to the liver after the liver has been explanted from a donor. In some embodiments, this short vascular portion is generally 0.25–5 inches in length, but other lengths are also possible.

[0209] Referring to Figures 21A-21D, exemplary embodiments of the hepatic artery cannula 2600 are illustrated. The cannula 2600 is generally tubular and is configured to be inserted into the tubing used in system 100 and includes a first section 2604 containing a first orifice 2612. The first section 2604 may also include a ring 2602 which can be used to help secure the first section 2604 within the tubing of system 100 by friction. The cannula 2600 may also include a second section 2608 which is smaller in diameter than the first section 2604 and forms a second orifice 2614. The second section 2608 may also include a channel 2610 drawn out from the surface of the second section 2608. In some embodiments, when the user ties the hepatic artery to the second section 2608, the user can suture the channel 2610 to assist in securing the hepatic artery. A collar 2606 may be provided between the first and second sections. The outer diameter of this collar can be slightly larger than that of the first section 2604, preventing the tubing of system 100 from overlapping the second section 2608 during insertion. As shown in the cross-sectional view in Figure 21D, the inner diameter of the cannula 2600 can be varied by adding a tapered shape 2616 to the inside. The cannula 2600 can be formed in various sizes, lengths, inner diameters, and outer diameters. In some embodiments of system 600, it may be advantageous to provide a considerably larger inner diameter in the first section 2604 and a considerably smaller inner diameter in the second section 2608 in order to offset the pressure and flow rate changes caused by the cannula 2600.

[0210] Referring to Figures 21H-21KD, in an alternative embodiment, the cannula 2600 is provided with an obliquely cut end 2618.

[0211] The outer diameter of the first part 2604 can be configured to be press-fitted into the interior of a silicone or polyethylene tubing. Therefore, the outer diameter of the first part 2604 can vary, but an exemplary range of possible diameters is 0.280–0.380 inches. The outer diameter of the second part 2608 can range from 4–50 Fr, more specifically 12–20 Fr. Furthermore, the cannula 2600 can be manufactured from a variety of biocompatible materials such as stainless steel, titanium, and / or plastic (the dimensions of the cannula 2600 can be adapted to be manufactured using different materials).

[0212] Furthermore, 10-20% of the population have a genetic variant that includes an accessory hepatic artery in the liver. In such cases, the hepatic artery cannula described above can be a bifurcated (e.g., Y-shaped) cannula. Exemplary embodiments of the Y-shaped hepatic artery cannula 2642 are shown in Figures 21E-21G, while corresponding features of cannula 2600 are shown using similar numbering. The bifurcated design of hepatic artery cannula 2642 allows system 100 to treat both vessels as a single input of hepatic artery flow without changing the configuration of system 100 and / or controller 150.

[0213] In an alternative embodiment, if the liver includes accessory hepatic arteries, two hepatic artery cannulas can be attached at one end to a portion of a Y-shaped tubing and connected at the other end to the organ chamber.

[0214] Referring to Figures 22A-22D, exemplary embodiments of the portal vein cannula 2650 are illustrated. The cannula 2650 is generally tubular and is configured to be inserted into tubing used in system 100 and includes a first section 2654 which includes a first orifice 2660. The first section 2654 may also include a ring 2654 which can be used to help secure the first section 2652 within the tubing of system 100 by friction. The cannula 2650 may also include a second section 2656 which is larger in diameter than the first section 2654 and forms a second orifice 2662. The second section 2656 may also include a channel 2658 drawn out from the surface of the second section 2656. In some embodiments, when the user ties the portal vein to the second section 5626, the user can suture the channel 2658 to assist in securing the portal vein. As can be seen in the cross-sectional view shown in Figure 22D, the inner diameter of the cannula 2600 can be varied by adding a tapered shape 2664 to the inside. The cannula 2650 can be formed in various sizes, lengths, inner diameters, and outer diameters. In some embodiments of the system 600, it may be advantageous to provide a considerably larger inner diameter in the first section 2654 and an even larger inner diameter in the second section 2656 in order to offset the pressure and flow rate changes caused by the cannula 2650.

[0215] Referring to Figures 22E-22G, in an alternative embodiment, the cannula 2650 includes an oblique-cut end 2666 between these first and second parts. The outer diameter of this collar may be slightly larger than that of the first part 2654 to prevent the tubing of system 100 from overlapping the second part 2656 during insertion. The cannula 2650 may also include an oblique-cut end 2668.

[0216] The outer diameter of the first part 2654 can be configured to be press-fitted into the interior of a silicone or polyethylene tubing. Therefore, the outer diameter of the first part 2654 can vary, but an exemplary range of possible diameters is 0.410–0.510 inches. The outer diameter of the second part 2656 can range from 25–75 Fr, more specifically 40–48 Fr. Furthermore, the cannula 2650 can be manufactured from a variety of biocompatible materials such as stainless steel, titanium, and / or plastic (the dimensions of the cannula 2600 can be adapted to be manufactured using different materials).

[0217] Referring to Figures 23A-23N, an exemplary hepatic artery connector 3000 is illustrated. The connector 3000 may also be part of a branch duct 315 connected to the hepatic artery of the liver. For example, the connector 3000 can be inserted into an organ chamber 104 and fixed to its wall. The connector 3000 may include a first portion 3006 that includes a circumferential channel 3007 and defines an opening 3008. In some embodiments, the outer diameter of the first portion 3006 is sized to connect to 1 / 4-inch tubing, but other diameters are also possible. In some embodiments, the tubing connected to the first portion 3006 may be connected by friction and / or a regular zip tie (or other similar fastener) may be tightened around the channel 3007 to secure the connected tubing. The connector 3000 may also include a second portion 3002 that defines an opening 3003. In some embodiments, the outer diameter of the second section 3002 can be sized to connect to a 1 / 4-inch tubing using a press / friction connection, but other diameters are also possible. In some embodiments, the perfusion fluid flows from opening 3008 towards opening 3003.

[0218] The connector 3000 may include an interface configured to engage with an opening in the wall of the organ chamber 104. For example, the connector 3000 may include a ridge 3003 sized to fit into a corresponding opening in the wall of the organ chamber 104. The backstop 3004 may be larger than the opening to prevent the connector from being inserted too deeply, and further, it may provide a surface for applying adhesive to bond the connector 3000 to the organ chamber 104. In some embodiments, the ridge 3003 may include a protrusion 3011 configured to rotate and position the connector 3000 within the organ chamber 104. For example, in some embodiments, the protrusion 3011 and the corresponding opening in the organ chamber 104 may be configured to allow the connector 3000 to rotate around the longitudinal axis of the second portion 3003. In some embodiments, this rotation may be optimized to prevent the formation of air bubbles.

[0219] The connector 3010 may also include a housing 3010 configured to accommodate a pressure sensor 130b. In this embodiment, two pressure sensors constitute the pressure sensor 130b. In such embodiments, these pressure sensors can be mounted in the opening 3009, which allows direct access to the fluid in the connector 3000. Furthermore, some embodiments of the connector 3000 may include a vent 3005, which can be connected to a valve that can be opened to release air bubbles trapped within the connector 3000. During operation, the user can attach one end of a tube to the second part 3002 and the other end of this tube to a hepatic artery cannula 2600 (which can be connected to a hepatic artery). In some embodiments, the user can place the liver in the organ chamber 104 and connect the cannula 2600 to one end of a tube, which can be connected to the hepatic artery using a suture. Since liver sizes vary, the user can then trim the tubing to the appropriate length and connect it to the second part 3003.

[0220] Referring to Figure 24A-23L, an exemplary portal vein connector 3050 is illustrated. In some embodiments, the portal vein module 3050 is configured and operates similarly to the connector 3000, with the exception that the first and second parts may be connected to 3 / 8-inch or 1 / 2-inch tubing instead of 1 / 4-inch, although it can be configured to operate with tubing of other dimensions. Also, as is evident from the name, the portal vein connector can be configured to connect the branch tubing 313 to the portal vein of the liver.

[0221] While some dimensions have been described above, these are for illustrative purposes only, and each of the components described above can be sized as needed to achieve the desired flow characteristics. For example, in some embodiments, it may be advantageous to use a larger diameter cannula to avoid introducing undesirable pressure or flow changes. Furthermore, during surgery, the diameter of the cannula can be selected by the surgeon so that the largest cannula that physically fits into the blood vessel is used.

[0222] It should be noted that some people believe the Fr scale ends at 34. Therefore, if an Fr size greater than 34 (or an Fr number that does not exist in the conventional Fr scale) is given, the size in millimeters can be determined by dividing the Fr number by 3.

[0223] 15. Flow Clamp Referring to Figures 25A-25B, exemplary embodiments of the flow clamp 190 are illustrated. The flow clamp 190 can be used to control the flow and / or pressure of perfusion fluid into the portal vein of the liver. The flow clamp 190 may include a cover 4001, a knob 4002, a pivot 4003, a pin 4004, a screw 4005, a bearing 4006, a slide 4007, a spindle 4008, and a body 4009. The slide 4007 may include a groove 4010 and a detent 4012 and may be configured to move up and down within the body 4009. In some embodiments, a tube carrying perfusion fluid is located within the body 4009 below the slide 4007. Figures 25C-25D show the flow clamp 190 with a molded part.

[0224] The flow clamp 190 can be configured to allow the user to quickly engage and release the clamp 190 while also allowing precise control over the amount of clamping force applied. In this embodiment, the cover 4001, the knob 4002, the pivot 4003, the pin 4004, the screw 4005, and the bearing 4006 constitute the switch unit 4011. The pivot 4003 of the switch unit 4011 can rotate around a longitudinal axis formed by a spindle 4008 (which can be composed of two separate screws). In this embodiment, when the switch unit 4011 is engaged as shown in Figure 25A (for example, with the screw 4005 vertical), the bearing 4006 forces the slide 4007 down within the body 4009 (which then presses against the tube carrying the perfusion fluid, if present, and restricts the internal flow). The extent to which the slide is forced downward is a function of how much the screw 4005 extends relative to the pivot 4003. When the switch unit 4011 is released, it pivots laterally, the screw is not oriented vertically, and does not restrict the movement of the slide 4007. When the switch unit 4011 pivots, the bearing can move along the groove 4010. In some embodiments, when the bearing 4006 stops at the detent 4012, the switch unit 4011 can be "locked" in place. The user can adjust the flow limit determined by the flow clamp 190 when engaged by rotating the knob 4002 to extend / contract the screw 4005. In some embodiments, the screw pitch may be 4-40 threads, but other pitches can also be used to adjust the precision of the flow clamp 190.

[0225] 16. Priming In some embodiments, the perfusion fluid includes a packed red blood cell bag, also known as "banked blood." Alternatively, the perfusion fluid includes blood collected from a donor through the process of bleeding during liver excision. Initially, this blood is stored in reservoir 160, and when the cannula position in the organ chamber assembly is connected through the bypass conduit, a normal flow mode of the perfusion fluid through the system without passing through the liver becomes possible, which is also known as the "priming tube." Before inserting the cannula into the excised liver, the bled donor blood can be circulated through the system and heated, oxygenated, and / or filtered to prime the system. During priming, nutrients, preservatives, and / or other therapeutic agents may also be provided through the infusion pump of the nutrient subsystem. During priming, various parameters may be initialized and calibrated through the operator interface. Once primed and operating properly, the pump flow can be reduced or removed from the cycle, the bypass conduit can be removed from the organ chamber assembly, and the cannula can be inserted from the liver into this organ chamber assembly. Thereafter, the pump flow can be restored or increased as appropriate. This priming procedure will be described in more detail later.

[0226] 17. IVC Cannula Insertion In some embodiments, the inferior vena cava (IVC) can be cannulated, but this is not a requirement. In these embodiments, additional pressure and / or flow sensors can be used to measure the pressure and / or flow of the perfusion fluid flowing from the liver. In some embodiments, the cannulated IVC can be directly coupled to sensor 140 and / or the reservoir. In other embodiments, the IVC can be cannulated to direct the drainage of the perfusion fluid (e.g., directed free drainage). For example, the cannulation end of a short tube connected to the IVC can be fixed in place with a clip so that the perfusion fluid is discharged directly above the measurement drain 2804. In other embodiments, the IVC is not cannulated and the perfusion fluid can drain freely therefrom. In yet another embodiment, the IVC can be partially ligated.

[0227] In embodiments where the IVC is cannulated and connected to tubing, it is preferred that the tubing be as short as possible to obtain the desired results. Since the physiological IVC pressure is low, even a thin tube of some length can cause the IVC pressure to increase. In embodiments of the system 600 that include pressing on the liver to facilitate drainage (e.g., pressurization of the chamber 104 described above), the liver may be able to tolerate a longer cannula / tubing.

[0228] 18. Bile Duct Cannulation In some embodiments of the system 600, the bile ducts of the liver can be cannulated using commercially available and / or custom cannulas. For example, a 14 Fr bile duct cannula can be used. Further, the bile bag 187 is configured to collect the bile produced by the liver. In some embodiments, the bag 187 is transparent so that the user can visually observe the color of the bile. Depending on the embodiment, the bag 187 can collect up to 0.5 L of bile, although other amounts are possible. Depending on the embodiment, the bag 187 can include graduations indicating how much volume has been collected. The system 600 is described as including a soft shell (e.g., the bag 187) for collecting bile, but a hard shell container can also be used. Some embodiments of the system 600 can include sensors (e.g., volumetric, ultrasonic, and / or cumulative flow rate) for measuring the amount of bile collected. This information can then be displayed to the user and / or transmitted to the cloud.

[0229] 19. Blood Collection / Filter Some embodiments of the system 600, which uses whole blood from a donor, may include a leukocyte filter (not shown). In these embodiments, the leukocyte filter can be used during system priming to filter the blood received from the donor's body via blood collection lines connected to the donor's arteries and / or veins. In some embodiments, the leukocyte filter may be configured to filter at least 1500 mL of blood in 6 minutes or less (other speeds are possible). In some embodiments, the leukocyte filter may filter more than 30% of the total leukocytes in up to 1500 mL of whole blood.

[0230] 20. Final Cleaning Management Kit During surgery, it is sometimes desirable to remove all perfusion fluid from the hepatic vascular system without disconnecting the liver from system 100. Therefore, embodiments of system 600 can be used with a final lavage management kit. This kit includes a bag (or other container) for collecting a certain amount of fluid (e.g., lavage solution and / or perfusion fluid) so that system 100 is not overwhelmed when the lavage solution is administered to the liver (e.g., via ports 4301, 4302). Thus, in some embodiments, system 100 may include drain lines (not shown) that can be used to drain fluid from reservoir 160 and / or other parts of system 100, eliminating the need to disconnect the liver from system 100 before adding additional fluid. In some embodiments, the system can also be configured with a bypass operation in which the liver is temporarily separated from system 100 using one or more valves. For example, in this embodiment, a valve can be used before valves 4301, 4302 to stop the flow of fluid within system 100. In this embodiment, an additional drain port can be included between drains 2804, 2806 and the valve. In this embodiment, the cleaning solution (or other solution) can be supplied through ports 4301, 4302 and discharged through the additional drain port without being circulated in the rest of the system 100. In some embodiments, the drain line can hold at least 3 L of liquid, but this is not a requirement.

[0231] D. Interface between single-use and multi-use modules As shown in Figure 3G and described in detail later, the reusable module 650 may include a front-end interface circuit board 636 that connects to the front-end circuit board of the disposable module 634 (shown as 637 in Figure 13J). As described in detail later, power and drive signal connections between the reusable module 650 and the disposable module 634 are made via corresponding electromechanical connectors 640 and 647 on the front-end interface circuit boards 636 and 637, respectively. For example, the front-end circuit board 637 can receive power for the disposable module 634 from the front-end interface circuit board 636 via electromechanical connectors 640 and 647. The front-end circuit board 637 can also receive drive signals for various components (e.g., heater assembly 110, flow clamp 190, and oxygen adder 114) from the controller 150 via the front-end interface circuit board 636 and electromechanical connectors 640 and 647. The front end circuit board 637 and the front end interface circuit board 636 exchange control and data signals (for example, between the controller 150 and the emergency module 634) via optical connectors (shown as 648 in Figure 20B). As will be detailed later, the configuration of the connectors used between the front end 637 and the front end interface 636 circuit boards ensures that critical power and data interconnections between the emergency and multi-use modules 634 and 650, respectively, continue to function reliably even when moving over rough ground that may be encountered during organ transport.

[0232] Turning to the installation of the single-use module 634 into the multi-use module 650, Figure 3H shows a detailed drawing of the bracket assembly 638 described above, which is positioned on the multi-use module 650 to receive the single-use module 634 and lock the single-use module 634 into place. Figure 3F shows a side perspective view of the single-use module 634 installed within the multi-use module 650 on the bracket assembly 638, and Figure 3C shows a side view of the single-use module 634 installed within the multi-use module 650. The bracket assembly 638 includes two mounting brackets 642a and 642b that can be mounted on the inner side of the rear panel of the housing 602 via mounting holes 644a-644d and 646a-646d, respectively. A crossbar 641 extends between the mounting brackets 642a and 642b and is rotatably attached to them. Locking arms 643 and 645 are spaced apart from each other and extend radially from the crossbar 641. Each locking arm 643 and 645 includes downward-extending locking projections 643a and 645b, respectively. A lever 639 is attached to the crossbar 641 and extends radially upward from the crossbar 641. When the lever 639 is actuated in the direction of arrow 651, the locking arms 643 and 645 rotate toward the rear surface 606b of the housing 602. When the lever 639 is actuated in the direction of arrow 653, the locking arms 643 and 645 rotate toward the front surface of the housing 602.

[0233] As described above with reference to Figure 6E, the perfusion pump interface assembly 300 includes four protruding heat-crimping points 321a-321d. During assembly, the protrusions 321a-321d are aligned with the corresponding holes (e.g., 657a, 657d in Figure 13B), and the outer side surface 304 of the pump interface assembly 300 is firmly attached to the C-bracket 656 of the temporary module chassis 635 by heat-crimping through these holes.

[0234] During installation, in the first stage, the single-use module 634 is lowered into the multi-use module 650 while being tilted forward (as shown in Figure 3F). In this process, the projection 662 slides into the slot 660. As shown in Figure 6E, this further positions the flange 328 of the pump interface assembly 300 into the docking port 342 of the perfusion pump assembly 106, and the tapered projections 323a and 323b of the pump interface assembly 300 onto the clockwise side of the corresponding features 344a and 344b of the pump assembly bracket 346. In the second step, the disposable module 634 is rotated backward until the locking arm support of the disposable module chassis 635 engages with the spring-loaded projections 643 and 645 of the locking arm 638. The projections 643 and 645 are then rotated upward until they clear the height of the locking arm support. At this point, the spring rotates the locking arm 638 downward, allowing the locking projections 643a and 645a to be releasably locked to the locking arm support of the disposable module chassis 635. This movement rotates the curved surface 668 of the disposable module projection 662 in Figure 13B, which engages with the flat side surface 670 of the basin slot 660 in Figure 20B. The lever 639 can be used to rotate the locking arm 638 upward when releasing the disposable module 635.

[0235] As shown in Figure 6E, this motion further rotates the pump interface assembly 300 counterclockwise relative to the pump assembly 106, causing the flange 328 to slide into the slot 332 of the docking port 342, and simultaneously causing the tapered projections 323a and 323b to slide downwards toward each bracket feature 344a and 344b. As the tapered projections 323a and 323b slide downwards toward each bracket feature 344a and 344b, the inner surfaces of the bracket features 344a and 344b engage with the tapered outer surfaces of the tapered projections 323a and 323b, pulling the inner side surface 306 of the pump interface assembly 300 toward the pump drive unit 334, thereby forming a fluid-tight seal between the pump interface assembly 300 and the pump assembly 106. When the lever 639 is locked in place, the disposable module 634 is securely held within the reusable module 650.

[0236] When the disposable module 374 is connected to the reusable module 650, an electrical and optical interconnection can be formed between the front end interface circuit board 636 on the reusable module 650 and the front end circuit board 637 on the disposable module 634. This electrical and optical connection enables the reusable module 650 to supply power, control, and collect information from the disposable module 634. Figure 20A is an exemplary conceptual diagram showing various optical couplers and electromechanical connectors on the front end circuit board 637 of the disposable module 634, used to communicate with the corresponding optical couplers and electromechanical connectors on the front end interface circuit board 636 of the reusable module 650. Because this correspondence is one-to-one, the various optical couplers and electromechanical connectors are described with reference only to the front end circuit board 637, and not to the front end circuit board 650.

[0237] In an exemplary embodiment, the front end circuit board 637 receives signals from the front end interface circuit board 636 via both optical couplers and electromechanical connectors. For example, the front end circuit board 637 receives power 358 from the front end interface circuit board 636 via electromechanical connectors 712 and 714. The front end circuit board 637 then supplies power to the components of the auxiliary module 634, such as various sensors and transducers. Optionally, the front end circuit board 637 converts this power to an appropriate level before distribution. Furthermore, the front end interface circuit board 636 can supply heater drive signals 281a and 281b to the corresponding connection point 282a on the heater 246 in Figure 6E via electromechanical connectors 704 and 706. Similarly, electromechanical connectors 708 and 710 connect heater drive signals 283a and 283b to the corresponding connection point 282b on the heater 248.

[0238] According to an exemplary embodiment, the front end circuit board 637 can receive signals from temperature, pressure, liquid flow rate, and oxygenation / hematocrit sensors, amplify these signals, convert them to a digital format, and provide them to the front end interface circuit board 636 using electrical and / or optical couplers. For example, the front end circuit board 637 can provide the front end interface circuit board 636 with a temperature signal 121 from a sensor 120 on the heater plate 250 via an optical coupler 676. Similarly, the front end circuit board 637 can provide the front end interface circuit board 636 with a temperature signal 123 from a sensor 122 on the heater plate 252 via an optical coupler 678. Furthermore, the front end circuit board 637 can provide the front end interface circuit board 636 with perfusion liquid temperature signals 125 and 127 from thermistor sensors 124 via optical couplers 680 and 682, respectively. Perfusion fluid pressure signals 129, 131, and 133 can be supplied from the pressure transducers 126, 128, and 130 to the front end interface circuit board 636 via the optical couplers 688, 690, and 692. Furthermore, the front end circuit board 637 can supply perfusion fluid flow rate signals 135, 137, and 139 from the flow sensors 134, 136, and 138 to the front end interface circuit board 636 via the optical couplers 694, 696, and 698. In addition, the front end circuit board 637 can supply oxygen saturation 141 and hematocrit 145 signals from the oxygen saturation sensor 140 to the front end interface circuit board 636 via the optical couplers 700 and 702. In another implementation example, this front end circuit receives signals from an integrated blood gas analysis probe. In another implementation example, the front end board passes control signals to the fluid path throttling to easily control the real-time splitting of the perfusion fluid flow into the portal vein conduit and the hepatic artery conduit. The controller 150 uses the signals provided to the front end interface circuit board 636 along with other signals to transmit data or otherwise control the operation of the system 600.

[0239] The front end circuit board 637 has been described along with the couplers mentioned above, but more or fewer couplers can be used depending on the number of connection points required.

[0240] In some exemplary embodiments, the front end interface board 636 and front end board 637 can be bypassed by directly wired connection of one or more of the sensors described above to the main system board 718 for processing and analysis. Such embodiments may be preferable when the user wishes to reuse one or more of the sensors before disposal. In one such example, the flow sensors 134, 136, and 138 and the oxygen and hematocrit sensors 140 are electrically connected directly to the system main board 718 through the electrical coupler 611 shown in Figure 23C, thereby bypassing any connection to circuit boards 636 and 637.

[0241] Figure 20B shows the operation of an exemplary pair of electromechanical connectors of the type used for the electrical interconnection between circuit boards 636 and 637. Similarly, Figure 20C shows the operation of a pair of optical couplers of the type used for the optically connected interconnection between circuit boards 636 and 637. One advantage of using both electrical connectors and optical couplers is that they ensure the integrity of the connection even when the system 600 is transported on rough ground, such as when it is loaded onto wheels on an airport runway, transported within an airport in bad weather, or transported in an ambulance on rough roads. Power for the front end panel 637 is isolated within a DC power supply located on the front end interface board 636.

[0242] As shown in Figure 20B, an electromechanical connector such as connector 704 includes parts such as part 703 located on the front end interface circuit board 636 and parts such as part 705 located on the front end circuit board 637. Part 703 includes an enlarged head 703 mounted on a substantially linear, rigid stem 703b. The head 703 includes a substantially flat surface 708 facing outwards. Part 705 includes a substantially linear, rigid pin 705, which includes an end 705a that contacts the surface 708 and a spring-loaded end 705b. The pin 705 can maintain electrical contact with the surface 708 of the enlarged head 703a while moving axially in and out as indicated by the directional arrow 721. This feature allows the disposable module 634 to maintain electrical contact with the multi-use module 650 even when subjected to mechanical shocks associated with transport on rough ground. An advantage of the flat surface 708 is that it allows for easy cleaning of the inner surface of the reusable module 650. In this exemplary embodiment, the system 600 utilizes connectors for electrical interconnection between the disposable module 634 and the reusable module 650. An example of a connector is part number 101342 from Interconnect Devices. However, any suitable connector may be used.

[0243] Optical couplers such as optical couplers 684 and 687 on the front end circuit board 637 are used, and corresponding equivalents such as optical couplers 683 and 685 on the front end interface circuit board 636 are also included. The optical transmitter and optical receiver portions of the optical coupler can be placed on either circuit board 636 or 637.

[0244] Similar to the electromechanical connectors used, the tolerance for optical alignment between the optical transmitter and the corresponding optical receiver ensures that circuit boards 636 and 637 remain in optical communication even during transport over rough ground. In the illustrated embodiment, system 100 uses optical couplers manufactured by Osram under part numbers SFH485P and / or SFH203PFA. However, any suitable coupler can be used.

[0245] These couplers and connectors facilitate data transmission within the system 100. The front end interface circuit boards 636 and 637 transmit data about the system 600 at intervals. As shown in Figure 20C, circuit board 636 transmits a clock signal synchronized with the controller 150's clock to the front end circuit board 637. The front end circuit board 637 receives this clock signal and uses it to synchronize its system data (temperature, pressure, or other desired information) transmission with the controller 150's clock period. This data is digitized by the processor in the front end circuit board 637 according to the clock signal and a preset sequence of data types and source addresses (i.e., the type and location of the sensor providing this data). The front end interface circuit board 636 receives this data from the front end circuit board 637 and transmits this data set to the main board 618 so that the controller 150 can use it for evaluation, display, and system control. By adding an additional optical coupler between the multi-use module and the one-time use module, control data from the multi-use module, including heater control signals or clamp / flow throttling control, can be transmitted to the one-time use module.

[0246] IV. Description of Typical System Operation A. General As will be described later, the system 600 can be configured to operate in a number of modes, including perfusion circuit priming mode, organ stabilization mode, maintenance mode, cooling mode, and self-test / diagnostic mode. In each mode, the system can be configured to operate in different ways (via the controller 150). For example, as will be detailed later, when operating in different modes, characteristics such as perfusion fluid flow rate, perfusion fluid pressure, and perfusion fluid temperature may change.

[0247] In addition, some embodiments of system 600 can include a self - test mode that can perform a diagnosis. For example, system 600 can automatically test the test circuits and sensors within the disposable and multi - use modules before an organ is instrumented on this system. System 600 can also confirm that the disposable module is properly attached to the multi - use module (e.g., that all connection points are secure and functioning). In case of a malfunction, the system can notify the user and prohibit further operation of the system until the problem is resolved.

[0248] B. Temperature Monitoring and Control Generally, the temperature of the organ housed in system 600 can be controlled by circulating warm or cooled perfusion fluid internally. Thus, the temperature of the organ can be controlled using the perfusion fluid itself without using a dedicated heater / cooler within organ chamber 104.

[0249] In some embodiments of system 600, controller 150 can be configured to receive signals from one or more temperature sensors such as temperature sensors 120, 122, 124. Although these sensors are described as being disposed on or near heater 110, this is not a requirement. For example, temperature sensors that measure the temperature of the perfusion fluid can be disposed throughout system 100 such as within branch tubes 315, 313, within measurement drain 2804, and / or within reservoir 160. Additional temperature sensors can be included to measure other temperature aspects of system 600. For example, system 600 can include an ambient air temperature sensor that measures the temperature of the surrounding environment of system 600, a temperature sensor that measures the temperature of the environment within organ chamber 104, and / or a sensor that measures the surface and / or internal temperature of the housed organ.

[0250] The controller 150 uses information from various temperature sensors within the system 600 to control the temperature of the environment and / or the internal perfusion fluid. For example, in some embodiments, the controller 150 can maintain the perfusion fluid leaving the heater at a desired temperature. In some embodiments, the controller 150 can calculate the temperature difference between the inflow and outflow of the perfusion fluid to the organ. If this temperature difference is large, the controller 150 can indirectly determine the organ temperature and adjust the temperature of the perfusion fluid flowing into the organ to achieve a desired organ temperature. Furthermore, in some embodiments, the organ chamber 104 may include a heater / cooler, such as a thermoelectric cooler, to heat / cool the environment within the organ chamber 104. Such a heater / cooler can be controlled by the controller 150.

[0251] While much of this disclosure focuses on heating organs to a desired temperature, this is not intended to be limiting. In some embodiments, the system 600 may include a cooling unit (not shown) in addition to and / or instead of the heater 110. In such embodiments, this cooling unit can be used to cool the perfusion fluid and ultimately the organ itself. This may be useful, for example, in post-preservation cryogenic treatments used for the heart, lungs, kidneys, and / or liver. In some embodiments, this cooling unit may consist of a gas exchanger with a built-in water cooling function, but other configurations are also possible.

[0252] C. Blood flow monitoring and control Many organs in the human body receive a blood supply with a set of pressure and flow characteristics (e.g., kidneys, lungs). As long as these organs are maintained ex vivo within an organ management system, a single pump and a single supply line can be used to supply perfusion fluid to the organs. However, the liver differs from other organs in that it has two blood supplies, each with different pressure and flow characteristics. As mentioned above, the liver receives approximately one-third of its blood supply from the hepatic artery and approximately two-thirds from the portal vein. The hepatic artery provides the liver with a pulsatile blood flow that is relatively high pressure but low flow rate. In contrast, the portal vein provides the liver with a non-pulsatile blood flow that is relatively low pressure and non-pulsatile but high flow rate. Due to these different flow characteristics, supplying perfusion fluid to the liver ex vivo is difficult when a single pump is used. Therefore, some embodiments of the organ management system 600 include a system configured to realize two separate perfusion fluid flows in a manner that mimics the human body. In particular, the branch vessel 315 of system 100 can deliver perfusion fluid to the hepatic artery in a pulsatile, high-pressure, and low-flow manner. In particular, the branch vessel 313 of system 100 can deliver perfusion fluid to the portal vein in a non-pulsatile, low-pressure, and high-flow manner.

[0253] As described above, the pump 106 can supply a flow of perfusion fluid at a predetermined flow rate, which can be divided by the divider 105. In some embodiments, this fluid flow can be divided into hepatic artery and portal vein in a ratio between 1:2 and 1:3. In some embodiments, the divider is configured such that branch 313 uses 3 / 8-inch tubing and branch 315 uses 1 / 4-inch tubing. In some embodiments, a portal vein clamp is used to help achieve this division ratio and / or to suppress the flow obtained in the portal vein section of the circuit (e.g., branch 313) to form a higher pressure flow in the hepatic artery section of the circuit (e.g., branch 315) and a lower pressure flow in the parallel portal vein section of the circuit. In some embodiments, the user can manually adjust the portal vein clamp (e.g., flow clamp 190) to bring the hepatic artery pressure within an acceptable range and adjust the pump flow rate to achieve an acceptable hepatic artery flow rate. By combining these two adjustments (portal vein clamp and pump flow), acceptable hepatic artery flow and pressure, as well as corresponding acceptable portal vein flow and flow, can be obtained.

[0254] In some embodiments, the portal vein clamp can be implemented as a mechanism controlled by the system, such as an electromechanical or pneumatically controlled clamp. The system adjusts the pump flow rate and portal vein clamp in response to pressure and flow values ​​measured in the hepatic artery and portal vein branches to achieve acceptable pressure and flow levels in these channels. For example, in embodiments using an automated portal vein clamp, if the controller 150 detects that the flow in the portal vein branch 315 is too low, the controller 150 can increase the flow rate supplied by the pump. Similarly, if the controller 150 detects that the pressure in the hepatic artery branch 315 is too low, the controller 150 can slightly close the portal vein clamp to increase the pressure in the hepatic artery branch 315.

[0255] In some embodiments, the controller 150 can monitor the level of perfusion fluid in the system 600. If the amount of perfusion fluid is below a recommended level, the controller 150 can alert the user to this fact and prompt them to take recommended actions such as adjusting the pump flow and / or adding additional perfusion fluid to the system. In addition, if the level falls below a critical level, the controller 150 can alert the user and automatically reduce the pump flow rate to a low or minimum level.

[0256] D. Gas monitoring and control In some embodiments, system 600 can be configured to automatically control the pressure within the system by changing the flow rate of pump 106 and / or by controlling the infusion of vasodilators. For example, one of the infusion agents supplied by solution pump 631 may be a vasodilator or may contain a vasodilator. When a vasodilator is administered, the perfusion fluid pressure with respect to a given flow rate within system 100 may decrease (due to dilation of the vascular system in the liver). Therefore, for example, reducing the infusion rate of the vasodilator can result in an increase in the pressure of the perfusion fluid. The optimal balance can be achieved with the minimum amount of vasodilator required to obtain adequate liver perfusion.

[0257] System 600 can be configured to control the gas content in the perfusion fluid in a manner that mimics the human body. Accordingly, in some embodiments, System 600 includes a gas exchanger (e.g., gas exchanger 114) configured to supply O2 and / or other desired gases to the perfusion fluid. In principle, the gas exchanger operates by facilitating the flow of high-concentration gases into low-concentration gas areas. In this way, O2 in the maintenance gas (the gas supplied to the gas exchanger) diffuses to the perfusion fluid where the O2 has been depleted, and relatively high levels of CO2 in this perfusion fluid can diffuse into the maintenance gas before being discharged from the gas exchanger. The maintenance gas supplied to the gas exchanger can consist of a suitable mixture of O2, N2, and CO2, in which the concentration of O2 is relatively higher and the concentration of CO2 is lower than in the perfusion solution from a metabolically active liver. In some examples, this gas consists only of O2 and N2.

[0258] Some embodiments of the system 600 include an oxygenation sensor (e.g., sensor 140) that can be used to provide information regarding the oxygenation of the perfusion fluid. If the oxygenation level is too low, the gas rate supplied to the gas exchanger can be increased to raise the oxygen level in the perfusion fluid. Similarly, if this level is too high, the gas rate supplied to the gas exchanger can be decreased. The gas supply to the gas exchanger can be controlled manually (e.g., via operator interface module 146) and / or automatically by the user. In automated embodiments, the controller 150 can automatically increase or decrease the gas flow from the onboard gas supply source to the gas exchanger to change the oxygenation level as desired.

[0259] However, the liver can present an additional challenge in achieving an appropriate perfusion fluid gas content. Due to its unique metabolism, the liver produces CO2 to replace the O2 in the perfusion fluid. In some embodiments, measuring only the O2 level is insufficient to determine the amount of CO2 in the perfusion fluid. Therefore, in some embodiments, the system 600 can be configured to separately monitor the CO2 level in the perfusion fluid to ensure that it is maintained within an acceptable range. In these embodiments, a gas exchanger can also be used to reduce or even remove CO2 from the perfusion fluid as it passes through.

[0260] To determine the carbon dioxide level in the perfusion fluid, several embodiments of the system 600 incorporate a blood sample port, allowing the user to take a blood sample to assess the carbon dioxide level in the perfusion fluid via a third-party blood gas analyzer. Based on this analysis, the user can specify the gas flow rate to the gas exchanger to achieve an acceptable carbon dioxide level in the perfusion fluid. For example, if the carbon dioxide level is higher than acceptable, it may be necessary to increase the gas flow rate to the gas exchanger to lower the carbon dioxide level. However, in long-distance transport, it may be advantageous to minimize the gas flow to the gas exchanger to maximize the lifespan of the onboard gas supply source, which is a critical factor.

[0261] Some embodiments of System 600 may include a blood gas analysis system (not shown). In these embodiments, the blood gas analysis system may be configured to sample the perfusion fluid flowing through System 100. For example, the blood gas analysis system may be configured to sample the perfusion fluid at one or more locations in System 100, such as in branch tubes 315, 313, in measuring drain 2804, and / or in main drain 2806. By measuring the concentrations of oxygen and / or carbon dioxide in the perfusion fluid, the controller 150 can automatically increase or decrease the gas flow to the gas exchanger as needed to obtain a desired gas level in the perfusion fluid.

[0262] E. Dispensing and control of solution As described above, several embodiments of system 600 may include a solution pump configured to supply one or more solutions. In some specific embodiments, the runtime perfusion solution comprises three perfusion solutions. The first solution may include one or more high-energy components (e.g., one or more carbohydrates); one or more amino acids; and / or one or more electrolytes; and / or one or more buffers (e.g., bicarbonates). In some specific embodiments, the first solution may include TPN (Clinimix E), buffers (e.g., sodium bicarbonate and phosphates), heparin, and insulin. The second solution may include one or more vasodilators. In some specific embodiments, the vasodilator used is Flolan®. The third solution may include bile acids or bile salts (e.g., sodium taurocholate). In some embodiments, these three solutions are stored separately from each other and administered separately (e.g., using three channels of solution pump 631). In other embodiments, these three solutions are optionally all aqueous solutions that can be mixed together to form the runtime perfusion solution. In some embodiments, it is sufficient to prepare a sufficient amount of heparin (for example, enough to maintain an activated whole blood coagulation time of 400 seconds ACT).

[0263] V. Solution Exemplary solutions that can be used in the organ management system 600 according to one or more embodiments are described below. Various solutions can be used at different timings in the preservation / treatment procedure.

[0264] A. Donor lavage If the organ being removed is an abdominal organ, the surgeon performing the removal shall perform donor lavage in vivo or ex vivo to remove donor blood and / or other substances from the organ. The lavage solution used during this donor lavage may be an intracellular or extracellular solution such as the University of Wisconsin solution, modified University of Wisconsin solution, or histidine tryptophan ketoglutarate (HTK) solution.

[0265] B. Initial washing solution In some embodiments, after donor washing (whether the donor washing was performed in vivo or ex vivo) and before being placed in the storage chamber of the organ management system 600, the liver can be washed in vivo or ex vivo with an initial washing solution to remove residual blood and solvents used in donor washing. This washing solution, referred to herein as the initial washing solution, is optionally a sterile solution. In some embodiments, the main components of the initial washing solution may include an electrolyte such as a buffer, such as a plasma light, and an anti-inflammatory agent such as Solumedrol. In some embodiments, the initial washing can be used to remove fluids used during donor washing. In some embodiments, the main components of the initial washing solution may include electrolytes and buffers. Non-limiting examples of electrolytes include sodium salts, potassium, calcium, magnesium, chlorides, hydrogen phosphate, and bicarbonate. Appropriate concentrations and combinations of electrolytes can help maintain the physiological osmotic pressure of the intracellular and extracellular environments of the liver. Non-limiting examples of buffers include bicarbonate ions. The buffer in this initial washing solution has the effect of maintaining the pH value in the liver at a physiological state such as, for example, about 7.3-7.6, 7.4-7.6, or 7.4-7.5 or close to it. Preferably, after the liver has been subjected to initial washing and cooled according to one or more embodiments described herein, the excised liver can be placed in an organ management system 600 according to one or more embodiments.

[0266] C. Priming solution and additives In some embodiments, the organ management system 600 can be primed with a priming solution before the liver is placed inside the organ management system 600. This priming solution can be sterile and can be used to assess the physical integrity of the system and / or to help remove air from the system. The components of the priming solution can be similar to or the same as those of the run-time perfusion solution, which will be detailed later. This priming solution may contain certain additives to adapt the system for liver preservation. For example, the liver constantly produces clotting factors that promote blood clotting. Anticoagulants can be added to the priming solution as additives to prevent the blood (e.g., donor blood used as part of the perfusion fluid for preserving the liver in the organ management system 600) from clotting during preservation. A non-limiting example of an anticoagulant is heparin. Heparin can be administered throughout the preservation session to maintain an ACT (activated whole blood clotting time) of 400 seconds or more, although other ACT values ​​can also be used. The amount of heparin required to achieve the desired ACT can be varied depending on the liver being preserved. In some embodiments, heparin can be administered continuously or at intervals of 0, 3, and 6 hours after instrumentation in the system 600. In some embodiments, before the liver is placed in the organ management system 600, the organ management system 600 can be primed with a blood product (e.g., donor blood) or a synthetic blood product. In some embodiments, the system 600 can be primed with a priming solution and / or blood or a synthetic blood product. The system 600 can be primed with a mixture of the priming solution and blood or a synthetic blood product, or sequentially with the priming solution and blood or a synthetic blood product. In some embodiments, the organ management system 600 is primed with a perfusion fluid described herein (e.g., a perfusion fluid used to preserve organs). Alternatively or additionally, any of the following can also be used in combination with either albumin or dextran: namely, donor blood, red blood cells (RBCs), or RBCs with fresh frozen plasma added.

[0267] Table 1 lists the components used in exemplary priming solutions.

[0268] [Table 1] JPEG0007869292000002.jpg88168

[0269] As detailed with reference to Figure 29 (and will be detailed later), this exemplary priming solution can be added to the organ management system 600 via priming step 5024.

[0270] D. Perfusion solution during execution During storage of an excised liver within the organ management system 600 (for example, during transport), the liver can be perfused using a perfusion fluid to maintain its function in a physiological state or close to it. In some embodiments, this perfusion fluid includes a running perfusion solution (also called a maintenance solution) and / or a blood product such as donor blood, compatible blood from another person, or artificial blood. To supply nutrients that can maintain the liver during storage, this perfusion fluid can be perfused periodically / continuously by, for example, a solution pump 631. In some embodiments, the running perfusion solution and / or the blood product are sterile.

[0271] The compositions of the run-time perfusion solution and priming solution are described in detail below. In some embodiments, the run-time perfusion solution, with specific solutes and concentrations, is selected or formulated to allow the organ to function in a physiological or near-physiological state. For example, such states include maintaining organ function in a physiological or near-physiological state and / or maintaining the liver in a state that allows for normal cellular metabolism such as protein synthesis, glucose storage, lipid metabolism, and bile production. In some embodiments, these priming and run-time solutions can be selected to be similar to or identical to each other.

[0272] In some embodiments, the run-time perfusion solution is formed from a composition by dilution with a fluid derived from a higher concentration solution, or by concentration with a fluid derived from a lower concentration solution. In some embodiments, a suitable run-time perfusion solution includes an energy source and / or one or more stimulants that help the organ continue its normal physiological function before and during transplantation, and / or one or more amino acids selected and formulated to allow the organ to continue its cellular metabolism during perfusion. This run-time perfusion solution may include therapeutic agents detailed below. Cellular metabolism includes, for example, the execution of protein synthesis while functioning during perfusion. Some exemplary solutions are aqueous-based, while others are non-aqueous, such as organic solvent-based, ionic liquid-based, or fatty acid-based.

[0273] This runtime perfusion solution will contain one or more energy-rich components that help the liver perform its normal physiological functions. These components may include metabolizable energy-rich substances and / or components of such substances that can be used by organs, such as the liver, to synthesize energy sources during perfusion. Examples of sources of high-energy molecules include, for example, one or more carbohydrates. Examples of carbohydrates include monosaccharides, disaccharides, oligosaccharides, polysaccharides, or combinations thereof, or their precursors or metabolites. Examples of monosaccharides suitable for the solution, though not intended to be limiting, include octose; heptose; hexoses such as fructose, allose, altrose, glucose, mannose, growth, idose, galactose, and talose; pentoses such as ribose, arabinose, xylose, and lyxose; tetroses such as erythritol and threose; and trioses such as glyceraldehyde. While not intended to be limiting, examples of disaccharides suitable for this solution include (+)-maltose (4-O-(α-D-glucopyranosyl)-α-D-glucopyranose), (+)-cellobiose (4-O-(β-D-glucopyranosyl)-D-glucopyranose), (+)-lactose (4-O-(β-D-galactopyranosyl)-β-D-glucopyranose), and sucrose (2-O-(α-D-glucopyranosyl)-β-D-fructofuranose). While not intended to be limiting, examples of polysaccharides suitable for the solution include cellulose, starch, amylose, amylopectin, sulfomucosodium polysaccharides (e.g., dermatan sulfate, chondroitin sulfate, sulodoxide, mesoglycan, heparan sulfate, idosan, heparin, and heparinoids), dextrin, and glycogen. In some embodiments, monosaccharides, disaccharides, and polysaccharides of aldoses, ketoses, or combinations thereof are used. One or more isomers, including enantiomas, diastereomas, and / or tautomers of monosaccharides, disaccharides, and / or polysaccharides, including those described herein and those not described herein, can be used in the running perfusion solutions described herein.In some embodiments, one or more monosaccharides, disaccharides, and / or polysaccharides can be chemically modified, for example, by derivatization and / or protection (by protecting groups) of one or more functional groups. In some embodiments, carbohydrates such as dextrose or other forms of glucose are preferred.

[0274] Other possible energy sources include coenzyme A, pyruvate, flavin adenosine dinucleotide (FAD), thiamine pyrophosphate chloride (co-carboxylase), β-nicotinamide adenine dinucleotide (NAD), β-nicotinamide adenine dinucleotide phosphate (NADPH), and nucleotides containing phosphate derivatives of nucleosides, i.e., mono-, di-, and tri-phosphates (e.g., UTP, GTP, GDF, and UDP), coenzymes, or other biomolecules with similar cellular metabolic functions, and / or their metabolites or precursors. For example, phosphate derivatives of adenosine, guanosine, thymidine (5-Me-uridine), cytidine, and uridine, as well as other naturally occurring and chemically modified nucleotides, should be considered.

[0275] In some embodiments, one or more carbohydrates can be provided in conjunction with a phosphate source such as a nucleotide. The carbohydrates may help the organ produce ATP or other energy sources during perfusion. The phosphate source can be provided directly through ATP, ADP, AMP, or other sources. In other exemplary embodiments, phosphate can be provided through phosphates such as glycerophosphate, sodium phosphate, or other phosphate ions. Phosphate can include these forms in any ionic state, including protonated forms and forms with one or more counterions. The energy source used may depend on the type of organ being perfused (for example, adenosine may be excluded when perfusing the liver).

[0276] One of the important functions of the liver is the production of bile. In some embodiments, the run-time perfusion solution contains one or more compounds that support bile production by the liver. Non-limiting examples of such compounds include cholesterol, primary bile acids, secondary bile acids, glycine, taurine, and bile acids (bile salts) that promote bile production by the liver ex vivo, all of which can be used by the liver for bile production. In some specific embodiments, this bile salt is sodium taurocholate salt.

[0277] Due to its function as the metabolic powerhouse of the human body, the liver typically requires a constant supply of energy and oxygen. Therefore, in addition to maintaining an appropriate concentration of energy source compounds in the perfusion fluid, the organ management system 600 described herein can be configured to continuously supply oxygen to the preserved liver. In some embodiments, oxygen is supplied by diffusing an oxygen gas stream into the perfusion fluid (e.g., in a gas exchanger 114) or blood products, for example, by binding oxygen to hemoglobin in blood products, thereby dissolving or saturating oxygen in a liquid medium. In some embodiments, the perfusion fluid supplied to the liver contains 200 mmHg or more of O2 in PaO2 (artificial perfusion fluid). In some embodiments, the perfusion fluid supplied to the liver contains less than 40 mmHg of carbon dioxide in PaCO2 to promote and maintain the oxidative metabolic function of the liver. In some embodiments, the perfusion fluid contains less than 30 mmHg of carbon dioxide in PaCO2 to maintain a pH value within the liver for maintaining the biological function of the liver.

[0278] The run-time perfusion solutions described herein may contain one or more amino acids, preferably multiple amino acids, to assist in protein synthesis by organ cells. Suitable amino acids include, for example, any natural amino acids. These amino acids may be in various enantiomatous or diastereomatous forms. For example, the solution may utilize either D-type or L-type amino acids, or a combination thereof, and the solution may be a more enantiorich solution of D-type or L-type isomers or a racemic solution. Suitable amino acids may be unnatural or modified amino acids, such as citrulline, ornithine, homocysteine, homoserine, β-amino acids such as β-alanine, amino-caproic acid, or combinations thereof.

[0279] Some exemplary perfusion solutions contain some, but not all, of the natural amino acids. In some embodiments, the run-time perfusion solution contains essential amino acids. For example, the run-time perfusion solution may be prepared using one or more or all of the following amino acids: glycine, alanine, arginine, aspartic acid, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and lysine acetate.

[0280] In some embodiments, non-essential and / or conditionally essential amino acids are not included in the run-time perfusion solution. For example, in some embodiments, asparagine, glutamine, and / or cysteine ​​are not included. In other embodiments, the solution contains one or more non-essential and / or conditionally essential amino acids. Thus, in some embodiments, asparagine, glutamine, and / or cysteine ​​are included.

[0281] This runtime perfusion solution may further contain electrolytes, particularly calcium ions, to promote enzymatic reactions and / or maintain osmotic pressure within the liver. Other electrolytes, such as sodium, potassium, chlorides, sulfates, magnesium, and other inorganic and organic charged chemical species, or combinations thereof, may also be used. It should be noted that, where charge and stability permit, any of the components described herein may be provided in ionic, protonated, or aprotonated form, as salts or free bases, or as ionic or covalent substituents, in combination with other components that can be hydrolyzed to make them available in aqueous solution, as appropriate.

[0282] In some embodiments, this runtime perfusion solution includes buffering components. For example, suitable buffering systems include 2-morpholinoethanesulfonic acid monohydrate (MES), cacodylic acid, H2CO3 / NaHCO3(pK a1 ), citric acid (pK a3 ), bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)-methane (Bis-Tris), N-carbamoylmethylimidinoacetic acid (ADA), 3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris propane) (pK a1 ), piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES), N-(2-acetamide)-2-aminoethanesulfonic acid (ACES), imidazole, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 3-(N-morpholino)propanesulfonic acid (MOPS), NaH2PO4 / Na2HPO4(pK a2), N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES), N-(2-hydroxyethyl)-piperazine-N'-2-ethanesulfonic acid (HEPES), N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid) (HEPPSO), triethanolamine, N-[tris(hydroxymethyl)methyl]glycine (Tricine), trishydroxymethylaminoethane (Tris), glycinamide, N,N-bis(2-hydroxyethyl)glycine (Bicin), glycylglycine (pK a2 These include ), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), or a combination thereof. In some embodiments, the solution comprises sodium bicarbonate, potassium phosphate, or a TRIS buffer.

[0283] This run-time perfusion solution may also contain other components that help maintain the liver and protect it from ischemia, reperfusion injury, and other adverse effects during perfusion. In some exemplary embodiments, these components may include hormones (e.g., insulin), vitamins (e.g., adult multivitamins, e.g., multivitamin MVI-adult), and / or steroids (e.g., dexamethasone and solvent).

[0284] In another context, this running perfusion solution can be supplied to blood products to support the liver during storage. Examples of suitable blood products include whole blood and / or one or more of its components, such as serum, plasma, albumin, and red blood cells. In embodiments where whole blood is used, the blood can be filtered to remove leukocytes and platelets, thereby removing fever-causing factors, antibodies, and / or other substances that could cause inflammation in organs. Thus, in some embodiments, the perfusion solution utilizes whole blood from which at least partially leukocytes have been removed and / or whole blood from which at least partially platelets have been removed.

[0285] Blood products and perfusion solutions, including the running perfusion solution, are supplied at physiological temperature and maintained at a temperature near physiological temperature during perfusion and recirculation. "Physiological temperature" as used here refers to temperatures between approximately 25°C and 37°C, for example, between approximately 30°C and 37°C, or between approximately 34°C and 37°C.

[0286] Other components or additives, including adenosine, magnesium, phosphate, calcium, and / or sources thereof, may be added to this run-time perfusion solution. In some embodiments, additional components are provided to help the liver perform its metabolism during perfusion. These components may include, for example, various forms of adenosine that can be used in ATP synthesis to maintain endothelial function and / or mitigate ischemia and / or reperfusion injury. Components may further include other natural and chemically modified nucleosides, including guanosine, thymidine (5-Me-uridine), cytidine, and uridine, and their nucleotides. In some embodiments, a phosphate source is provided in addition to the magnesium ion source, and in some embodiments, adenosine is provided to further enhance ATP synthesis in the cells of the perfused liver. Further amino acids may also be added to assist protein synthesis by liver cells. The amino acids in question may include, for example, any of the natural amino acids or those described above.

[0287] In some embodiments, the runtime perfusion solution includes one or more vasodilators (for example, vasodilators can be used to increase or decrease intravascular pressure by increasing or decreasing vascular tone). In some specific embodiments, the vasodilator used is Flolan®, but other vasodilators can also be used.

[0288] Table 2 lists the components that can be used in the run-time perfusion solution to preserve the liver as described herein. This run-time perfusion solution may contain one or more of the components listed in Table 2.

[0289] [Table 2] JPEG0007869292000004.jpg254146JPEG0007869292000005.jpg254148JPEG0007869292000006.jpg254141JPEG0007869292000007.jpg184170

[0290] Table 3 lists the components that can be used in exemplary run-time perfusion solutions. The amounts listed in Table 3 are suitable amounts for other components in the table and can be proportionally increased or decreased to provide a sufficient amount of composition. In some embodiments, the amounts listed in Table 3 can be changed by ±10%, and they can still be used in the solutions described herein.

[0291] [Table 3] JPEG0007869292000009.jpg254143JPEG0007869292000010.jpg224170

[0292] In the exemplary embodiments of the runtime perfusion solution, the components listed in Table 3 can be combined in the relative amounts given therein per approximately 1 L of aqueous fluid to form the runtime perfusion solution. In some embodiments, the amount of aqueous fluid in the runtime perfusion solution can be changed by ± approximately 10%. The pH of the runtime perfusion solution can be adjusted between approximately 7.0 and 8.0, for example, between approximately 7.3 and 7.6. The runtime perfusion solution may be sterilized, for example, by autoclaving, to increase its purity.

[0293] Table 4 lists another exemplary runtime perfusion solution, which contains tissue culture media mixed with an aqueous fluid and has the components revealed in Table 4, and can be used in the perfusion solution as described herein. The amounts of the components listed in Table 4 are relative to each other and to the amount of aqueous solution used. In some embodiments, about 500 mL of aqueous fluid is used. In some embodiments, the amount of aqueous solution can be changed by ± about 10%. The amounts of components and aqueous solution can be proportionally increased or decreased as appropriate for use. The pH of the perfusion solution in this embodiment can be adjusted to about 7.0 to about 8.0, for example, about 7.3 to about 7.6.

[0294] [Table 4] JPEG0007869292000012.jpg254130

[0295] Since amino acids are the building blocks of proteins, the unique characteristics of each amino acid contribute to several important properties of the protein, such as providing structure or catalyzing biochemical reactions. The selection and concentration of amino acids provided in the running perfusion solution contribute to supporting normal physiological functions, including, in addition to providing protein structure, sugar metabolism for energy supply or storage, regulation of protein metabolism, mineral transport, nucleic acid (DNA and RNA) synthesis, blood glucose regulation, and support for electroactivity. Furthermore, by using the specific amino acid concentrations present in this running perfusion solution, the pH of the running perfusion solution can be predictably stabilized.

[0296] In some embodiments, an anticoagulant can be added as an additive to the run-time perfusion solution to prevent the blood used as part of the perfusion fluid for preserving the liver in the organ management system 600 from clotting during preservation. A non-limiting example of an anticoagulant is heparin. In some embodiments, the amount of heparin may be sufficient to prevent clotting for 500–600 seconds, but other durations are also possible.

[0297] In some embodiments, the run-time perfusion solution contains several amino acids. In some embodiments, the run-time perfusion solution contains electrolytes such as calcium and magnesium.

[0298] In some embodiments, the run-time perfusion solution contains one or more amino acids and one or more carbohydrates, such as glucose or dextrose. Additives, such as those described herein, may also be administered to the run-time perfusion solution immediately before infusion into the liver perfusion system. For example, additional additives that may be included with this solution or added by the user include hormones and steroids such as dexamethasone and insulin, and adult multivitamins, such as MVI-Adult for infusion. Additional small and macromolecules, including therapeutic agents and / or components typically found in blood or plasma, such as albumin, may be included in the run-time perfusion solution or added by the user at the time of use.

[0299] In some embodiments, the therapeutic agent can be added either before or after liver perfusion. This therapeutic agent may also be added directly to the system before or during organ perfusion, independently of the running perfusion solution.

[0300] Referring further to Table 3 or 4, some components used in this exemplary run-time perfusion solution are small organic molecules or macrobiotic molecules that may decompose or denature and become inactive after sterilization. Therefore, these components can be prepared separately from the remaining components of the run-time perfusion solution. This separate preparation involves the step of purifying each component separately by known techniques. The remaining components of the run-time perfusion solution are sterilized, for example, by autoclaving, and then combined with the biological components.

[0301] Table 5 lists several biological components that can be separately purified and, after sterilization, added to the solutions described herein (runtime perfusion solution and / or priming solution) according to this two-step process. These additional or auxiliary components can be added individually, in various combinations, as a single composition, or as a compounded solution to the runtime perfusion solution, priming solution, or a combination thereof. For example, in some embodiments, insulin and MVI-Adult listed in Table 5 are added to the runtime perfusion solution. In another example, Solumedrol and sodium bicarbonate listed in Table 5 are added to the priming solution. Further additional components can be compounded in combination or as a set and added to the solution before being added to the runtime perfusion solution and / or priming solution. In some embodiments, additional components are added directly to the perfusion solution. The amounts of the components listed in Table 5 are relative to each other, and / or to the amounts of one or more components listed in Tables 1-4, and to the amount of aqueous solution used when preparing the run-time perfusion solution and / or priming solution. These amounts can be proportionally increased or decreased as appropriate to the required solution volume.

[0302] [Table 5] JPEG0007869292000014.jpg62170

[0303] In one embodiment, a composition for use in a runtime perfusion solution is provided, comprising one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids. This composition may also include other substances, such as those used in the solution described herein.

[0304] Another embodiment provides a system for perfusing the liver, which comprises the liver and a substantially cell-free composition comprising one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids. This substantially cell-free composition may include systems substantially free of cellular material; in particular, systems not derived from cells. For example, a substantially cell-free composition may include compositions and solutions prepared from non-cellular sources.

[0305] In another context, this run-time perfusion solution and / or priming solution can be provided in the form of a kit containing one or more organ maintenance solutions. An exemplary run-time perfusion solution may contain the components described above in one or more solutions for use with a liver perfusion solution. In some embodiments, this run-time perfusion solution may contain a number of solutions, which provide this run-time perfusion solution in various combinations. Alternatively, the kit may contain dry components that can be regenerated in fluid to form one or more run-time perfusion solutions or priming solutions. The kit may further contain components derived from this run-time perfusion solution or priming solution as one or more concentrated solutions, in which case dilution of these concentrated solutions provides the preservative, nutrient, and / or supplemental solutions as described herein. The kit may further include a priming solution.

[0306] In some embodiments, the kit is provided as a single package containing one or more solutions (or components necessary to prepare one or more solutions by mixing with a suitable fluid), instructions for sterilization, fluid flow and temperature control during perfusion, and use, as well as other information necessary or appropriate for applying the kit to organ perfusion. In some embodiments, the kit contains only a single run-time perfusion solution (or a set of dry components to be used in the solution after mixing with a suitable fluid), and is provided together with other information or substances necessary or useful for operating this run-time perfusion solution or priming solution.

[0307] In some embodiments, the runtime perfusion solution is a single solution. In some embodiments, the runtime perfusion solution may include one main runtime perfusion solution and one or more nutrient supplement solutions. The nutrient supplement solution may include any compound or biological component suitable for the runtime perfusion described above. For example, the nutrient supplement solution may include one or more components shown in Tables 1-5 above. Furthermore, Table 6 lists components used in exemplary nutrient supplement solutions. In some embodiments, the nutrient solution further includes sodium glycerol phosphate. The amounts of components in Table 6 are relative to the amount of aqueous solvent used in the solution (approximately 500 mL), but may be increased or decreased proportionally as appropriate. In some embodiments, the amount of aqueous solvent is varied by approximately ±10%. In these embodiments, when the main runtime solution and one or more nutrient solutions are used, these solutions can be connected separately to and controlled separately in the circulatory system of the organ management system 600. Therefore, if it is necessary to adjust one or more components in any nutrient solution, the operator may remake the nutrient solution with respect to these components at different concentrations, or adjust only the flow rate and / or pressure of the nutrient solution without affecting the flow rate and / or pressure of the main running perfusion solution and other nutrient solutions.

[0308] [Table 6]

[0309] In one embodiment, the run-time perfusion solution and the priming solution have the same composition, which is described in any one or a combination thereof in Tables 1-6.

[0310] In some embodiments, the perfusion solution comprises 1200-1500 ml of pRBC, 400 ml of 25% albumin, 700 ml of plasma light, antibiotics (Gram-positive and Gram-negative) 1 g of cefazolin (or equivalent antibiotic) and 100 mg of cypro (or equivalent antibiotic), 500 mg of solu-medrol (or equivalent anti-inflammatory agent), 50 mmol of Hco3, multivitamins, and 10,000 units of heparin administered at 3 and 6 hours PT.

[0311] In some specific embodiments, the perfusion solution comprises an RBC pack containing liver donor blood or a red blood cell concentrate (RBC) pack or fresh frozen plasma, and a runtime perfusion solution containing one or more components selected from the group consisting of human albumin or dextran.

[0312] E. Final washing solution After a suitable recipient for liver transplantation has been identified and before the liver is removed from the organ management system 600, the liver may undergo another washing process with a washing solution. This washing solution has a similar function to the initial washing solution, which is to remove residual blood and stabilize the liver. This washing solution is referred to herein as the final washing solution. In some embodiments, this final washing solution comprises a composition similar to or identical to the initial washing solution described above. The main components of the final washing solution may include electrolytes (e.g., plasma light) and buffers as described herein. In some embodiments, one or more commercially available preservative solutions used in cryogenic organ transplantation are used as the final washing solution. After the liver has been final washed and cooled according to one or more embodiments described herein, the liver may be removed from the organ management system 600 for transplantation to the recipient.

[0313] VI. Method The method for using the organ management system 600 disclosed herein is described in detail below. Figure 29 is a flowchart 5000 illustrating an exemplary and non-exclusive method for extracting a donor liver and inserting it into the system 600 described herein via a cannula. However, the process 5000 shown in Figure 29 is for illustrative purposes only and is modifiable. For example, the steps described herein can be modified, changed, rearranged, and / or omitted.

[0314] A. Organ removal As shown in Figure 29, the process of obtaining and preparing a liver for cannula insertion and transport begins with providing a suitable liver donor (step 5004). The system 600 can then be transported to the donor location, and the process of receiving and preparing the donor liver for cannula insertion and storage can proceed via two routes 5006 and 5008. Route 5006 mainly includes the step of preparing the donor liver for storage, while route 5008 mainly includes the step of transporting this liver to the recipient location via the organ management system 600 after the system has been prepared to receive and store the donor liver.

[0315] Referring to Figure 29, the first route 5006 includes the steps of phlebotomy (step 5010), explantation of the liver (step 5014), washing of the liver with an initial washing solution (step 5016), and preparation and cooling of the liver for the system (step 5018). Specifically, in phlebotomy step 5010, the donor's blood is partially and / or completely removed and may be set aside for use as a blood product in the perfusion fluid for liver perfusion during storage in the system. This step is performed by inserting a catheter into either an artery or vein of the donor, so that the donor's blood can flow out of the donor and be collected in a blood collection bag. The donor's blood is allowed to flow out until the required amount of blood, typically 1.0–2.5 liters, is collected, at which point the catheter is removed. The blood extracted by phlebotomy is then optionally filtered and added to the system's fluid reservoir as a preparation step for use in the system. Alternatively, blood can be phlebed from a donor and leukocytes and platelets filtered in a single step using a device with a filter integrated into the cannula and blood collection bag. An example of such a filter is the Pall BC2B filter. Alternatively, blood products can be used in the perfusion fluid instead of donor blood.

[0316] After bloodletting from the donor, the donor liver can be removed (step 5014). Any standard hepatectomy method known in the art of this invention can be used. During hepatectomy, the hepatic vessels, including the hepatic artery, portal vein, inferior vena cava (IVC), and bile ducts, are properly prepared and cut, leaving sufficient length for cannula insertion (e.g., standard techniques suitable for human or animal transplantation). In some embodiments, the gallbladder is removed during hepatectomy, and care is taken to preserve the common bile duct to maintain a stable bile flow during liver preservation. The liver is often washed (e.g., donor wash) or placed in saline after removal in a hospital setting. In step 5016, the removed liver can then be washed with an initial washing solution to remove residual blood and / or with a donor washing solution to improve liver stability. Exemplary compositions of this initial washing solution are detailed above.

[0317] After the liver has been removed, and before being placed in the organ management system 600, its metabolic function can be reduced or stopped by cooling (step 5018) to avoid damage to the liver that may occur during transport or when the liver is placed in the organ management system 600. In some embodiments, the liver can be cooled to a temperature of approximately 4°C-10°C, 5°C-9°C, 5°C-8°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C, or any range defined by the values ​​described herein. The liver can be cooled by ice or refrigeration. Other temperatures below 4°C and above 10°C are also possible. Alternatively, an initial washing solution can be used to first cool the liver and then perfuse it to cool it. Thus, in these alternative embodiments, steps 5016 and 5018 can be performed simultaneously. Once the liver is prepared and cooled to an appropriate temperature, it is ready for placement in the organ management system 600.

[0318] Continuing to refer to Figure 29, during liver preparation via route 5006, as soon as the liver is prepared and cooled, the system is prepared through the stages of route 5008, allowing it to be primed and ready to accommodate the liver for cannula insertion and storage. By rapidly transferring the liver from the donor to this system and subsequently perfusing the liver with perfusion fluid, medical operators can minimize the amount of time the liver is depleted of oxygen and other nutrients, thereby reducing ischemia and other adverse effects that can occur with current organ management techniques. In some embodiments, the time between the injection of the initial lavage solution into the liver and the start of perfusion fluid flow through the organ management system 600 is less than approximately 15 minutes. In other exemplary embodiments, this time is less than approximately 1 / 2 hour, less than approximately 1 hour, less than approximately 2 hours, or even less than approximately 3 hours. Similarly, the time between transplanting the liver into the organ management system 600 and bringing the liver to a temperature close to its physiological temperature (e.g., approximately 34°C to 37°C) can be a rapid time to reduce ischemia within the liver tissue. In some exemplary embodiments, this time is less than approximately 5 minutes, but in other applications, it may be less than approximately 1 / 2 hour, less than approximately 1 hour, less than approximately 2 hours, or even less than approximately 3 hours. In other words, once the cooled liver is first placed in the organ management system 600, the liver temperature can be gradually raised to the desired temperature over a predetermined amount of time, reducing the potential damage that may occur due to abrupt temperature changes.

[0319] As shown in Figure 29, the system is prepared via route 5008 through a series of steps, which include preparing a disposable module (step 5022), priming the system with a priming solution (step 5024), filtering blood from a donor and adding it to the system, such as the reservoir (step 5012), optionally priming the system with blood and / or perfusion fluid, and connecting the liver to the system (step 5020). Specifically, step 5022 of preparing a disposable module includes assembling a disposable module as described herein (e.g., disposable module 634). After assembling this disposable module, or after providing it in a suitable assembly, it is inserted and connected to a multi-use module (e.g., multi-use module 650) via the process described above.

[0320] In particular, in step 5024, the liver management system 600 is first primed with a priming solution, the composition of which has already been described in detail. In some embodiments, to assist priming, the system may be equipped with organ bypass conduits installed within the organ chamber assembly. For example, in some specific embodiments, this bypass conduit includes three sections installed at the hepatic artery cannula insertion interface, the portal vein cannula insertion interface, and the inferior vena cava (IVC) cannula insertion interface. By using bypass conduits installed / cannula-inserted in the liver chamber assembly, the operator can circulate perfusion fluid through all the pathways used during actual operation. This allows the system to be thoroughly inspected and the liver primed before cannula insertion in position.

[0321] In step 5012, blood from the donor can be filtered and added to the system, for example, in a reservoir 160. This filtration process can reduce inflammatory effects by completely or partially removing leukocytes and platelets. In addition, the system can be optionally primed with donor blood as described above and / or mixed with one or more priming solutions or run-time perfusion solutions to further prime the system as described above. Furthermore, this blood and run-time perfusion solution can be mixed to form a perfusion fluid that will later be used for liver infusion and preservation. In step 5026, with the bypass conduit (described above) in place, the system can be further primed with blood and / or perfusion fluid by operating a pump to pump blood and / or perfusion fluid into the system. While the perfusion fluid circulates through the system in priming step 5026, it is optionally heated to a desired temperature (e.g., normal temperature) as it passes through the system's heater assembly. Therefore, before inserting a cannula into the excised liver, the system can be primed by circulating a priming solution, phlebotomized donor blood, and / or a mixture thereof (e.g., perfusion fluid) through the system, and then heating, oxygenating, and / or filtering it. Furthermore, nutrients, preservatives, and / or other therapeutic agents can also be provided during priming by adding these components to the priming solution. During priming, various parameters can be initialized and calibrated through the operator interface. Once the system is primed and functioning properly, the pump flow can be reduced or removed from the cycle, the bypass conduit can be removed from the organ chamber assembly, and a cannula can be inserted from the liver into this organ chamber assembly.

[0322] 1. Insertion of the cannula In step 5020, the liver can be cannulated and placed on the organ management system 600 while it is being cooled as described above. During liver preservation, perfusion fluid flows into the liver via the hepatic artery and portal vein and out of the liver via the inferior vena cava (IVC). Therefore, to ensure proper perfusion through the liver (as described above), the hepatic artery, inferior vena cava (IVC), and portal vein can each be cannulated and connected to the corresponding pathways of the liver management system 600. In some embodiments, the IVC is not cannulated and is left to drain freely. The bile duct can also be cannulated and connected to a reservoir to collect bile produced by the liver (e.g., bile bag 187).

[0323] The system 600 described herein can be designed to conform to the anatomical structure of the human hepatic artery. In the vast majority of patients, the hepatic artery is the sole main artery of the liver, so the organ management system 600 allows for connection to the hepatic artery with a single-port cannula. However, in certain cases (i.e., about 10-20% of the patient population where genetic differences exist), liver donors have accessory hepatic arteries in addition to the main hepatic artery. Therefore, in some embodiments, the liver management system 600 can be provided with a dual-cannula configuration (e.g., cannula 2642) so that cannulas are inserted into both the main and accessory hepatic arteries and connected to the same perfusion pathway. In some specific embodiments, this dual cannula is Y-shaped. Other suitable shapes or designs of the dual cannula should also be considered.

[0324] In some embodiments, the cannula can be designed linearly to reduce unnecessary flow pressure drops along the cannula flow path. In other embodiments, the cannula can be designed curved or angled as required by the shape, size, or anatomical structure of other components of the organ management system 600. In some specific embodiments, the cannula is designed to have an appropriate shape, such as linear, angled, or a combination thereof, so that the overall flow pressure within the cannula is maintained at a desired level that mimics a physiological state.

[0325] 2. Instrumentation The liver can then be instrumented in the organ management system 600, more specifically within the organ chamber 104 (stage 5020). Care should be taken to avoid excessive movement of the liver during instrumentation to reduce damage to the liver. As already detailed, the liver chamber can be specifically designed to maintain the liver in a stable position that reduces its movement.

[0326] B. Storage / Transportation 1. Controlled early perfusion and rewarming In some embodiments, once the liver is instrumented in the organ management system 600 with the blood vessels properly cannulated, the liver is subjected to pre-perfusion and / or rewarming treatment to return it to normal temperature (34-37°C) (step 5021). In some embodiments, the organ chamber includes a heating circuit for gradually warming the pre-cooled liver to normal temperature over a predetermined period of time. In other embodiments, the initial perfusion fluid (for pre-perfusion) can heat the liver to near or up to normal temperature (34-37°C) to perfuse and warm the liver. As described herein, the liver stored in the organ management system 600 can be maintained in a state close to a physiological state, including normal temperature, and the normal biological function of the liver is maintained.

[0327] After the liver is instrumented in this system and warmed to a normal temperature, the pumps in the organ management system 600 (e.g., pump 106) can be adjusted to perfuse the liver, for example, into the hepatic artery and portal vein. The perfusion fluid exiting the IVC (or hepatic vein depending on the method of hepatectomy) can be collected and subjected to various treatments, including reoxygenation and carbon dioxide removal. Various nutrients can be added to the used perfusion fluid to increase the nutrient concentration to the required level for recirculation.

[0328] In some embodiments, during hepatic perfusion on the organ management system 600, the inflow pressures in the hepatic artery and portal vein are carefully controlled to ensure adequate nutrient delivery to the liver and maintain its function. In some embodiments, the flow pressure in the hepatic artery may be, for example, 50–120 mmHg, and the flow pressure in the portal vein may be, for example, 5–15 mmHg, but pressures outside these ranges may be, for example, 1, 2, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120 mmHg or any other range defined by the values ​​shown herein. In some embodiments, the flow rates in the hepatic artery and portal vein can be maintained within ranges defined by approximately 0.25–1.0 L / min or higher, and approximately 0.75–2.0 L / min or higher, or any other range defined by the values ​​shown herein. In some embodiments, the flow rates in the hepatic artery and portal vein can be maintained at approximately 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.10, 1.20, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.1, 2.2, 2.3, 2.4, 2.5 L / min, or within any range defined by the values ​​shown herein.

[0329] In some embodiments, the organ management system 600 and the fluid flow, such as flow rate and / or flow pressure in the hepatic artery and portal vein, can be controlled chemically and / or mechanically. Chemical or mechanical control of the flow can be achieved automatically or manually.

[0330] 2. Automatic / Manual Control The mechanical control of fluid flow in the organ management system 600, hepatic artery, and portal vein will be described first. In some embodiments, the flow pressure or flow rate in the flow channels of the organ management system 600 can be measured by pressure sensors or flow sensors incorporated in the flow channels or at other locations in the system. Similarly, pressure or flow sensors can be located in cannulas for the hepatic artery and / or portal vein or in connectors connecting said cannulas to these vessels. These pressure or flow sensors can provide an operator with readings regarding the flow in the flow channels and / or in the hepatic artery and / or portal vein. Other pressure monitoring methods or techniques known in the art of the present invention have also been considered. If the pressure or flow rate reading deviates from a desired value, the operator can manually adjust the flow pump to increase or decrease the pumping pressure and / or flow rate of the perfusion fluid. Alternatively, the organ management system 600 may include a flow control module with programmable desired values ​​for flow rate and / or flow pressure, which automatically adjusts the pumping pressure of the perfusion fluid, thereby adjusting the flow rate if the flow pressure and / or flow rate deviate from a desired value. Manual and / or automatic control will be described in more detail later.

[0331] 3. Chemical control In other embodiments, the organ management system 600 and the pressure and / or fluid flow within the hepatic artery and portal vein can be chemically controlled. In some specific embodiments, this pressure can be controlled or increased using one or more vasodilators (for example, the pressure within the vessel can be increased or decreased by increasing or decreasing vasotonicity using vasodilators). Vasodilation refers to the dilation of blood vessels by the relaxation of smooth muscle cells within the vessel wall. When blood vessels dilate, the flow of perfusion fluid increases due to a decrease in vascular resistance. The fluid flow within the hepatic artery and / or portal vein can be increased by dilating the hepatic artery and / or portal vein using any vasodilator known in the art of the present invention. In some specific embodiments, the vasodilator used is Flolan®. In particular, when insufficient fluid flow is indicated by low flow pressure or flow rate and / or by any liver viability assessment technique detailed later, the operator can manually add a vasodilator to the system's flow module or to the perfusion fluid to increase the fluid flow rate. Alternatively, the organ management system 600 may include a flow control module that automatically adds one or more vasodilators to the flow path or perfusion fluid to increase the flow rate. The amount of vasodilator supplied may be, for example, in the range of 1-100 micrograms / hour, or more specifically, in the range of 1-5 micrograms / hour. These ranges are for illustrative purposes only, and any range within 0-100 micrograms per hour is usable.

[0332] Several of the embodiments described above can be adapted for use in combination with a liver stored in System 600. For example, in this embodiment, closed-loop control of hepatic artery pressure (HAP) is possible using an algorithm. The algorithm used may be a proportional-integral-derivative (PID controller). The PID controller can calculate how much the HAP deviates from a desired setpoint and attempt to minimize this error by increasing or decreasing the flow rate of a vasodilator (e.g., Flolan®).

[0333] Therefore, in some embodiments, the controller 150 (or other part of the system) can calculate this error (e.g., how far HAP is from the user setpoint) and adjust the flow rate of the vasodilator to make this error zero. In embodiments where this algorithm is executed once per second, these adjustments may be very small. Small and frequent adjustments can help stabilize the control by ensuring that noise within the system does not lead to large changes in the flow rate of the vasodilator. The algorithm can perform an attempt to bring HAP to the user setpoint. This means that when HAP is above the setpoint, the algorithm can increase the flow rate of the vasodilator solution until HAP reaches the user setpoint. When HAP is below the user setpoint, the algorithm can decrease the flow rate of the vasodilator solution until HAP reaches the user setpoint.

[0334] In some embodiments, this PID control algorithm does not reduce the flow rate of the vasodilator until it falls below a setpoint. This can lead to an undershoot of the target pressure. To compensate for this, some embodiments allow the use of a virtual setpoint that is +3 mmHg (or other value) above the user setpoint. This may be user-definable or hard-programmable. When HAP is at least 7 mmHg above the user setpoint, the software can enable the user setpoint and attempt to control HAP up to +3 mmHg above the user setpoint. This allows for a certain undershoot of the virtual setpoint. Once HAP stabilizes at the virtual setpoint, the software can control HAP down to the user setpoint. This approach can help "capture" HAP when it drops without causing a large undershoot.

[0335] Referring to Figure 28, a graph relating to the above is shown for elevated aortic pressure in the cardiac system. Figure 28 shows the example graph 9500. This graph shows that the AOP (e.g., 9505) decreases to a virtual setpoint (9510), undershoots this virtual setpoint, and then gradually decreases to a user setpoint (50 mmHg).

[0336] In some embodiments, HAP is controlled using drugs, so it can be advantageous to ensure that the system does not supply excessive amounts of vasodilators to the liver when unnecessary. To achieve this, the system can analyze how far HAP is from a setpoint, and when HAP is above the setpoint, the system (e.g., solution pump 631) can add vasodilators at a standard rate. If HAP is below the setpoint, the system 600 can reduce it at four times the flow rate at which vasodilators would be added. This helps the system keep HAP slightly above the setpoint in the "active management" range (e.g., about +0.5 to +1 mmHg), while minimizing undershoot and helping to reduce the vasodilator rate more quickly.

[0337] Although the above description focuses on the liver, the same technique can be adapted for use in the heart by replacing HAP with AOP.

[0338] 4. Grading In steps 5028 and 5030, the operator can assess liver function to determine the viability of the liver for transplantation (current or possible future viability at that time). Exemplarily, step 5028 includes assessment of liver function using any of the assessment techniques detailed later. For example, the operator can monitor the fluid flow, pressure, and temperature of the system while inserting a cannula into the liver. The operator can also monitor one or more liver function biomarkers to assess the state of the liver. During assessment step 5030, based on the data obtained during examination 5028 and other information, the operator can determine whether and how system characteristics (e.g., fluid flow, pressure, nutrient concentration, oxygen concentration, and temperature) should be adjusted, and further, whether additional therapeutic modes (e.g., surgery, medication, as detailed later) should be administered to the liver. The operator can make any such adjustments in step 5032, and then repeat steps 5028 and 5030 to re-examine and re-evaluate the liver and the system. In some embodiments, the operator may also choose to perform surgical, therapeutic, or other procedures on the liver during (or at any other time) the adjustment step 5032 (as will be detailed later). For example, the operator may perform assessments of liver function, such as performing ultrasound or other imaging tests on the liver, measuring arterial and venous blood gas levels, and performing other assessment tests.

[0339] Therefore, after or during the preservation of the liver in this system, operators can perform surgery on the liver or administer therapeutic or other procedures such as immunosuppressive therapy, chemotherapy, genetic testing and treatment, or radiotherapy. Because this system allows the liver to be perfused at near physiological temperature, fluid flow rate, and oxygen saturation levels, the liver can be maintained for extended periods (e.g., at least 3 days, at least 1 week, at least 3 weeks, or at least 3 months) and repeated evaluation and treatment are possible.

[0340] In some embodiments, the system allows a medical operator to evaluate the liver for suitability to an intended recipient by finding a suitable recipient (step 5034). For example, while the liver is cannulated into the system, the operator can perform human leukocyte antigen (HLA) matching tests on the liver. Such tests may require 12 hours or more and are performed to ensure the suitability of the liver to the intended recipient. Liver preservation using the system described herein allows for preservation times exceeding the time required to complete HLA matching, potentially improving post-transplant outcomes. In the example of HLA matching tests, the HLA test can be performed on the liver while the perfusion solution is being pumped into it. Any other matching tests known in the art of the invention should also be considered.

[0341] In the exemplary embodiment, steps 5028 (examination), 5030 (evaluation), and 5032 (adjustment) can be performed on a system operating in normal flow mode. In normal flow mode, an operator can examine liver function under normal physiological blood flow conditions or similar conditions. Based on evaluation 5030, the system settings can be adjusted in step 5032 if necessary, and the flow, heating, and / or other characteristics can be modified to stabilize the liver in preparation for transport to the recipient location in step 5036. In step 5036, the system can be transported to the recipient location with the preserved liver.

[0342] C. Preparation for transplantation 1. Final wash / liver cooling In some embodiments, the liver may be washed with a final washing solution to remove, for example, residual blood and / or run-time perfusion solution before being removed from the system 600 and / or transplanted into the recipient. The composition of this final washing solution is described in detail above.

[0343] In some embodiments, before removing the liver from the organ management system 600, the liver can be cooled again to a temperature of approximately 4°C-10°C, 5°C-9°C, 5°C-8°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C, or any range defined by the values ​​described herein. The liver can be cooled by contact with ice or by refrigeration of the liver storage chamber. In some embodiments, the system 600 may include a cooling unit configured to directly cool the liver and / or cool the fluid circulating within the system 100. The liver can be cooled by first cooling the final washing solution and then using it to wash the liver. Thus, in these embodiments, the liver can undergo final washing and cooling simultaneously. Once the liver is prepared and cooled to an appropriate temperature, it can be ready for transplantation into a suitable recipient.

[0344] For example, in some embodiments, the liver can be cooled and washed while it is in the system 600. The user can connect one 1-liter bag containing cooled washing solution to the hepatic artery washing port (e.g., 4301), but keep the port closed. The user can connect two 1-liter bags containing cooled washing solution to the portal vein washing ports (e.g., 4302), but keep the ports closed. The user connects the washing collection bag to the perfusion module to the perfusion fluid collection port located immediately after the pump extendable chamber of the perfusion module (e.g., port 4309). The user can then use standard surgical forceps against the perfusion module tubing immediately before the split between the hepatic artery and portal vein, simultaneously with stopping the circulation pump 106. The hepatic artery and portal vein washing ports can be opened to allow the washing solution to enter the hepatic artery and portal vein. The forceps can be removed from the perfusion fluid collection bag so that the mixture of perfusion fluid and washing solution fills this perfusion fluid collection bag rather than the organ chamber.

[0345] If a decision is made to cool the liver at the end of storage, the following exemplary procedure can be used. 1. Obtain and configure the heater / cooler unit (place it near the OCS, plug in the electrical lines, turn on the power, turn on the water circuit control, and turn off the water circuit valve). Do not yet connect the heater / cooler water line to the liver perfusion module gas exchanger water line. 2. Set the water circuit temperature of the heater / cooler to approximately the current liver temperature (for example, around 37°C) and allow it to reach that temperature. 3. Connect the water line of the heater / cooler equipped with Hansen Quick Connect to the water line of the liver perfusion module oxygenator. 4. Turn off heater 100. 5. Set the water circuit temperature of the heater / cooler to a temperature lower than the liver temperature but not more than 10°C lower, and open the water line valve to allow flow to reach the liver perfusion module gas exchanger water line. When the actual temperature of the perfusion fluid reflected in the user interface approaches the water temperature setpoint of the heater / cooler, gradually adjust the water temperature setpoint of the heater / cooler to a temperature lower than the perfusion fluid / liver temperature but not more than 10°C higher, and repeat until the blood / liver reaches the desired temperature. 6. Once the liver temperature reaches the desired temperature, remove the liver from system 600.

[0346] Although the above description focuses on the final washing and cooling of the liver, similar or identical procedures can be used when preserving other organs. For example, in some embodiments, the final washing / cooling techniques described above can also be applied to the heart and / or lungs preserved in System 600.

[0347] VII. Evaluation In some embodiments of the disclosed subject matter, various techniques or methods are provided for assessing the viability of the liver while it is stored in the organ management system 600 (e.g., viability for transplantation). Generally, the biological function and state of the liver can be assessed using known biomarkers in the art and known imaging techniques for evaluating liver function, such as liver enzymes. In addition, since the liver stored in the organ management system 600 is easily handled by the operator, techniques that are not readily available in in vivo healthcare operations, such as visual inspection or palpation of the liver, can also be used. Based on the evaluation results, one or more parameters of the organ management system 600, such as the nutrient or oxygen content in the perfusion fluid or the flow rate and flow pressure of the perfusion fluid, can be adjusted to improve liver viability.

[0348] In some embodiments, liver viability can be assessed using perfusion parameters of the organ management system 600. In particular, in some embodiments, the flow pressure of the perfusion fluid in the cannulated hepatic artery and / or portal vein can be measured as an indicator of liver viability. In some embodiments, a stable flow pressure in the 50-120 mmHg range in the hepatic artery line can indicate that the preserved liver is receiving an adequate supply of essential nutrients. For example, in some embodiments, a stable flow pressure of approximately 50, 60, 70, 80, 90, 100, 110, or 120 mmHg, or any range of pressures defined by the values ​​shown herein, can indicate that the preserved liver is receiving an adequate supply of essential nutrients. Flow pressures outside this range may indicate leakage or blockage in the system, or may prompt the operator to adjust the flow pressure to ensure that the liver is receiving adequate nutrients. In other embodiments, the flow rate of the perfusion fluid in the cannulated hepatic artery and / or portal vein can be measured as an indicator of liver viability. In other embodiments, a hepatic artery flow rate in the range of 0.25–1 L / min can indicate that the preserved liver is receiving an adequate supply of essential nutrients. For example, in some embodiments, a hepatic artery flow rate of approximately 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00 L / min, or any range defined by the values ​​shown herein, can indicate that the preserved liver is receiving an adequate supply of essential nutrients. Flow rates outside this range may indicate leakage or blockage in the system, or may prompt the operator to adjust the flow rate to ensure that the liver is receiving adequate nutrients. Flow rates and pressures can be measured using pressure and / or flow sensors described herein.

[0349] In some embodiments, liver viability can be assessed by visual inspection or examination of the liver. For example, if the liver is pink or red, it may indicate that the liver is functioning normally, while if the liver is dark or bluish, it may indicate that the liver is functioning abnormally or is deteriorating (e.g., hypoperfusion). In other embodiments, liver viability is assessed by palpation of the liver. If the liver is soft and flexible, it is likely that the liver is functioning normally. On the other hand, if the liver is tense or hard, it is likely that the liver is functioning abnormally or is deteriorating (e.g., hypoperfusion).

[0350] A. Bile production In some embodiments, the bile duct is cannula-inserted and connected to a reservoir in the organ management system 600, allowing for easy examination of the color and quantity of bile produced by the liver to assess liver viability. In some embodiments, black or dark green bile may indicate normal liver function, while light or clear bile may indicate abnormal liver function or deterioration. In yet another embodiment, bile production can be used to assess liver viability (and / or the determination that the liver is producing bile may be a good indicator). Any bile production, even small amounts, is a sign of a healthy liver, but higher bile production indicates better liver function. In some embodiments, bile production of approximately 250 mL-1 L, 500 mL-1 L, 500 mL-750 mL, 500 mL, 750 mL, or 1 L per day, or any range defined by the values ​​shown herein, indicates that the liver stored in the organ management system 600 is functioning normally and is viable.

[0351] B. Blood gas, liver enzyme, and lactate ester measurements / trends In some embodiments, liver viability can be assessed using various biomarkers or compounds in the perfusion fluid. For example, liver metabolic assessment can be performed by calculating oxygen delivery, oxygen consumption, and oxygen demand. In particular, the amounts of oxygen and carbon dioxide dissolved in the perfusion fluid can be monitored as indicators of liver function. The concentrations of these gases in the perfusion fluid (or blood product) before and after liver perfusion can be measured and compared. In some specific embodiments, the concentrations of oxygen and carbon dioxide can be measured by various sensors within the flow module or subsystem of the organ management system 600.

[0352] In some embodiments, the perfusion fluid (e.g., the fluid entering the hepatic artery and exiting the IVC) can be sampled using oxygen concentration (or other) sensors before and after liver perfusion to measure the concentrations of oxygen and carbon dioxide, respectively. A significant increase in carbon dioxide concentration in the perfusion fluid and / or a significant decrease in oxygen concentration in the perfusion fluid after liver perfusion can indicate that the liver is performing its oxidative metabolic function well. On the other hand, a slight increase or no increase in carbon dioxide concentration in the perfusion fluid and / or a slight decrease or no decrease in oxygen concentration in the perfusion fluid after liver perfusion can indicate that the liver is not performing its oxidative metabolic function properly. The difference between PvO2 and PaO2 can indicate metabolically active, aerobically active metabolism and oxygen consumption.

[0353] In some embodiments, liver function can be assessed by performing a hepatic function blood test (LEFT). In particular, in some embodiments, liver function can be evaluated by measuring aspartate aminotransferase (AS...

Claims

1. It is an organ management system: A pump configured to supply perfusion fluid into the perfusion circuit; Gas exchanger and; A hepatic artery interface configured to supply the perfusion fluid to the hepatic artery of the ex vivo liver; A portal vein interface configured to supply the perfusion fluid to the portal vein of the ex vivo liver; Includes a pressure sensor configured to measure the pressure of the perfusion fluid, The aforementioned organ management system is: The aforementioned ex vivo liver is examined to generate test results; It is configured to adjust the characteristics of the organ management system in response to the aforementioned test results, The above test results indicate the lactate ester levels in the ex-vivo liver. The lactic acid ester level is the difference between the first lactic acid ester value and the second lactic acid ester value. The first lactate ester value relates to the perfusion fluid flowing into the ex-vivo liver, The second lactate ester value relates to the perfusion fluid flowing out of the ex-vivo liver, in an organ management system.

2. The organ management system according to claim 1, wherein the test results further indicate the oxygen concentration of the perfusion fluid, the carbon dioxide level of the perfusion fluid, the nutrient concentration level of the perfusion fluid, the blood gas level of the perfusion fluid, the temperature level of the perfusion fluid, the flow rate of the perfusion fluid, the pH of the perfusion fluid, the flow pressure of the perfusion fluid, the expansion pressure of the perfusion fluid, the aspartate amino acid transferase (AST) level of the ex-vivo liver, or the activated whole blood clotting time (ACT) of the ex-vivo liver.

3. The organ management system according to claim 2, wherein the organ management system is configured to maintain the expansion pressure of the perfusion fluid between 5 mmHg and 35 mmHg.

4. The organ management system according to claim 2, wherein the characteristics of the organ management system are the flow rate of the perfusion fluid, the pressure of the perfusion fluid, the nutrient concentration of the perfusion fluid, the oxygen concentration of the perfusion fluid, the temperature of the perfusion fluid, or the anticoagulant level of the perfusion fluid.

5. The above test results further indicate the activated whole blood coagulation time (ACT) of the ex vivo liver; The organ management system according to claim 4, wherein the characteristic of the organ management system is the level of the anticoagulant in the perfusion fluid.

6. The organ management system according to claim 5, wherein the anticoagulant level is the level of heparin.

7. The organ management system according to claim 1, wherein the organ management system is configured to re-examine the ex-vivo liver.

8. The organ management system according to claim 1, wherein the organ management system is configured to adjust the characteristics of the organ management system in order to improve the transplantability of the ex-vivo liver.

9. It is an organ management system: A pump configured to supply perfusion fluid into the perfusion circuit; Gas exchanger and; A hepatic artery interface configured to supply the perfusion fluid to the hepatic artery of the ex vivo liver; A portal vein interface configured to supply the perfusion fluid to the portal vein of the ex vivo liver; A flow sensor configured to measure the flow rate of the perfusion fluid; The system includes a drain configured to receive the perfusion fluid from the inferior vena cava of the ex-vivo liver, The aforementioned organ management system is: The aforementioned ex vivo liver is examined to generate test results; It is configured to adjust the characteristics of the organ management system in response to the aforementioned test results, The above test results indicate the lactate ester levels in the ex-vivo liver. The lactic acid ester level is the difference between the first lactic acid ester value and the second lactic acid ester value. The first lactate ester value relates to the perfusion fluid flowing into the ex-vivo liver, The second lactate ester value relates to the perfusion fluid flowing out of the ex-vivo liver in this organ management system.

10. The organ management system according to claim 9, wherein the test results further indicate the oxygen concentration of the perfusion fluid, the carbon dioxide level of the perfusion fluid, the nutrient concentration level of the perfusion fluid, the blood gas level of the perfusion fluid, the temperature level of the perfusion fluid, the flow rate of the perfusion fluid, the pH of the perfusion fluid, the flow pressure of the perfusion fluid, the expansion pressure of the perfusion fluid, the aspartate amino acid transferase (AST) level of the ex-vivo liver, or the activated whole blood clotting time (ACT) of the ex-vivo liver.

11. The organ management system according to claim 10, wherein the organ management system is configured to maintain the expansion pressure of the perfusion fluid between 5 mmHg and 35 mmHg.

12. The organ management system according to claim 11, wherein the characteristics of the organ management system are the flow rate of the perfusion fluid, the pressure of the perfusion fluid, the nutrient concentration of the perfusion fluid, the oxygen concentration of the perfusion fluid, the temperature of the perfusion fluid, or the anticoagulant level of the perfusion fluid.

13. The above test results further indicate the activated whole blood coagulation time (ACT) of the ex vivo liver; The organ management system according to claim 12, wherein the characteristic of the organ management system is the level of the anticoagulant in the perfusion fluid.

14. The organ management system according to claim 13, wherein the anticoagulant level is the level of heparin.

15. The organ management system according to claim 9, wherein the organ management system is configured to re-examine the ex-vivo liver.

16. The organ management system according to claim 9, wherein the organ management system is configured to adjust the characteristics of the organ management system by processing the perfusion fluid.

17. The organ management system according to claim 16, wherein the organ management system is configured to remove carbon dioxide from the perfusion fluid.

18. The organ management system according to claim 9, wherein the organ management system is configured to adjust the characteristics of the organ management system in order to improve the transplantability of the ex-vivo liver.

19. An organ management system comprising: A pump configured to supply perfusion fluid into the perfusion circuit; Gas exchanger and; A hepatic artery interface configured to supply the perfusion fluid to the hepatic artery of the ex vivo liver; A portal vein interface configured to supply the perfusion fluid to the portal vein of the ex vivo liver; Includes a pressure sensor configured to measure the pressure of the perfusion fluid, The aforementioned organ management system is: The aforementioned ex vivo liver is examined to generate test results; It is configured to adjust the characteristics of the organ management system in response to the aforementioned test results, The above test results show the activated whole blood clotting time (ACT) of the ex-vivo liver, The organ management system wherein the characteristic of the organ management system is the anticoagulant level of the perfusion fluid.

20. An organ management system comprising: A pump configured to supply perfusion fluid into the perfusion circuit; Gas exchanger and; A hepatic artery interface configured to supply the perfusion fluid to the hepatic artery of the ex vivo liver; A portal vein interface configured to supply the perfusion fluid to the portal vein of the ex vivo liver; Includes a pressure sensor configured to measure the pressure of the perfusion fluid, The aforementioned organ management system is: The aforementioned ex vivo liver is examined to generate test results; It is configured to adjust the characteristics of the organ management system in response to the aforementioned test results, The above test results show the activated whole blood clotting time (ACT) of the ex-vivo liver, The aforementioned characteristic of the organ management system is the level of heparin, an organ management system.

21. An organ management system comprising: A pump configured to supply perfusion fluid into the perfusion circuit; Gas exchanger and; A hepatic artery interface configured to supply the perfusion fluid to the hepatic artery of the ex vivo liver; A portal vein interface configured to supply the perfusion fluid to the portal vein of the ex vivo liver; A flow sensor configured to measure the flow rate of the perfusion fluid; The system includes a drain configured to receive the perfusion fluid from the inferior vena cava of the ex-vivo liver, The aforementioned organ management system is: The aforementioned ex vivo liver is examined to generate test results; It is configured to adjust the characteristics of the organ management system in response to the aforementioned test results, The above test results show the activated whole blood clotting time (ACT) of the ex-vivo liver, The organ management system wherein the characteristic of the organ management system is the anticoagulant level of the perfusion fluid.

22. An organ management system comprising: A pump configured to supply perfusion fluid into the perfusion circuit; Gas exchanger and; A hepatic artery interface configured to supply the perfusion fluid to the hepatic artery of the ex vivo liver; A portal vein interface configured to supply the perfusion fluid to the portal vein of the ex vivo liver; A flow sensor configured to measure the flow rate of the perfusion fluid; The system includes a drain configured to receive the perfusion fluid from the inferior vena cava of the ex-vivo liver, The aforementioned organ management system is: The aforementioned ex vivo liver is examined to generate test results; It is configured to adjust the characteristics of the organ management system in response to the aforementioned test results, The above test results show the activated whole blood clotting time (ACT) of the ex-vivo liver, The aforementioned characteristic of the organ management system is the level of heparin, an organ management system.

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