Abstract:
A system and method for regulating cooperatively the pressures and flows of input vessels such as both the portal vein and hepatic artery for the liver. This invention solves problems of less-than-therapeutic portal vein flow during perfusion preservation by implementing cooperative regulation between the inputs, e.g., portal vein and hepatic artery pumping systems, on an organ preservation apparatus. It includes an algorithm that adapts to the situation wherein the portal vein has reached minimum flow and maximum pressure. The cooperative regulation algorithm senses the problem with the portal vein and solves it by adjusting the hepatic artery flow conditions.

Description:
TECHNICAL FIELD 
     This disclosure is directed to methods and systems for perfusing, in a defined and controlled manner, one or more organs, tissues or the like (hereinafter “organs”) to sustain, maintain or improve the viability of the organs. 
     BACKGROUND 
     Perfusion apparatus for transplantable organs are described in the scientific and patent literature. For example, U.S. Pat. No. 6,977,140, assigned to Organ Recovery Systems, Inc., which is hereby incorporated by reference herein in its entirety, describes such an apparatus. U.S. Pat. No. 6,977,140 does not, however, address certain aspects of perfusing a multi-inflow organ, such as a human liver. 
     Ideally organs are harvested in a manner that limits their warm ischemia time. Unfortunately, many organs, especially from non-beating heart donors, are harvested after extended warm ischemia time periods, e.g., 45 minutes or more. Machine perfusion of these organs at low temperature is preferable (Transpl Int 1996 Daemen). Further, low temperature machine perfusion of organs at low pressures is also preferable (Transpl. Int 1996 Yland). Roller or diaphragm pumps are often used to deliver perfusate at controlled pressures. Numerous control circuits and pumping configurations are used to achieve preferable perfusion conditions. See, for example, U.S. Pat. Nos. 5,338,662 and 5,494,822 to Sadri; U.S. Pat. No. 4,745,759 to Bauer et al.; U.S. Pat. Nos. 5,217,860 and 5,472,876 to Fahy et al.; U.S. Pat. No. 5,051,352 to Martindale et al.; U.S. Pat. No. 3,995,444 to Clark et al.; U.S. Pat. No. 4,629,686 to Gruenberg; U.S. Pat. Nos. 3,738,914 and 3,892,628 to Thorne et al.; U.S. Pat. Nos. 5,285,657 and 5,476,763 to Bacchi et al.; U.S. Pat. No. 5,157,930 to McGhee et al.; and U.S. Pat. No. 5,141,847 to Sugimachi et al. 
     Use of the above described pumps for machine perfusion of organs, however, may introduce a risk of under- or over-pressurization of the organ. High pressure perfusion, above about 60 mm Hg, for example, can wash off the vascular endothelial lining of the organ and damage organ tissue. In particular, at hypothermic temperatures, an organ does not have neurological or endocrinal connections to protect itself by dilating its vasculature under high pressure. Low pressure perfusion may provide insufficient perfusate to the organ resulting in organ failure. 
     This concern over precise control is particularly acute in multi-inflow organs. In the living liver, blood flows into the organ via the portal vein and the hepatic artery. The blood combines in the sinusoids of the liver, and then flows out through the hepatic vein. In vivo, the hepatic artery receives relatively higher pressure arterial blood (ca. 100 mmHg), while the portal vein receives relatively lower pressure venial blood (ca. 18 mmHg). A system of vascular tension and sphincters regulates the relative resistance of blood through the portal vein and hepatic artery to manage proper flow from each inflow port into the sinusoids despite the unequal initial pressures. 
     During organ perfusion preservation, a goal is to perfuse fluids through the vessels of the ex vivo liver (1) in sufficient volume, i.e., flow, to enable proper dilution of waste products and proper provision of nutrients; and (2) at sufficient pressure to maintain vessel patency while limiting maximum flow and pressure to avoid damage. In a single inflow organ like the kidney, for example, this often is achieved simply by regulating the pressure and flow into the single inflow artery within well-defined minimum and maximum pressure and flow therapeutic windows. Regulation methods for single inflow organs are well known. 
     Conventionally, flow regulation into a liver is treated just as in a kidney. The portal vein pressure and the hepatic artery pressure, and respectives flows, are separately and independently maintained within well-defined therapeutic windows between maximum and minimum levels, regulated to a constant level of pressure or flow, or a combination of both. Methods of separate and independent regulation of portal and hepatic pressure and flow are well known. 
     SUMMARY 
     A need exists for a method and system for perfusing an organ at a defined and/or controlled pressure that can take into account organ resistance, i.e., pressure/flow, to avoid damage to the organ and to maintain the organ&#39;s viability. 
     This disclosure is directed to methods and systems for cooperatively regulating pressures and flows of different input vessels of an organ, such as the portal vein and hepatic artery for a liver. Studies identified a phenomenon in isolated liver perfusion in which increasing flow through the hepatic artery is associated with a consequent decreasing flow through the portal vein under constant perfusion pressure, i.e., pressure-regulated, conditions. These studies revealed that the portal vein flow may decrease to a level that is below the minimum therapeutic window as the hepatic flow increases. 
     Disclosed methods and systems seek to address, among other objectives, problems of less-than-therapeutic portal vein flow during organ perfusion preservation by implementing cooperative regulation between the inputs, e.g., portal vein and hepatic artery pumping systems, on an organ perfusion preservation apparatus. These methods and systems may include a control algorithm that responds when conditions in the portal vein are detected to reach minimum flow and maximum pressure as measurable parameters. In such instances, the flow cannot be increased by increasing the pressure and the pressure cannot be reduced by decreasing the flow. These conditions may be resolved by implementing a cooperative control algorithm that is provided with a sensor input of the problem condition within the portal vein, and cooperatively adjusts hepatic artery flow conditions. For example, the control algorithm may reduce the hepatic artery flow, maintaining it within the hepatic artery therapeutic window, enabling the portal vein flow to return to within the therapeutic window. 
     In an organ perfusion apparatus, gross organ perfusion pressure may be provided by a pneumatically pressurized medical fluid reservoir controlled by a computer. The computer may be programmed to respond to an input from a sensor or similar device, for example, disposed in a flow path such as in an end of tubing placed in a vessel of the perfused organ. The computer may be used in combination with a stepping motor/cam valve or pinch valve to (1) enable perfusion pressure fine tuning, (2) prevent overpressurization, and/or (3) provide emergency flow cut-off in the vessel. Alternatively, the organ may be perfused directly from a computer controlled pump, such as a roller pump or a peristaltic pump, with proper pump control and/or sufficient fail-safe controllers to prevent overpressurization of the organ, especially as a result of a system malfunction. Substantially eliminating overpressurization potential may reduce the consequent potential damage to the vascular endothelial lining, and to the organ tissue in general, and mitigate the effects of flow competition and flow extinction in a lower pressure vessel. 
     Further embodiments of the control algorithm may accommodate error recognition and alarm response to aberrant conditions. Such conditions may include when the portal flow and the hepatic pressure are both reduced below the respective therapeutic windows, or when the portal vein or the hepatic vein is occluded. 
     Further embodiments may recognize that the vascular sphincters may operate in an on-off fashion and exhibit hysteresis in their on-off (or open-closed) pressure thresholds. As a consequence, sequencing of establishment of portal flow versus hepatic flow may become significant. For example, if higher pressure hepatic artery perfusion is established first, then the sphincters controlling the portal vein flow into the sinusoids may become closed and require an opening pressure above the portal vein pressure. If this happens, the portal flow downstream of that particular sphincter would cease and the tissue fed by that vessel would be properly perfused. 
     Embodiments may recognize the action of the sphincters and implement a control algorithm that establishes a sequence of portal vein-before-hepatic artery flow. This sequence recognizes that the organ perfusion apparatus may undergo numerous startings and stoppings of flow to accommodate bubble purging, fault recovery, drug dosing, organ adjustments and other effects. Some of these events are described in the above-enumerated patent disclosures. 
     An organ diagnostic apparatus may also be provided to produce diagnostic data such as an organ viability index. The organ diagnostic apparatus may include features of an organ perfusion apparatus, such as sensors and temperature controllers, as well as cassette interface features. The organ diagnostic apparatus may provide analysis of input and output fluids in a perfusion system. Typically, the organ diagnostic apparatus is a simplified perfusion apparatus providing diagnostic data in a single pass, in-line perfusion. 
     Disclosed embodiments may also provide an organ cassette that allows an organ to be easily and safely moved between apparatus for perfusing, storing, analyzing and/or transporting the organ. The organ cassette may be configured to provide uninterrupted sterile conditions and efficient heat transfer during transport, recovery, analysis and storage, including transition between the transporter, perfusion apparatus and/or organ diagnostic apparatus, and/or other apparatus. 
     Disclosed embodiments may also provide an organ transporter that allows for transportation of an organ, particularly over long distances. The organ transporter may include features of an organ perfusion apparatus, such as sensors and temperature controllers, as well as organ cassette interface features. 
     Disclosed embodiments of the perfusion apparatus, transporter, cassette, and organ diagnostic apparatus may be networked to permit remote management, tracking and monitoring of the location and therapeutic and diagnostic parameters of the organ being stored or transported. Information systems may be used to compile historical data of organ transport and storage, and provide cross-referencing with hospital and United Network for Organ Sharing (UNOS) data on the donor and recipient for the organ. The information systems may also provide outcome data to allow for ready research of perfusion parameters and transplant outcomes. 
     These and other features and advantages of the disclosed methods and systems are described in, or apparent from, the following detailed description of various exemplary embodiments. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Various exemplary embodiments of disclosed methods and systems for a perfusion apparatus for implementing a control algorithm will be described, in detail, with reference to the following drawings wherein: 
         FIG. 1  illustrates an organ perfusion apparatus according to this disclosure; 
         FIG. 2  is a schematic diagram of the apparatus of  FIG. 1 ; 
         FIG. 3  is a diagram of a microprocessor controller which may be integrated with the apparatus of  FIG. 2 , the organ cassette of  FIG. 4D , and/or the organ transporter of  FIG. 9 ; 
         FIGS. 4A-4D  are perspective views of various embodiments of an organ cassette according to the invention; 
         FIG. 5  is a schematic diagram of an organ perfusion apparatus configured to simultaneously perfuse multiple organs; 
         FIGS. 6A and 6B  illustrate an alternate embodiment of an organ cassette according to this disclosure; 
         FIG. 7  shows an exterior perspective view of an organ transporter according to the present invention; 
         FIG. 8  is a cross-sectional view of the organ transporter of  FIG. 7 ; 
         FIG. 9  is an alternative cross-sectional view of the organ transporter of  FIG. 7 ; 
         FIG. 10  is a schematic diagram of the relationship between the pressure and flow of the fluids in the hepatic artery and portal vein of a liver; 
         FIG. 11  illustrates a perfusion apparatus adapted to execute the disclosed control algorithm; and 
         FIG. 12  is a flow chart of a method for executing the disclosed control algorithm. 
     
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     For a general understanding of the features of the invention, reference is made to the drawings. In the drawings, like reference numerals have been used throughout to designate like elements. 
     Disclosed systems and methods are involved in transport, storage, perfusion and diagnosis of organs. However, the disclosed systems and methods may have other applications, and thus should not be construed to be limited to particular contexts of use. Various disclosed features may be particularly suitable for use in the context of, and in conjunction and/or connection with the features of the apparatus and methods disclosed in U.S. patent application Ser. No. 09/162,128 (now abandoned), U.S. Pat. Nos. 6,977,140 and 6,673,594, and U.S. Patent Application Publications Nos. 2004-0248281, 2004-0221719, and 2004-0111104, the disclosures of which are hereby incorporated by reference herein in their entirety. 
       FIG. 1  illustrates an organ perfusion apparatus  1 .  FIG. 2  is a schematic illustration of the apparatus  1  of  FIG. 1 . The apparatus  1  may be at least partially microprocessor controlled, and pneumatically actuated. A microprocessor  150  with connections to sensors, valves, thermoelectric units and pumps of apparatus  1  is schematically depicted in  FIG. 3 . Microprocessor  150  and apparatus  1  may be configured to be further connected to a computer network to provide data sharing, for example, across a local area network or across the Internet. 
     The apparatus  1  may be capable of perfusing one or more organs simultaneously, at both normothermic and hypothermic temperatures. All medical fluid contact surfaces may be formed of, or coated with, materials compatible with the medical fluid used, more preferably non-thrombogenic materials. As shown in  FIG. 1 , the apparatus  1  may include a housing  2  that includes front cover  4 , which may be translucent, and a reservoir access door  3 . The apparatus  1  may include one or more control and display areas  5   a ,  5   b ,  5   c ,  5   d  for monitoring and controlling perfusion. 
     As schematically shown in  FIG. 2 , enclosed within the housing  2  is a reservoir  10  that may include multiple reservoir tanks such as the depicted three reservoir tanks  15   a ,  15   b ,  17 . Reservoir tanks, depicted as  15   a ,  15   b , may be standard one liter infusion bags, each with a respective pressure cuff  16   a ,  16   b . A pressure source  20  may be provided for pressurizing the pressure cuffs  16   a ,  16   b . The pressure source  20  may be pneumatic and may include an onboard compressor unit  21  supplying external cuff activation via gas tubes  26 ,  26   a ,  26   b , as shown in  FIG. 2 . Disclosed embodiments, however, are not limited to use of an onboard compressor unit as any adequate pressure source can be employed. Other available pressures sources may include a compressed gas (e.g., air, CO 2 , oxygen, nitrogen, etc.) tank (not shown). Alternatively, an internally-pressurized reservoir tank (not shown) may be used. Reservoir tanks  15   a ,  15   b ,  17  may, in embodiments, be bottles or other suitably rigid reservoirs that can supply perfusate by gravity or can be pressurized by compressed gas. 
     Gas valves  22  and  23  may be provided on gas tube  26  to allow for control of the pressure provided by the onboard compressor unit  21 . Anti-backflow valves  24   a ,  24   b  may be provided respectively on gas tubes  26   a ,  26   b . Pressure sensors P 1 , P 2 , P 3 , P 4 , P 5 , and P 6  may be provided to relay detected pressure conditions to the microprocessor  150 , shown in  FIG. 3 . Corresponding flow sensors (not shown) may also be provided. The perfusion, diagnostic and/or transporter apparatus may be provided with sensors to monitor perfusion fluid pressure and flow in the particular apparatus to detect faults in the particular apparatus, such as pressure elevated above a suitable level for maintenance of the organ. Gas valves GV 1  and GV 2  may be provided to release pressure from the cuffs  16   a ,  16   b . One or both of gas valves GV 1  and GV 2  may be vented to the atmosphere. Gas valve GV 4  in communication with reservoir tanks  15   a ,  15   b  via tubing  18   a ,  18   b  may be provided to vent air from the reservoir tanks  15   a ,  15   b  through tubing  18 . Tubing  18 ,  18   a ,  18   b ,  26 ,  26   a  and/or  26   b  may be configured with filters and/or check valves to prevent biological materials from entering the tubing or from proceeding along the fluid path. The check valves and/or filters may be used to prevent biological materials from leaving one organ perfusion tubeset and being transferred to the tubeset of a subsequent organ in a multiple organ perfusion configuration. The check valves and/or filters may also be used to prevent biological materials, such as bacteria and viruses, from being transferred from organ to organ in subsequent uses of the perfusion apparatus in the event that such biological materials remain in the perfusion apparatus after use. The check valves and/or filters may be provided to prevent contamination problems associated with reflux in the gas and/or vent lines. For example, the valves may be configured as anti-reflux valves to prevent reflux. The third reservoir tank  17  is preferably pressurized by pressure released from one of the pressure cuffs via gas valve GV 2 . 
     The medical fluid may be a natural fluid, such as blood, or otherwise synthetic fluid, which may, for example, be a simple crystalloid solution, or may be augmented with an appropriate oxygen carrier. The oxygen carrier may, for example, be washed, stabilized red blood cells, cross-linked hemoglobin, pegolated hemoglobin or fluorocarbon based emulsions. The medical fluid may also contain antioxidants known to reduce peroxidation or free radical damage in the physiological environment and specific agents known to aid in organ protection. An oxygenated, e.g., cross-linked hemoglobin-based bicarbonate, solution may be preferred for a normothermic mode while a non-oxygenated, e.g., simple crystalloid solution preferably augmented with antioxidants, solution may be preferred for a hypothermic mode. The specific medical fluids used in both the normothermic and hypothermic modes may be designed or selected to reduce or otherwise prevent the washing away of, or damage to, the vascular endothelial lining of the organ. For a hypothermic perfusion mode, as well as for flush and/or static storage, a preferred solution is disclosed in U.S. Pat. No. 6,492,103, the disclosure of which is hereby incorporated herein by reference in its entirety. Examples of additives which may be used in perfusion solutions are also disclosed in U.S. Pat. No. 6,046,046 to Hassanein, the disclosure of which is hereby incorporated by reference herein in its entirety. Other suitable solutions and materials may be used. 
     The medical fluid within reservoir  10  may be brought to a predetermined temperature by a first thermoelectric unit  30   a  in heat transfer communication with the reservoir  10 . A temperature sensor T 3  may relay the temperature within the reservoir  10  to the microprocessor  150 , which adjusts some in turn the thermoelectric unit  30   a  to maintain a desired temperature within the reservoir  10  and/or display the temperature on a control and display area such as  5   a  for manual adjustment. Alternatively, or in addition, particularly where the organ perfusion device is going to be transported, the medical fluid within the reservoir  10  can be cooled utilizing a cryogenic fluid heat exchanger apparatus such as that disclosed in U.S. Pat. No. 6,014,864, the disclosure of which is hereby incorporated by reference herein in its entirety. 
     An organ chamber  40  may be provided which supports a cassette  65 , as shown in  FIG. 2 . The cassette  65  may be configured to hold an organ to be perfused. Otherwise the organ chamber  40  may support a plurality of cassettes  65 , as shown in  FIG. 5 , which may be disposed one adjacent the other. Various embodiments of the cassette  65  are shown in  FIGS. 4A-4D . The cassette  65  may be formed of a material that is light but durable so that the cassette  65  is highly portable. The material may also be transparent to allow visual inspection of the organ. 
       FIG. 4A  illustrates a cassette  65  that holds an organ  60  to be perfused. The cassette  65  may include side walls  67   a , a bottom wall  67   b  and an organ supporting surface  66 . The organ supporting surface  66  may be formed of a porous, perforated or mesh material to allow fluids to pass through. The cassette  65  may also include a top  67   d  and may be provided with one or more openings  63  for tubing (see, for example,  FIG. 4D ). The openings  63  may include seals  63   a , e.g., septum seals or o-ring seals and optionally be provided with plugs (not shown) to prevent contamination of the organ  60  and maintain a sterile environment. Also, cassette  65  may be provided with a closeable and/or vent  61  (see, for example,  FIG. 4D ). Additionally, the cassette  65  may be provided with tubing for connection to the organ  60  and/or to remove medical fluid from an organ bath, and one or more connection devices  64  for connecting the tubing to, for example, tubing  50   c ,  81 ,  82 ,  91  and/or  132  (see, for example,  FIG. 4D ) of an organ storage, transporter, perfusion and/or diagnostic apparatus. 
     Vent  61  may include a filter device, and provide for control and/or equalization of pressure within the cassette  65  without contamination of the contents of the cassette  65 . For example, organs are frequently transported by aircraft, in which pressure changes are the norm. Even ground transportation can involve pressure changes as motor vehicles pass through tunnels, over mountains, etc. In addition, one or more lids  410  and  420  of cassette  65  can create an airtight seal with the cassette  65 . This air tight seal can create a pressure difference between the inside and outside of cassette  65 . It may be desirable to provide for pressure equalization of the cassette  65  under such circumstances. However, free flow of air to achieve pressure equalization might introduce contaminants into the cassette  65 . Thus, a vent  61  including a filter may be provided to allow the air flow without permitting introduction of contaminants into the cassette  65 . 
     The filter may facilitate clean air passing in both directions, while restricting dirt, dust, liquids and other contaminants from passing. The pore size of the filter can be selected to prevent bacteria from passing. 
     A pressure control valve (not shown) may optionally be associated with vent  61  as well. Such a valve may be configured and controlled to restrict the rate at which external pressure changes are transmitted to the inside of the cassette  65 , or even to prevent pressure increases and/or decreases, as desired. 
     The cassette  65 , and/or the organ supporting surface  66 , openings  63 , tubings and/or connection device  64 , may be specifically tailored to the type of organ and/or size of organ to be perfused. Flanges  67   c  of the side support walls  67   a  may be used to support the cassette  65  disposed in an organ storage, transporter, perfusion and/or diagnostic apparatus. The cassette  65  may further include a handle  68  that allows the cassette  65  to be easily handled, as shown, for example, in  FIGS. 4C and 4D . Each cassette  65  may also be provided with its own mechanism, e.g., stepping motor/cam valve  75  (for example, in the handle portion  68 , as shown in  FIG. 4C ) for fine tuning the pressure of medical fluid perfused into the organ  60 , as discussed in more detail below. Alternatively, or in addition, pressure may, in embodiments, be controlled by way of a microprocessor  150 , as shown in  FIG. 3 , which may receive pressure sensor data from pressure sensor P 1 . Likewise, flow sensors may be controlled in a similar manner. 
       FIGS. 6A-6B  illustrate an alternate embodiment of cassette  65 . In  FIG. 6A , cassette  65  is shown with tubeset  400 . Tubeset  400  may be connected to perfusion apparatus  1 , shown in other detail in  FIG. 1 , or to an organ transporter or an organ diagnostic apparatus. In this manner, cassette  65  may be moved between various apparatus without jeopardizing the sterility of the interior of cassette  65 . Cassette  65  may be made of a sufficiently durable material that it can withstand penetration and harsh impact. Cassette  65  may be provided with one or more lids, depicted in  FIG. 6A  as an inner lid  410  and an outer lid  420 . As shown in  FIG. 6A , the tube set may be connected to a bubble trap device BT. Such a bubble trap device is described in detail in a U.S. Patent Application Publication No. US 2004-0221719, the disclosure of which is hereby incorporated by reference herein in its entirety. 
     The cassette  65  is a portable device. As such, the one or more lids  410 ,  420  can create a substantially airtight seal with the cassette  65 . This air tight seal can create a pressure difference between the inside and outside of cassette  65 . Pressure sensors that control perfusion of the organ may be referenced to the atmospheric pressure. In such embodiments, it is desirable that the air space around the organ in cassette  65  is maintained at atmospheric pressure. Accordingly, the cassette  65  may also include one or more devices for controlling the pressure. The devices for controlling pressure can be active or passive devices such as valves or membranes. Membranes  415 ,  425 , for example, may be located in the inner lid  410  and outer lid  420 , respectively. It should be appreciated that any number of membranes may be located in the cassette  65 , including in the cassette lids  410 ,  420 . The membranes  415 ,  425  are preferably hydrophobic membranes that help maintain an equal pressure between the inside and the outside of the cassette  65 . The membranes  415 ,  425 , if sufficiently flexible, may remain impermeable or substantially impermeable to collapse. Alternatively, the membranes  415 ,  425  may include filters that will let clean air pass in both directions. In such instances, the membranes  415 ,  425  should not allow dirt, dust, liquids and other contaminants to pass. The pore size in the filters of the membranes  415 ,  425  may be selected to prevent bacteria from passing. The presence of the membranes  415 ,  425 , and corresponding filters, help maintain the sterility of the system. 
     The lids  410 ,  420  may be removable or may be hinged or otherwise connected to the body of cassette  65 . Clasp  405 , for example, may provide a mechanism to secure lids  410 ,  420  to the top of cassette  65 . Clasp  405  may additionally be configured with a lock to provide further security and stability. A biopsy and/or venting port  430  may be included in inner lid  410 , or in both inner lid  410  and outer lid  420 . Port  430  may provide access to the organ  60  to allow for additional diagnosis of the organ  60  with minimal disturbance of the organ  60 . Cassette  65  may also have an overflow trough  440  (shown in  FIG. 6B  as a channel present in the top of cassette  65 ). When lids  410 ,  420  are secured on cassette  65 , overflow trough  440  may provide a region to check to determine if the inner seal is leaking. Perfusate may be poured into and out of cassette  65  and may be drained from cassette  65  through a stopcock or removable plug. 
     Cassette  65  and/or lids  410 ,  420  may be constructed of an optically transparent material to allow for viewing of the interior of cassette  65  and monitoring of the organ  60  and to allow for video images or photographs to be taken of the organ  60 . A perfusion apparatus or cassette  65  may be wired and fitted with a video camera or a photographic camera, digital or otherwise, to record the progress and status of the organ  60 . Captured images may be made available over a computer network such as a local area network or the Internet to provide for additional data analysis and remote monitoring. Cassette  65  may also be provided with a tag that would signal, e.g., through a bar code, magnetism, radio frequency, or other means, the location of the cassette  65 , that the cassette  65  is in an apparatus  1 , and/or the identity of the organ  60  to perfusion, storage, diagnostic and/or transport apparatus. Cassette  65  may be sterile packaged and/or may be packaged or sold as a single-use disposable cassette, such as in a peel-open pouch. A single-use package containing cassette  65  may also include tubeset  400  and/or tube frame  200 , discussed further below. 
     Cassette  65  may be configured such that it may be removed from an organ perfusion apparatus and transported to another organ perfusion and/or diagnostic apparatus in a portable transporter apparatus as described herein or, for example, a conventional cooler or a portable container such as that disclosed in U.S. Pat. No. 6,209,343, or U.S. Pat. No. 5,586,438 to Fahy, the disclosures of which are hereby incorporated by reference herein in their entirety. 
     In various exemplary embodiments, when transported, the organ  60  may be disposed on the organ supporting surface  66  and the cassette  65  may be enclosed in a sterile bag  69 , as shown, for example, in  FIG. 4A . When the organ is perfused with medical fluid, effluent medical fluid collects in the bag  69  to form an organ bath. Alternatively, cassette  65  may be formed with a fluid tight lower portion in which effluent medical fluid may collect, or effluent medical fluid may collect in another compartment of an organ storage, transporter, perfusion and/or diagnostic apparatus, to form an organ bath. The bag  69  would preferably be removed prior to inserting the cassette  65  into an organ storage, transporter, perfusion and/or diagnostic apparatus. Further, where a plurality of organs  60  are to be perfused, multiple organ compartments may be provided. 
       FIG. 7  shows an external view of an embodiment of a transporter  1900 . The transporter  1900  of  FIG. 7  has a stable base to facilitate maintaining an upright position and handles  1910  for carrying transporter  1900 . Transporter  1900  may also be fitted with a shoulder strap and/or wheels to assist in carrying transporter  1900 . A control panel  1920  may be provided. Control panel  1920  may display characteristics, such as, but not limited to, infusion pressure, attachment of the tube frame, power on/off, error or fault conditions, flow rate, flow resistance, infusion temperature, bath temperature, pumping time, battery charge, temperature profile (maximums and minimums), cover open or closed, history log or graph, and additional status details and messages, some or all of which may be further transmittable to a remote location for data storage and/or analysis. Flow and pressure sensors or transducers in transporter  1900  may be provided to monitor various organ characteristics including pump pressure and vascular resistance of an organ, which can be stored in computer memory to allow for analysis of, for example, vascular resistance history, as well as to detect faults in the apparatus, such as elevated pressure. 
     Transporter  1900  may include latches  1930  that require positive user action to open, thus avoiding the possibility that transporter  1900  inadvertently opens during transport. Latches  1930  may hold top  1940  in place on transporter  1900  in  FIG. 7 . Top  1940  or a portion thereof may be constructed with an optically transparent material to provide for viewing of the cassette and organ perfusion status. Transporter  1900  may be configured with a cover open detector that monitors and displays whether the cover is open or closed. Transporter  1900  may be configured with an insulating exterior of various thicknesses to allow the user to configure or select an appropriate transporter  1900  for varying extents and distances of transport. In embodiments, compartment  1950  may be provided to hold patient and organ data such as charts, testing supplies, additional batteries, hand-held computing devices and/or configured with means for displaying a UNOS label and/or identification and return shipping information. 
       FIG. 8  is a cross-section view of a transporter  1900 . Transporter  1900  may be fitted with a conformed cassette  65  and include pump  2010 . Cassette  65  may preferably be placed into or taken out of transporter  1900  without disconnecting tubeset  400  from cassette  65 , thus maintaining sterility of the organ. In embodiments, sensors in transporter  1900  can detect the presence of cassette  65  in transporter  1900 , and, depending on the sensors, can read the organ identity from a barcode or radio frequency or other “smart” tag that may be attached, or integral, to cassette  65 . This can allow for automated identification and tracking of the organ in the cassette  65 , and helps to monitor and control the chain of custody. A global positioning system receiver may be added to transporter  1900  and/or cassette  65  to facilitate tracking of the organ. Transporter  1900  may be interfaceable to a computer network by hardwire connection to a local area network or by wireless communication, for example, while in transit. This interface may allow data such as perfusion parameters, vascular resistance, and organ identification, and transporter  1900  and cassette  65  location, to be tracked and displayed in real-time or captured for future analysis. 
     Transporter  1900  may contain a filter  2020  to remove sediment and other particulate matter from the perfusate to prevent clogging of the apparatus or the organ. Transporter  1900  may also contains batteries  2030 , which may be located at the bottom of transporter  1900  or beneath pump  2010  or at any other location that provides easy access to change batteries  2030 . Transporter  1900  may also provide an additional storage space  2040 , for example, at the bottom of transporter  1900 , for power cords, batteries and other accessories. Transporter  1900  may also include a power port for a DC hookup, e.g., to a vehicle such as an automobile or airplane, and/or for an AC hookup. 
     As shown in  FIG. 8 , the cassette wall CW of cassette  65  is preferably configured to mate with a corresponding configuration of inner transporter wall TW of the temperature  1900  to maximize contact, and facilitate heat transfer, as discussed in more detail below. 
       FIG. 9  is an alternate cross-sectional view of transporter  1900 . In  FIG. 9 , the transporter  1900  may have an outer enclosure  2310  which may, for example, be constructed of metal, plastic or synthetic resin that is sufficiently strong to withstand penetration and impact. Transporter  1900  may contain insulation  2320 , such as a thermal insulation made of, for example, glass wool or expanded polystyrene. Insulation  2320  may be of various thicknesses. Transporter  1900  may be cooled by coolant  2110 , which may be, e.g., an ice and water bath or a cryogenic material. In embodiments using cryogenic materials, the design should be such that organ freezing is prevented. Transporter  1900  may be configured to hold various amounts of coolant. An ice and water bath is preferable because it is inexpensive and generally cannot get cold enough to freeze the organ. The level of coolant  2110  may, for example, be viewed through a transparent region of transporter  1900  or be automatically detected and monitored by a sensor. Coolant  2110  may be replaced without stopping perfusion or removing cassette  65  from transporter  1900 . Coolant  2110  may be maintained in a fluid-tight compartment  2115  of transporter  1900 . An inner transporter wall TW as shown in  FIG. 8 , may be interposed between the coolant  2110  and cassette wall CW in the apparatus of  FIG. 9 . Compartment  2115  preferably prevents the loss of coolant  2110  in the event transporter  1900  is tipped or inverted. Heat is conducted from the walls of the cassette  65  into coolant  2110  enabling control within the desired temperature range. Coolant  2110  may provide a failsafe cooling mechanism where transporter  1900  automatically reverts to cold storage in the case of power loss or electrical or computer malfunction. Transporter  1900  may also be configured with a heater to raise the temperature of the perfusate. 
     An electronics module  2335  may also be provided in transporter  1900 . Electronics module  2335  may be cooled by vented air convection  2370 , and may further be cooled by a fan. Preferably, electronic module  2335  is positioned separate from the perfusion tubes to prevent the perfusate from wetting electronics module  2335  and to avoid adding extraneous heat from electronics module  2335  to the perfusate. Transporter  1900  may include a pump  2010  that provides pressure to perfusate tubing  2360  (e.g., of tube set  400 ) to deliver perfusate  2340  to organ  60 . Pressure sensor P 1  may be provided on perfusate tubing  2360  to relay conditions therein to the microprocessor  150 , shown in  FIG. 3 . Transporter  1900  may be used to perfuse various organs such as a kidney, heart, liver, small intestine and lung. Transporter  1900  and cassette  65  may accommodate various amounts to perfusate  2340 . 
     Cassette  65  and transporter  1900  may be constructed to fit or mate such that efficient heat transfer is enabled. The transporter  1900  may rely on conduction to move heat from the cassette  65  to coolant  2110  contained in compartment  2115 . This movement of heat allows the transporter  1900  to maintain a desired temperature of the perfusion solution. The geometric elements of cassette  65  and transporter  1900  may be configured such that when cassette  65  is placed within transporter  1900 , the contact area between cassette  65  and transporter  1900  is as large as possible and they are secured for transport. 
     Pump  2010 , which may be a peristaltic pump, or any type of controllable pump, may be used to move fluid throughout the infusion circuit of, for example, the organ perfusion apparatus of  FIG. 2 , the organ cassette  65  of  FIG. 6   a , and/or the organ transporter  1900  of  FIG. 8 , and into organ  60 . 
     It should be appreciated that the organ  60  may be any type of organ, a kidney, liver, or pancreas, for example, and the organ may be from any species, such as a human or other animal. 
     In a flow path for perfusate (infusion circuit), immediately preceding, or within, organ  60 , may lie a pressure sensor P 1 , which can sense the pressure of fluid flow at the position before the fluid enters, or dispersed in, organ  60 . As fluid is moved throughout the infusion circuit, organ  60  provides resistance. Pressure sensor P 1  detects the pressure that the organ  60  creates by this resistance as the fluid moves through it. At a position after organ  60 , there is little pressure, as the fluid typically flows out of the organ  60  freely and into an organ bath. 
     The liver is a three-terminal device where flows enter separately into the portal vein and hepatic artery and exit combined through the hepatic vein.  FIG. 10  is a schematic view of the relationship between the pressure and flow of the fluid in the hepatic artery and portal vein in an exemplary embodiment of the perfusion apparatus in the liver. In  FIG. 10 , Fv is the flow of the fluid out of the liver in the hepatic vein. Fpv is the flow of fluid in the portal vein. Fha is the flow of the fluid in the hepatic artery. In exemplary embodiments, these values satisfy the relationship Fv=Fpv+Fha. Ppv is the pressure of fluid in the portal vein. Pha is the pressure of the fluid in the hepatic artery. 
     In a liver perfusion apparatus, one machine (comprising pump, valves, sensors, tubing, etc.) may supply fluid to the portal vein and a separate or related or combined machine may supply the hepatic artery (for simplicity, but without limitation, this machine or machines will be referred to herein as if they are separate “machines.”) 
     As Pha increases, a threshold is reached at which Fpv begins to decline (f(Ppv, Pha)). After that point, if Pha continues to be increased, Fpv will decline in response. This phenomena is referred to as “flow competition.” Fpv can decline to zero during flow competition, resulting in a condition of flow extinction in the portal vein. Reducing Pha will tend to reverse this effect, although there will exist an amount of hysteresis. 
       FIG. 11  illustrates a schematic view of an exemplary control algorithm unit  3000  for use in operating organ perfusion machines such as those described herein and is particularly adapted to provided cooperative control of the flow of fluid to a plurality of input vessels in multiple input vessel organs such as the liver. Control algorithm unit  3000  may include a sensor interface  3100 , a pressure/determination unit  3200 , a controller  3300  one or more storage units  3400 , a data interface  3500 , and a user interface  3600 , all connected by a data/control buss  3700 . It will be understood that the control algorithm unit  3000  may contain other units as appropriate for controlling the perfusion methods described herein. Further, control algorithm unit  3000  may be adaptable to, and may operate in conjunction with, any of the devices or apparatus envisioned by this disclosure, including, but not limited to, an organ cassette, an organ perfusion apparatus, or an organ storage device and/or an organ transporter. 
     The sensor interface  3100  may provide a path by which sensors (not shown) for sensing parameters of the fluid flow in the vessels of an organ  60  may transmit measurement data regarding sensed parameters to the control algorithm unit  3000 . Such parameters may include, for example, the pressure and flow of the fluid flowing in one or more vessels perfusing the organ. Further, the sensor interface  3000  may be a device in the form of, for example, a microprocessor for interfacing between sensors of the apparatus in which the control algorithm unit  3000  is installed, or with which it is operating and a determination unit  3200 , or may include integral sensors in the unit  3100  itself for sensing one or more parameters. 
     In exemplary embodiments, the sensor interface  3100  may, either directly or indirectly, sense the pressure and flow of fluids flowing in the hepatic artery and portal vein of a liver. The sensor interface  3100  may also sense the pressure and flow of fluids exiting the liver through the hepatic vein. The data may be used, for example, by the determination unit  3200  for comparison to the data prescribed by the therapeutic window or may be related to other parameters of vitality. Comparative parameter data regarding either therapeutic windows or the sensed parameters, or otherwise, may be stored in, or accessible via, for example, the one or more storage units  3400 , via the data interface  3500  for connecting to an external data source, or via some user input provided at the user interface  3600 , which may be configured, for example, as a graphical user interface. 
     The control algorithm unit  3000  may comprise a determination unit  3200 . The determination unit  3200  may compare the metrics of a parameter sensed by the sensors accessible with sensor interface  3100  to the pre-set boundaries of the therapeutic window that may be available from the several data sources discussed above. The determination unit  3200  may compare the sensed values to the therapeutic window and determine whether the sensed parameter is within the therapeutic window. The determination unit  3200  may be, for example, a microprocessor. 
     In exemplary embodiments, the determination unit  3200  may compare the pressure and flow of fluid flowing in the hepatic artery and fluid flowing in the portal vein of the liver. It will be understood that the determination unit may make value to pre-set value comparisons, but also may be capable of higher-order valuations as needed by, for example, the complexity of the organ or the number of parameters being compared. 
     Based on the comparisons, the determination unit  3200  may determine whether the perfusion apparatus with which the unit  3000  is associated should be operated in an individual or cooperative capacity with regard to controlling the flow of fluid flowing in a plurality of vessels in an organ. For example, the determination unit  3200  may determine that a flow of fluid flowing in the portal vein falls outside the therapeutic window. In such an instance, the determination unit  3200  may indicate to the controller  3300  that the perfusion apparatus should be operated in a cooperative mode to manage fluid pressure and flow for the fluid flowing in both the hepatic artery and the portal vein in an effort to control the parameters in the hepatic artery in a manner to influence the flow of the fluid flowing in the portal vein back to within the therapeutic window. 
     The control algorithm unit  3000  may comprise a separate or integrated controller  3300  or control algorithm to execute the control functions of the unit  3000 . The controller  3300  may implement an algorithm based on the determination made by the determination unit  3200 . The controller  3300  may control the perfusion apparatus with which the unit  3000  is associated, or it may control individual units or devices within that apparatus. The controller  3300  may execute control to manipulate the functions of the apparatus to alter the parameters of the fluid flowing in the vessels. For example, in the liver, the controller  3300  may decrease the pressure of the fluid perfused by the apparatus perfusing the liver through the hepatic artery to cooperatively affect the flow of the fluid flowing in the portal vein. In this exemplary manner, the controller  3300  is able to manage a single or a plurality of units in an apparatus perfusing an organ, such as the liver, through a plurality of vessels by any one of, or combination of, starting, stopping, increasing or decreasing a function of the parameter of a fluid flowing through a vessel as delivered by the perfusion apparatus 
     The unit  3000  may comprise one or more storage units  3400 . The one or more storage units  3400  may operate in several capacities within the unit  3000  or outside the unit  3000  in the form of auxiliary storage media such as, for example, a computer readable storage medium with a compatible reading device. As shown in  FIG. 11 , in exemplary embodiments, one or more storage units  3400  may store values sensed by the sensor interface  3100  to be later provided to the determination unit  3200  or the controller  3300 . The storage unit may also be capable of receiving input from the determination unit  3200  regarding, for example, determinations made but not to be applied immediately, but rather stored for a time and then sent to the controller  3300 . 
     A control algorithm for coordinating the control of the machines within a single perfusion apparatus, such as a liver perfusion apparatus, will now be described. 
     The combination of flow and pressure in a vessel generally describe a therapeutic window for organ perfusion. If the flow or pressure is too high, the organ may be damaged; if the flow or pressure is too low, then the therapeutic benefits of perfusion are not realized at all, or as fully as desired. The therapeutic window is empirical, and may be established within an organ perfusion apparatus by a user or manufacturer. For example, the user may set a target value that each machine may attempt to maintain while maintaining a parameter according to a preset therapeutic value. For example, each machine may attempt to maintain a target pressure while maintaining flow above a therapeutic minimum. The organ perfusion apparatus is directed to maintaining pressure and flow within the therapeutic window. 
     For comparative reference, generally organs, such as kidneys, for example, are considered two-terminal devices. In a kidney, flow enters the renal artery and exits the renal vein. Flow through the kidney can be increased or decreased by increasing or decreasing the fluid pressure going into the renal artery. During perfusion, higher fluid pressure at the entrance to the renal artery delivers higher flow into the renal artery. Because the relationship between pressure and flow changes during perfusion as blood vessels tighten and loosen, an automatic controller within a kidney perfusion apparatus continually measures and adjusts pressure and flow up or down to stay within the therapeutic window. This mode of controller operation can be considered the Linear mode. 
     During relatively low flow conditions, such as may be encountered at the start of perfusion when the blood vessels are constricted in a liver, the flow into the portal vein and hepatic artery of a liver may be controlled independently using the Linear mode (as described for the kidney above). The pressure and flow of each vessel may be raised and lowered independently to maintain operation within appropriate therapeutic windows. 
     As the flow into the hepatic artery increases, a threshold is reached (which varies from liver to liver), at which further increase in hepatic artery flow may result in reduction of portal vein flow. This is flow competition. Flow competition may increase to a degree that it drives the parameter for the fluid flowing in the portal vein below the therapeutic minimum even though the portal vein pressure has reached the therapeutic maximum. At this point, further control of the portal vein within the therapeutic window cannot be maintained by adjusting the portal vein machine alone. A perfusion apparatus including the systems and methods according to this disclosure may detect such conditions and the deformentation may be made that a controller should direct the perfusion apparatus to a Cooperative mode of operation, with a goal of coordinated maintenance of both hepatic artery and portal vein pressure and flow within appropriate therapeutic windows. 
     During Cooperative mode operation, the controller  3300  may control the hepatic artery flow and initially reduce this flow until the portal vein flow is detected to increase back into the therapeutic window. Once both sets of pressure and flow conditions are reestablished within the therapeutic window, then revised parameters may be set by the controller  3300 , which are within the therapeutic window at a sufficient value for each parameter to attempt to maintain stable perfusion in the apparatus and organ. With new parameters established, the controller  3300  may return to operating in the Linear mode, and new parameter settings may be, for example, stored in one or more storage units  3400 . Furthermore, the user may be notified regarding the establishment of Cooperative mode operation and may display the new parameter settings. 
     In conditions where flow competition is detected, the competition can be so sever that it arrests flow in, for example, the portal vein and reduces it to zero. In such instances, the controller  3300  may operate to momentarily interrupt flow completely in the hepatic artery allowing portal vein flow to be reestablished, and, once portal vein flow is detected, to restart either Linear mode or Cooperative mode operation may be continued, where hepatic artery flow is restarted, preferentially after starting the portal vein flow under most circumstances (for example after bubble purge or fault recovery or user-directed flow start-up). 
     It should be recognized that leaks in a fluid circuit, occluded vessels, improperly cannulated vessels, and impact forces to the apparatus may change flow and pressure to an extent to be outside the therapeutic window. These fault conditions generally cause extreme transients outside the therapeutic window such that the fault conditions may be differentiated from flow competition. The controller  3300  may make this differentiation to determine whether to implement Cooperative mode, including recovery from portal vein extinction, or error handling, and make corrections appropriately. 
     With reference to  FIG. 12 , the following example control algorithm is provided. 
     In step  4100 , pressure and flow of a therapeutic window are established with user settings, in apparatus pre-sets, as stored parameters, and/or combinations thereof. A user or computer sets a desired systolic pressure and/or flow, which is the pressure and flow of the fluid supply before entering the organ at pressure sensor P 1 , as discussed above. A peristaltic pump, for example, or any other type of controllable pump, may begin operation at step  4100 . 
     In step  4200 , the perfusion apparatus is started and operation is begun. The perfusion process is started, for example, by user pressing an INFUSE button. In step  4300 , infusion of portal vein and hepatic artery flow is operated by the perfusion apparatus in an initial, likely, Linear mode. In exemplary embodiments, it is preferable to sequence a portal vein supply machine or pump to start before the hepatic artery supply machine or pump to reduce the risk of flow extinction due to flow competition at start-up. 
     In steps  4400 ,  4425 ,  4450  and  4475 , pressure sensor P 1 , and the corresponding flow sensor, are queried to determine whether the pressure and flow of the fluid flowing in the hepatic artery and portal vein are within the respective therapeutic windows. If the portal vein or hepatic artery pressure or flow cannot be maintained within the respective therapeutic window, the pressure and flow environments are analyzed in step  4500  to identify the severity of causal conditions to determine whether the perfusion apparatus will go to, for example, Cooperative mode (step  4600 ), Error handling mode (step  4700 ), or Flow extinction recovery mode (step  4800 ). 
     In step  4600 , the perfusion apparatus goes to Cooperative mode. In Cooperative mode, a controller may reduce hepatic artery flow until portal vein flow returns to within the therapeutic window. Then, in step  4650 , the controller establishes a new hepatic artery goal pressure that is well within the therapeutic window for all parameters. After the perfusion apparatus stabilizes within the parameter(s) in the therapeutic window, the controller may cause the apparatus to return operation, in perfusion step  4300 , to a Linear mode. 
     In step  4700 , the controller may drive the perfusion apparatus to an Error handling mode. In the Error handling mode, the controller may determine if conditions suggest a fault condition such as, for example, occlusion, leak, over-pressure, or under-pressure, and then activates an alarm, coincident with implementing a stored or otherwise directed error handling and/or recovery algorithms. Based on the detected error, the controller may appropriately reset the perfusion apparatus, such as by a user, or automatically, in step  4750  and the direct the control method to return to step  4200  to restart. 
     In step  4800 , the controller may detect actual or impending conditions of zero flow in the portal vein and drive the perfusion apparatus according to a Flow extinction mode. In an exemplary Flow extinction mode, the controller stops the hepatic artery supply machine, or both machines, in step  4850 . Then, the controller operates to start portal vein flow to a set level within the therapeutic window in step  4200 . After starting portal vein flow, the controller restarts hepatic artery flow. The controller then returns the perfusion apparatus to either Linear mode (step  4200 ) or, ultimately, Cooperative mode (step  4600 ) depending on the conditions of the pressure and flow environment relative to the therapeutic window. 
     All patents, patent applications, scientific articles and other sources and references cited herein are explicitly incorporated by reference herein for the full extent of their teachings as if set forth in their entirety explicitly in this application. 
     It should be understood that the foregoing disclosure emphasizes certain specific embodiments of the invention and that modifications or alternatives equivalent thereto are within the spirit and scope of the invention.