Abstract:
A method for controlling a pump for delivery of liquid to an organ over a series of fixed-length time intervals f, each interval f comprising a time t 1  and a time t 2  wherein t 1 +t 2  equals the length of interval f. The method comprises allowing output pressure of the pump to decrease over time t 1 , increasing output pressure of the pump over time t 2 , comparing achieved pump output pressure to a predetermined pressure at about the end of interval f, and at least one of (i) adjusting t 1  and t 2  if necessary so the predetermined pressure is approximated by the output pressure at the end of the next interval f, and (ii) adjusting a rate of change of the output pressure during at least one of t 1  and t 2  if necessary so the predetermined pressure is approximated by the output pressure at the end of the next interval f.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    1. Field of the Invention  
           [0002]    The invention relates to apparatus and methods for perfusing, in a defined and controlled manner, one or more organs, tissues or the like (hereinafter generally referred to as organs) to sustain, maintain and/or improve the viability of the organ(s).  
           [0003]    2. Description of Related Art  
           [0004]    Preservation of organs by machine perfusion has been accomplished at hypothermic temperatures with crystalloid perfusates and without oxygenation. See, for example, U.S. Pat. Nos. 5,149,321, 5,395,314, 5,584,804, 5,709,654, 5,752,929 and 5,827,222 to Klatz et al., which are hereby incorporated by reference. Hypothermic temperatures provide a decrease in organ metabolism, lower energy requirements, delay depletion of high energy phosphate reserves and accumulation of lactic acid and retard morphological and functional deterioration associated with disruption of blood supply.  
           [0005]    Ideally organs would be procured in a manner that limits their warm ischemia time to essentially zero. Unfortunately, in reality, many organs, especially from non-beating heart donors, are procured after extended warm ischemia time periods (i.e., 45 minutes or more). The machine perfusion of these organs at low temperature has demonstrated significant improvement (Transpl Int 1996 Daemen). Further, prior art teaches that the low temperature machine perfusion of organs is preferred at low pressures (Transpl. Int 1996 Yland) with roller or diaphragm pumps delivering the perfusate at a controlled pressure. Numerous control circuits and pumping configurations have been utilized to achieve this objective and to machine perfuse organs in general. 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. However, the use of such pumps for machine perfusion of organs may increase the risk of under or over-pressurization of the organ. High pressure perfusion (e.g., above about 60 mm Hg), for example, can wash off the vascular endothelial lining of the organ and in general damages organ tissue, in particular at hypothermic temperatures where the organ does not have neurological or endocrinal connections to protect itself by dilating its vasculature under high pressure. Lower than needed pressure perfusion may result in organ failure.  
           [0006]    Therefore, a need exists for a method and apparatus for perfusing an organ at a user or predefined pressure which takes into account organ resistance (i.e., pressure/flow) to avoid damage to the organ and to maintain the organ&#39;s viability.  
         SUMMARY OF THE INVENTION  
         [0007]    The present invention focuses on avoiding damage to an organ during perfusion while monitoring, sustaining and/or restoring the viability of the organ and preserving the organ for transplant, storage and/or transport. More particularly, the organ perfusion apparatus and method according to the present invention are directed to perfusing an organ at a user or predefined pressure or pressure wave, to monitor, sustain and/or restore the viability of the organ and/or for transporting and/or storing the organ.  
           [0008]    In perfusion, gross organ perfusion pressure may be provided by a pneumatically pressurized medical fluid reservoir controlled by a computer. The computer can respond to a sensor or similar device, for example, disposed in an end of tubing placed in the organ. The computer may be used in combination with a stepping motor/cam valve or pinch valve which provides for perfusion pressure fine tuning, prevents overpressurization and/or provides emergency flow cut-off. 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 sufficiently fail-safe controllers to prevent overpressurization of the organ, especially as a result of a system malfunction. Substantially eliminating overpressurization prevents and/or reduces damage to the vascular endothelial lining and to the organ tissue in general.  
           [0009]    Roller and peristaltic pumps produce pressure spikes which appear due to the rollers in the pumps. These spikes may be removed by having a motor which increases and decreases running speed according to the location of the roller head or the continuous feedback of a pressure sensor. A mechanical damper, typically an air pocket, is typically used to absorb the pressure spikes. Although known roller and peristaltic pumps may reduce the pressure spikes, however, the introduction of pressure spikes into the fluid flow according to embodiments of the present invention advantageously enables the maintaining of the pressure of fluid flowing into an organ between a user or pre-defined specified systolic pressure and a diastolic pressure of the organ.  
           [0010]    According to one embodiment of the present invention, the introduction of pressure spikes resulting in the aforementioned benefits may be achieved by a method of delivering a liquid to an organ or tissue by means of a pump.  
           [0011]    Exemplary embodiments of the invention may be used for various organs, such as the kidneys, and may be adapted to more complex organs, such as the liver, having multiple vasculature structures, for example, the hepatic and portal vasculatures of the liver.  
           [0012]    An organ diagnostic apparatus may also be provided to produce diagnostic data such as an organ viability index. The organ diagnostic apparatus includes features of an organ perfusion apparatus, such as sensors and temperature controllers, as well as cassette interface features, and provides 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.  
           [0013]    Embodiments of the invention also provide an organ cassette which 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 organ diagnostic apparatus, and/or other apparatus.  
           [0014]    Embodiments of this invention also provide an organ transporter which 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 cassette interface features.  
           [0015]    Embodiments of this 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 or organs being stored or transported. The 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. The systems may also provide outcome data to allow for ready research of perfusion parameters and transplant outcomes.  
           [0016]    These and other features and advantages of this invention are described in, or are apparent from, the following detailed description of various exemplary embodiments of systems and methods according to this invention.  
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0017]    The above and other aspects and advantages of the invention will become apparent from the following detailed description of embodiments when taken in conjunction with the accompanying drawings, in which:  
         [0018]    [0018]FIG. 1 is an organ perfusion apparatus according to the invention;  
         [0019]    [0019]FIG. 2 is a schematic diagram of an apparatus of FIG. 1;  
         [0020]    [0020]FIG. 3 is a diagram of a microprocessor controller which may be integrated with the apparatus of FIG. 2, the organ cassettes of FIG. 4D, and/or the organ transporter of FIG. 9;  
         [0021]    [0021]FIGS. 4A-4D show perspective views of various embodiments of an organ cassette according to the invention;  
         [0022]    [0022]FIG. 5 is a schematic diagram of an organ perfusion apparatus configured to simultaneously perfuse multiple organs;  
         [0023]    [0023]FIGS. 6A and 6B show an embodiment of an organ cassette of the present invention;  
         [0024]    [0024]FIG. 7 shows an exterior perspective view of an organ transporter according to the present invention;  
         [0025]    [0025]FIG. 8 shows a cross section view of an organ transporter of FIG. 7;  
         [0026]    [0026]FIG. 9 shows an alternative cross-section view of an organ transporter of FIG. 7;  
         [0027]    [0027]FIG. 10 is a pressure vs. time graph which shows the organ perfusion pressure and the pump state of the pump supplying the pressure at a given time for variable pump activation/inactivation periods;  
         [0028]    [0028]FIG. 11 is a flow diagram which shows the process flow of FIG. 10;  
         [0029]    [0029]FIG. 12 is a pressure vs. time graph which shows the organ perfusion pressure and the pump state of the pump supplying the pressure at a given time for static pump activation/inactivation periods;  
         [0030]    [0030]FIG. 13 is a flow diagram which shows the process flow of FIG. 12. 
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0031]    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.  
         [0032]    The invention is described herein largely in the context of apparatus and methods involved in transport, storage, perfusion and diagnosis of tissues and organs. However, the inventive apparatus and methods have many other applications, and thus the various inventive structures, devices, apparatus and methods described herein should not be construed to be limited to particular contexts of use. Various features of the disclosed invention are 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 (attorney docket no. WPB 40219), Ser. No. 09/537,180 (attorney docket no. WPB 40219A), 60/459,986 (attorney docket no. 115623), 60/459,981 (attorney docket no. 115624), 60/460,875 (attorney docket no. 115621) and Ser. No. 09/645,525 (attorney docket no. 040219.02), the entire disclosures of which are hereby incorporated by reference.  
         [0033]    [0033]FIG. 1 shows an organ perfusion apparatus  1  according embodiments of the invention. FIG. 2 is a schematic illustration of the apparatus of FIG. 1. The apparatus  1  is preferably at least partially microprocessor controlled, and pneumatically actuated. A microprocessor  150  connection to the sensors, valves, thermoelectric units and pumps of the apparatus  1  is schematically shown in FIG. 3. Microprocessor  150  and apparatus  1  may be configured to and are preferably capable of further being connected to a computer network to provide data sharing, for example across a local area network or across the Internet.  
         [0034]    The organ perfusion apparatus  1  is preferably capable of perfusing one or more organs simultaneously, at both normothermic and hypothermic temperatures (hereinafter, normothermic and hypothermic perfusion modes). All medical fluid contact surfaces are preferably 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  which includes front cover  4 , which is preferably translucent, and a reservoir access door  3 . The apparatus preferably has one or more control and display areas  5   a ,  5   b ,  5   c ,  5   d  for monitoring and controlling perfusion.  
         [0035]    As schematically shown in FIG. 2, enclosed within the housing  2  is a reservoir  10  which preferably includes three reservoir tanks  15   a ,  15   b ,  17 . Two of the reservoir tanks  15   a ,  15   b  are preferably standard one liter infusion bags, each with a respective pressure cuff  16   a ,  16   b . A pressure source  20  can be provided for pressurizing the pressure cuffs  16   a ,  16   b . The pressure source  20  is preferably pneumatic and may be an on board compressor unit  21  supplying at least 10 LPM external cuff activation via gas tubes  26 , 26   a , 26   b , as shown in FIG. 2. The invention, however, is not limited to use of an on board compressor unit as any adequate pressure source can be employed, for example, a compressed gas (e.g., air, CO 2 , oxygen, nitrogen, etc.) tank (not shown) preferably with a tank volume of 1.5 liters at 100 psi or greater for internal pressurization. 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.  
         [0036]    Gas valves  22 - 23  may be provided on the gas tube  26  to allow for control of the pressure provided by the onboard compressor unit  21 . Anti-back flow valves  24   a ,  24   b  may be provided respectively on the 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 pressure conditions detected to the microprocessor  150 , shown in FIG. 3. 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 further 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 .  
         [0037]    The medical fluid may be a natural fluid such as blood, but is preferably synthetic and 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 tissue protection. An oxygenated (e.g., cross-linked hemoglobin-based bicarbonate) solution is preferred for a normothermic mode while a non-oxygenated (e.g., simple crystalloid solution preferably augmented with antioxidants) solution is 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 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 the solution disclosed in U.S. Pat. No. 6,492,103, the entire disclosure of which is incorporated herein by reference. Examples of additives which may be used in perfusion solutions for the present invention are also disclosed in U.S. Pat. No. 6,046,046 to Hassanein, the entire disclosure of which is incorporated by reference. Of course, other suitable solutions and materials may be used, as is known in the art.  
         [0038]    The medical fluid within reservoir  10  is preferably 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  relays the temperature within the reservoir  10  to the microprocessor  150 , which adjusts the thermoelectric unit  30   a  to maintain a desired temperature within the reservoir  10  and/or displays the temperature on a control and display areas  5   a  for manual adjustment. Alternatively or in addition, and preferably where the organ perfusion device is going to be transported, the medical fluid within the hypothermic perfusion fluid reservoir can be cooled utilizing a cryogenic fluid heat exchanger apparatus such as that disclosed in filed U.S. Pat. No. 6,014,864, which is hereby incorporated by reference.  
         [0039]    An organ chamber  40  is provided which supports a cassette  65 , as shown in FIG. 2, which holds an organ to be perfused, or a plurality of cassettes  65 , as shown in FIG. 5, preferably disposed one adjacent the other. Various embodiments of the cassette  65  are shown in FIGS. 4A-4D. The cassette  65  is preferably 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.  
         [0040]    [0040]FIG. 4A shows a cassette  65  which holds an organ  60  to be perfused. Various embodiments of such a cassette  65  are shown in FIGS. 4A-4D,  6 A,  6 B,  10  and  12 . The cassette  65  is preferably 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.  
         [0041]    Preferably the cassette  65  includes side walls  67   a,  a bottom wall  67   b  and an organ supporting surface  66 , which is preferably formed of a porous, perforated or mesh material to allow fluids to pass therethrough. The cassette  65  may also include a top  67   d  and may be provided with an opening(s)  63  for tubing (see, for example, FIG. 4D). The opening(s)  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 and maintain a sterile environment. Also, cassette  65  may be provided with a closeable and/or filtered vent  61  (see, for example, FIG. 4D). Additionally, the cassette  65  may be provided with tubing for connection to an organ and/or to remove medical fluid from the organ bath, and a connection device(s)  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.  
         [0042]    Vent  61  preferably includes a filter device, and provides for control and/or equalization of pressure within and without the cassette without contamination of the contents of the cassette. 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 .  
         [0043]    It is often desirable to provide for pressure equalization of the cassette under such circumstances. However, free flow of air to achieve pressure equalization might introduce contaminants into the cassette. Thus, a filtering vent  61  is preferably provided to allow the air flow without permitting introduction of contaminants into the cassette.  
         [0044]    The filter preferably will let clean air pass in both directions but will not allow dirt, dust, liquids and other contaminants to pass. The pore size in the filters can be any size desired and can be small enough to prevent bacteria from passing.  
         [0045]    A pressure control valve can optionally be associated with vent  61  as well. Such a valve may be configured or controlled to restrict the rate at which external pressure changes are transmitted to the inside of the cassette, or even to prevent pressure increases and/or decreases, as desired.  
         [0046]    The cassette  65 , and/or the organ support, opening(s), tubing(s) and/or connections(s), 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  can 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  which 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  disposed therein, as discussed in more detail below. Alternatively, or in addition, pressure may, in embodiments, be controlled by way of a microprocessor, as shown in FIG. 3, which received pressure sensor data from pressure sensor P 1 .  
         [0047]    [0047]FIGS. 6A-6B show an alternative embodiment of cassette  65 . In FIG. 6A, cassette  65  is shown with tubeset  400 . Tubeset  400  can be connected to perfusion apparatus  1  or to an organ transporter or an organ diagnostic apparatus, and allows cassette  65  to be moved between various apparatus without jeopardizing the sterility of the interior of cassette  65 . Preferably, cassette  65  is made of a sufficiently durable material that it can withstand penetration and harsh impact. Cassette  65  is provided with a lid, preferably two lids, 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. A preferred such device is described in detail in a U.S. provisional patent application, serial No. 60/459,981, filed simultaneously herewith entitled “Device for separating bubbles from a liquid path” (attorney docket no. 115624).  
         [0048]    The cassette  65  is a portable device. As such, one or more lids  410  and  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 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  and  425 , for example, can be located in the inner lid  410  and outer lid  420 , respectively. It should be appreciated that any number of membranes can be located in the cassette (including its lid(s)) without departing from the spirit and scope of the invention. The membranes  415  and  425  are preferably hydrophobic membranes which help maintain an equal pressure between the inside and the outside of the cassette. The membranes  415  and  425 , if sufficiently flexible, can be impermeable or substantially impermeable. Alternatively, they may include filters that will let clean air pass in both directions, however, the membranes  415  and  425  will not allow dirt, dust, liquids and other contaminants to pass. The pore size in the filters can be any size desired, and preferably, the pore size of the membranes  415  and  425  can be small enough to prevent bacteria from passing. The actions of the membranes  415  and  425  and corresponding filters help maintain the sterility of the system.  
         [0049]    Preferably, cassette  65  is made of a sufficiently durable material that it can withstand penetration and harsh impact. Cassette  65  is provided with a lid, preferably two lids, an inner lid  410  and an outer lid  420 . The lids  410  and  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  and  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 additionally be included in inner lid  410  or both inner lid  410  and outer lid  420 . Port  430  may provide access to the organ to allow for additional diagnosis of the organ with minimal disturbance of the organ. 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  and  420  are secured on cassette  65 , overflow trough  440  provides a region that is easy 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.  
         [0050]    Cassette  65  and/or its lid(s) may be constructed of an optically transparent material to allow for viewing of the interior of cassette  65  and monitoring of the organ and to allow for video images or photographs to be taken of the organ. 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. 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, that the cassette is in the apparatus, and/or the identity of the organ 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.  
         [0051]    Cassette  65  is preferably 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, both of which are hereby incorporated by reference in their entirety.  
         [0052]    In various exemplary embodiments according to this invention, when transported, the organ may be disposed on the organ supporting surface  66  and the cassette  65  may be enclosed in a preferably 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  can 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. In either case, the bag  69  would preferably be removed prior to inserting the cassette into an organ storage, transporter, perfusion and/or diagnostic apparatus. Further, where a plurality of organs are to be perfused, multiple organ compartments may be provided. Alternatively, cassette  65  can be transported in the cassette and additionally carried within a portable organ transporter.  
         [0053]    [0053]FIG. 7 shows an external view of an embodiment of a transporter  1900  of the invention. The transporter  1900  of FIG. 7 has a stable base to facilitate 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  is preferably also 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 are preferably 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 calculate 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.  
         [0054]    Transporter  1900  preferably has latches  1930  that require positive user action to open, thus avoiding the possibility that transporter  1900  inadvertently opens during transport. Latches  1930  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 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.  
         [0055]    [0055]FIG. 8 shows a cross-section view of a transporter  1900 . Transporter  1900  contains cassette  65  and 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 sensor, 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 and helps monitor and control the chain of custody. A global positioning system 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 while in transit. This interface may allow data such as perfusion parameters, vascular resistance, and organ identification and transporter and cassette location to be tracked and displayed in real-time or captured for future analysis.  
         [0056]    Transporter  1900  also preferably contains a filter  2020  to remove sediment and other particulate matter, preferably ranging in size from  0 . 05  to  15  microns in diameter or larger, from the perfusate to prevent clogging of the apparatus or the organ. Transporter  1900  preferably also contains batteries  2030 , which may be located at the bottom of transporter  1900  or beneath pump  2010  or at any other location but preferably one that provides easy access to change batteries  2030 . Batteries  2030  may be rechargeable outside of transporter  1900  or while within transporter  1900  and/or are preferably hot-swappable one at a time. Batteries  2030  are preferably rechargeable rapidly and without full discharge. 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.  
         [0057]    As shown in FIG. 8, the cassette wall CW is preferably configured to mate with a corresponding configuration of inner transporter wall TW to maximize contact, and thus heat transfer, therebetween as discussed in more detail below.  
         [0058]    [0058]FIG. 9 shows an alternative cross-section of transporter  1900 . In FIG. 9, the transporter  1900  may have an outer enclosure  2310  which may, for example, be constructed of metal, or preferably a plastic or synthetic resin that is sufficiently strong to withstand penetration and impact. Transporter  1900  contains insulation  2320 , preferably a thermal insulation made of, for example, glass wool or expanded polystyrene. Insulation  2320  may be various thicknesses ranging from  0 . 5  inches to  5  inches thick or more, preferably 1 to 3 inches, such as approximately 2 inches thick. 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. An ice and water mixture is preferably an initial mixture of approximately 1 to 1, however, in embodiments the ice and water bath may be frozen solid. Transporter  1900  can be configured to hold various amounts of coolant, preferably up to 10 to 12 liters. An ice and water bath is preferable because it is inexpensive and generally can not get cold enough to freeze the organ. Coolant  2110  preferably lasts for a minimum of 6 to 12 hours and more preferably lasts for a minimum of 30 to 50 hours without changing coolant  2110 . 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  can preferably be replaced without stopping perfusion or removing cassette  65  from transporter  1900 . Coolant  2110  is preferably maintained in a watertight compartment  2115  of transporter  1900 . For example, an inner transporter wall TW as shown in FIG. 8 can 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 perfusate reservoir/cassette  65  into coolant  2110  enabling control within the desired temperature range. Coolant  2110  is a failsafe cooling mechanism because 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.  
         [0059]    Transporter  1900  may be powered by batteries or by electric power provided through plug  2330 . 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  preferably has 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  is provided on prefusate 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 , for example up to 3 to 5 liters. Preferably, approximately 1 liter of a hypothermic perfusate  2340  is used to perfuse organ  60 .  
         [0060]    Cassette  65  and transporter  1900  are preferably constructed to fit or mate such that efficient heat transfer is enabled. Preferably, the transporter  1900  contains a compartment  2115  for receiving the cassette. The transporter  1900  preferably relies 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  are preferably constructed 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.  
         [0061]    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 of FIG. 6 a , and/or the organ transporter of FIG. 8, and into organ  60 .  
         [0062]    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, e.g., human, cow, pig, etc.  
         [0063]    Preferably, immediately preceding organ  60  lies pressure sensor P 1 , which can sense the pressure of fluid flow at the position before the fluid enters organ  60 . As fluid is moved throughout the infusion circuit, organ  60  provides resistance. Pressure sensor P 1  detects the pressure that the organ creates by its 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 freely and into an organ bath.  
         [0064]    [0064]FIG. 10 is a pressure vs. time graph which shows the organ perfusion pressure and the pump state of pump  2010  supplying the pressure at a given time for embodiments of the invention involving variable pump activation periods. A user or computer sets a desired systolic pressure, which is the pressure of the fluid flow before entering organ  60  at pressure sensor P 1 , as discussed above. A fixed time interval f is also set, which may be, for example, set to a frequency of a low 1 beat per minute, or a high 200 beats per minute. Typically, f is set to produce between 20 and 60 beats per minute. Preferably, f is set to produce thirty beats per minute, or one beat every two seconds. The interval f may be predetermined, or may be user defined, and may be an interval that produces any frequency desired by the user.  
         [0065]    At time 0 , pump  2010  is activated and pumps fluid at a fixed rate through the infusion circuit, increasing the pressure measured by pressure sensor P 1  until the pressure reaches the inputted systolic pressure value at time 1 . At this initial stage, pump  2010  preferably runs continuously from time 0  to time 1 . The duration from time 0  to time 1 , is variable depending on the organ being perfused and does not necessarily depend on the frequency or time interval f.  
         [0066]    Once it is determined that the pressure at pressure sensor P 1  has reached the inputted systolic pressure (as represented by the solid line parabolic spike peaking at the user set systolic pressure at time 1 ) or it is determined that the pressure at pressure sensor P 1  has exceeded the inputted systolic pressure value (as represented by the dotted line parabolic spike peaking above the user set systolic pressure at time 1 ), pump  2010  is deactivated at time 1  for a time interval t 1 . Accordingly, the pressure measured at pressure sensor P 1  begins to fall. At a point in time between time 1  and time 2  when the diastolic pressure has been reached, pump  2010  is activated again until the fixed time interval f ends at time 2 . Preferably, at a time typically halfway between time 1  and time 2 , which is the time interval f/2, pump  2010  is activated. Here, between time 1  and time 2 , t 1 =t 2 =f/2.  
         [0067]    It should be appreciated that pump  2010  can be deactivated and reactivated during the interval f so that the desired systolic pressure may be reached. For example, according to an exemplary embodiment of the present invention, if, at time 2  the desired systolic pressure is not reached at the end of the fixed time interval f, i.e., the systolic pressure at time 2  is less than the user or computer defined systolic pressure, then pump  2010  is stopped for a shorter period of time as represented by the t 1  shown between time 2  and time 3 . Accordingly, pump  2010  is then activated at an earlier time from the beginning of time 2  during the next fixed interval f between time 2 , and time 3 , so that the inputted systolic pressure may be reached, or at least more closely approximated at time 3 . According to this exemplary embodiment, between time 2  and time 3 , t 1 &lt;t 2 , which indicates that the pump is running for a longer time than it is inoperative.  
         [0068]    According to another exemplary embodiment of this invention, if between time 2  and time 3 , the systolic pressure is reached (not shown), then pump  2010  can be controlled to maintain the systolic pressure until the end of time 3 .  
         [0069]    According to another exemplary embodiment of this invention, if, at time 3 , the systolic pressure is greater than the user&#39;s inputted systolic pressure value at the end of the fixed time period f, as represented by the parabolic spike at time 1  which exceeds the user or computer defined systolic pressure, then pump  2010  is deactivated longer during the next fixed period f starting at time 3  in order for the user or computer defined systolic pressure to be reached at time 4 . According to this exemplary embodiment, between time 3  and time 4 , t 1 &gt;t 2 , which indicates that the pump is stopped for a longer time than it is running.  
         [0070]    As such, according to exemplary embodiments of this invention, t 1  (the time during which the pump is stopped) and t 2  (the time during which the pump is activated) may be constantly increasing and/or decreasing over various fixed periods f so that the diastolic pressure (a free variable controlled by the organ) is as low as possible.  
         [0071]    The method according to the foregoing embodiments of the present invention constantly balances t 1  and t 2  such that the sum of t 1  and t 2  adds up to the fixed period f. This compensates for the fact that the organ resistance measured by pressure sensor P 1  changes over time due to the shape altering characteristics of living tissue. Advantageously, embodiments of the present invention are able to overcome this varying resistive nature of living organs by constantly increasing and decreasing time intervals t 1  and t 2  over sequential fixed periods f so that a fluid may be introduced to the organ at a constant rate.  
         [0072]    In FIG. 11, a user or computer enters a systolic pressure value at operation  15 . A peristaltic pump, for example, or any other type of controllable pump, begins operation at operation  25 . At operation  35 , a pressure sensor, such as pressure sensor P 1  checks to determine if the pressure as measured in front of organ  60  is greater than or equal to the systolic pressure value previously set by the user. If pressure is lower than the systolic pressure value, then operation  35  is repeated until it determines that the pressure is greater than or equal to the systolic pressure value. When this occurs, processing proceeds to operation  43 .  
         [0073]    At operation  43 , pump  2010  may be stopped altogether, and processing proceeds to operation  45 . At operation  45 , t 1  and t 2  both are set equal to fixed period f/2, and processing proceeds to operation  50 .  
         [0074]    At operation  50 , pump  2010  remains inactive for a time period t 1 . When this time period is over, processing proceeds to operation  62 . At operation  62 , pump  2010  is started and remains running for a time period t 2 . After time period t 2  has expired, and pump  2010  has stopped, processing proceeds to operation  70 .  
         [0075]    At operation  70 , pressure sensor P 1  is queried to determine whether the fluid flow pressure for organ  60  is equal to the set systolic pressure value. If the determined pressure is equal to the systolic pressure, then the values of t 1  and t 2  are the desired values for the current permeability of and resistance generated by organ  60 . Accordingly, the values of t 1  and t 2  are not changed, and processing loops back to operation  50 .  
         [0076]    If, however, operation  70  determines that the pressure is not equal to the set systolic pressure value, then processing proceeds to operation  80 .  
         [0077]    At operation  80 , pressure sensor P 1  is queried to determine whether the fluid flow pressure is less than the systolic pressure value. If so, then processing proceeds to operation  90 . If, however, the fluid flow pressure is not less than the user or computer defined systolic pressure value (i.e., the pressure is greater than the systolic pressure value), processing proceeds to operation  95 .  
         [0078]    At operation  90 , the value of t 1  is decreased, and the value of t 2  is increased by a determined amount, which may be calculated by microprocessor  150  using the difference between the user or computer defined systolic pressure value and the actual systolic pressure at the end of a fixed frequency f. Processing loops back to operation  50 .  
         [0079]    At operation  95 , the value of t 1  is increased, and the value of t 2  is decreased by a determined amount, which may be calculated by microprocessor  150  using the difference between the user or computer defined systolic pressure value and the actual systolic pressure at the end of a fixed frequency f, and processing loops back to operation  50 .  
         [0080]    In alternative embodiments illustrated by FIG. 12, t 1  and t 2  are equal throughout all time intervals f, so that pump  2010  is activated for half of every fixed interval f, and deactivated for the other half of fixed interval f. The duty cycle of the motor utilized in pump  2010  is increased and decreased over time to achieve the desired systolic pressure value.  
         [0081]    For example, according to various exemplary embodiments of FIG. 12, before time 0 , pump  2010  is inoperative. A user or computer sets a desired systolic pressure, which is the pressure of the fluid flow before entering organ  60  at pressure sensor P 1 , as discussed above. A fixed interval f is also set as discussed above.  
         [0082]    At time 0 , pump  2010  is activated at a specific duty cycle, and pumps fluid using this initial duty cycle through the infusion circuit, increasing the pressure measured by pressure sensor P 1  until the pressure reaches the inputted systolic pressure value at time 1 . At this initial stage, between time 0  and time 1 , pump  2010  may run continuously as represented by t 2 =time 1 −time 0 .  
         [0083]    Once pressure at pressure sensor P 1  detects the inputted systolic pressure (as represented by the solid line parabolic spike peaking at the user set systolic pressure at time 1 ) or the pressure at pressure sensor P 1  has exceeded the inputted systolic pressure value (as represented by the dotted line parabolic spike peaking above the user set systolic pressure at time 1 ), pump  2010  is deactivated at time 1 , for a time interval t 1 . Accordingly, the pressure measured at pressure sensor P 1  begins to fall. At a point in time between time 1  and time 2  pump  2010  is activated again until the fixed period frequency f ends at time 2 . Preferably, at a time halfway between time 1  and time 2 , which is the time interval f/2, pump  2010  is activated. Here, between time 1  and time 2 , as with all fixed periods f in this embodiment, t 1  and t 2  are constant. In this embodiment, t 1 =t 2 =f/2; however, it should be appreciated that in other embodiments t 1  and t 2  do not have be equal.  
         [0084]    It should be appreciated that the duty cycle of pump  2010  may be increased or decreased during time interval f so that the desired systolic pressure may be reached. For example, according to an exemplary embodiment of this invention, if, at time 2  the systolic pressure is not reached at the end of the fixed time period f, i.e., the systolic pressure at time 2  is less than the user or computer defined systolic pressure, then the duty cycle of pump  2010  is increased during the next fixed period f so that the inputted systolic pressure may be reached, or at least more closely approximated at time 3 . According to this exemplary embodiment, between time 2  and time 3 , t 1 =t 2 , but the duty cycle of pump  2010  has been increased over that of the duty cycle of the pump between time 1  and time 2 .  
         [0085]    According to another exemplary embodiment of this invention, if, at time 3 , the systolic pressure is greater than the user&#39;s inputted systolic pressure value at the end of the fixed time period f, as represented by the parabolic spike exceeding the user or computer defined systolic pressure, then pump  2010  is activated with a lower duty cycle during the next fixed period f starting at time 3  so that the inputted systolic pressure may be reached at time 4 .  
         [0086]    According to this exemplary embodiment, between time 3  and time 4 , t 1 =t 2 , but the duty cycle of pump P 1  has been decreased as compared to that of the duty cycle of the pump between time 2  and time 3 .  
         [0087]    As such, according to exemplary embodiments of this invention, the duty cycle of pump  2010  may be constantly increasing and/or decreasing over various fixed periods f so that the diastolic pressure (a free variable controlled by the organ) is as low as possible.  
         [0088]    The method according to the above embodiments of the present invention controls a pump duty cycle such that it takes a time period t 2  to rise from the diastolic pressure to the systolic pressure This compensates for the fact that the organ resistance measured by pressure sensor P 1  changes over time due to the shape altering characteristics of living tissue. Advantageously, embodiments of the present invention are able to overcome this varying resistive nature of living organs by constantly increasing and decreasing the duty cycle of pump  2010  over sequential fixed periods f.  
         [0089]    In FIG. 13, a user or computer enters a systolic pressure value at operation  100 . A peristaltic pump, for example, or any other type of controllable pump, begins operation at operation  120 . At operation  130 , a pressure sensor, such as pressure sensor P 1  checks to determine if the pressure as measured in front of organ  60  is greater than or equal to the systolic pressure value previously set by the user. If the sensed pressure is lower than the systolic pressure value, then operation  130  is repeated until the sensed pressure is greater than or equal to the systolic pressure value. When this occurs, processing proceeds to operation  140 .  
         [0090]    At operation  140 , pump  2010  is preferably stopped altogether, and processing proceeds to operation  145 . At operation  145  (or initially if desired), t 1  and t 2  both are set equal to fixed period f/2, and an initial duty cycle is determined for pump  2010  which may be calculated by microprocessor  150  using the difference between the user or computer defined systolic pressure value and the actual systolic pressure at the end of a fixed interval f, and processing proceeds to operation  155 .  
         [0091]    At operation  155 , pump  2010  remains inactive for a time period t 1 . When this time period is over, processing proceeds to operation  160 . At operation  160 , pump  2010  is started and remains running for a time period t 2 . When time period t 2  has expired, pump  2010  stops, and processing proceeds to operation  170 .  
         [0092]    At operation  170 , pressure sensor P 1  is queried to determine whether the fluid flow pressure for organ  60  is equal to the set systolic pressure value. If the determined pressure is equal to the systolic pressure, then the current duty cycle of pump  2010  is the desired duty cycle for the current permeability of and resistance generated by organ  60 ; hence, the duty cycle of pump  2010  is not changed, and processing loops back to operation  155 .  
         [0093]    If, however, operation  170  determines that the pressure is not equal to the set systolic pressure value, then processing proceeds to operation  180 .  
         [0094]    At operation  180 , pressure sensor P 1  is queried to determine whether the fluid pressure is less than the systolic pressure value. If so, then processing proceeds to operation  190 . If, however, the fluid pressure is not less than the user or computer defined systolic pressure value (i.e., the pressure is greater that the systolic pressure value), processing proceeds to operation  195 .  
         [0095]    At operation  190 , the duty cycle is increased by a determined amount, which may be calculated by microprocessor  150  using the difference between the user or computer defined systolic pressure value and the actual systolic pressure at the end of a fixed interval f, so that during the next interval f a pressure closer to the set systolic pressure may be obtained. Processing next returns to operation  155 .  
         [0096]    At operation  195 , the duty cycle is decreased by a determined amount, which may be calculated by microprocessor  150  using the difference between the user or computer defined systolic pressure value and the actual systolic pressure at the end of a fixed interval f, so that during the next interval f a pressure closer to the set systolic pressure may be obtained, and processing returns to operation  155 .  
         [0097]    While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations may be apparent to those skilled in the art. Accordingly, the embodiments of the invention as set forth herein are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention.