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EP-4252536-B1 - PERFUSION SYSTEM

EP4252536B1EP 4252536 B1EP4252536 B1EP 4252536B1EP-4252536-B1

Inventors

  • WIEGMANN, Bettina
  • HAVERICH, AXEL

Dates

Publication Date
20260513
Application Date
20220401

Claims (9)

  1. Perfusion system (1) for performing ex-vivo perfusion of a separated biological tissue body (21) in form of an extremity of a human or an animal, comprising at least one basic system for providing a basic circuit of the ex-vivo perfusion with at least the following components: a) at least one tissue body receiving chamber (18) for receiving the separated extremity (21), b) at least one reservoir (4) for storing a perfusate (5), c) at least one perfusion pump (11), by means of which a perfusate (5) flow through the separated extremity (21) can be variably adjusted and the perfusate (5) can be supplied to and removed from the separated extremity (21) via cannulas, d) at least one integrated monitor (3) that displays at least arterial and venous pressures in the separated extremity (21), e) at least one gas blender and oxygenator, via which the mixing ratio of gases applied to the perfusate (5), in particular oxygen and/or carbon dioxide, is regulated, f) a standard/hypothermic device for setting the perfusate temperature used to heat and/or cool the separated extremity (21), g) at least one control unit (2) for controlling the controllable components of the perfusion system (1), the control unit (2) being adapted to - provide a warning signal, - maintain the flow rate of the perfusate (5) through the separated extremity (21) within a predetermined range, - regulate the mixing ratio of gases applied to the perfusate (5) - and adjust the perfusate temperature, characterized in that h) the at least one reservoir (4) is configured to store the perfusate (5) with level monitoring and air bubble detection, i) the perfusion system (1) comprises at least one electrical stimulation system (28) for electrical nerve stimulation and/or electrical muscle stimulation of the separated extremity (21), and/or that the perfusion system (1) has extremity-specific motion splints that are motor-driven adapted for continuous passive motion of the separated extremity (21), and j) the control unit (2) is adapted to provide the warning signal based on the level monitoring and the air bubble detection and/or to perform an automatic control function to prevent an air embolism from occurring in the separated extremity (21) and to determine arterial and venous pressures in the separated extremity (21) using sensors (16) of the perfusion system (1) and output them on the integrated monitor (3).
  2. The perfusion system of claim 1, characterized in that the perfusion system (1) has a tissue body receiving chamber (18) that is modularly adaptable to the type of the separated extremity (21) by modular design to allow different sized extremities to be integrated into the tissue body receiving chamber (18).
  3. The perfusion system of claim 2, characterized in that the tissue body receiving chamber (18) has one, more or all of the following features a) to i): a) an X-ray cassette insert (20) for generating X-ray images of the separated biological tissue body (21) arranged in the tissue body receiving chamber (18), b) fold-away side walls (13) for unimpeded surgical care of the separated extremity (21) located in the tissue body receiving chamber (18) under physiological perfusion conditions and adherence to sterile conditions, c) variably adjustable support elements for low-contact or non-contact support of the separated extremity (21) arranged in the tissue body receiving chamber (18) to prevent storage-related ischemic pressure necrosis, d) at least one weight transducer for continuous real-time detection of the weight of the separated extremity (21) arranged in the tissue body receiving chamber (18) for continuous assessment of possible edema development and thus ischemia-reperfusion damage, e) variable use, automatically airtight closing ports, which can be used as glove ports for manual inspection and wound care of the separated extremity (21) arranged in the tissue body receiving chamber (18) and/or as ports for temporary integration of a thermal imaging camera in order to draw conclusions about the perfusion effectiveness via the local surface temperatures of the separated extremity (21) arranged in the tissue body receiving chamber (18), f) at least one permanently integrated thermal imaging camera, g) at least one funnel-shaped perfusate outlet (25) at the bottom of the tissue body receiving chamber (18) for draining off fluids, in particular perfusate (5) and/or wound fluid, h) at least one heating device (19) for heating the interior of the tissue body receiving chamber (18), in particular a heat mat, for improving the vitality and/or for additional temperature control of the separated extremity (21) arranged in the tissue body receiving chamber (18) in addition to the temperature control via the perfusate (5), i) sensors (16) for continuous recording of temperature and humidity in the tissue body receiving chamber.
  4. The perfusion system according to any one of the preceding claims, characterized in that the perfusion system (1) has an oxygen supply system (15) for delivering substantially pure oxygen to the tissue body receiving chamber (18).
  5. The perfusion system according to claim 4, characterized in that the control unit (2) is arranged to influence the humidity in the tissue body receiving chamber (18) and/or to perform hyperbaric oxygen therapy on the separated extremity (21) arranged in the tissue body receiving chamber (18) by controlling the oxygen supply system (15).
  6. The perfusion system according to any of the preceding claims, characterized in that the perfusion system (1) has an exchangeable filter system for integrating different perfusate filters, in particular for a microaggregate filter, a leukocyte filter, a hemodia filter, a cytokine filter.
  7. The perfusion system according to one of the preceding claims, characterized in that the perfusion system (1) has at least one delivery device (8, 9) controllable by the control unit (2), in particular a syringe pump, for automatic pH regulation and/or for automatic reduction of pH fluctuations in the perfusate (5) passed through the separated extremity (21).
  8. The perfusion system according to one of the preceding claims, characterized in that the perfusion system (1) has at least one delivery device (8, 9) controllable by the control unit (2), in particular a syringe pump, for automatic potassium and/or glucose regulation and/or further controlled application of drugs in the perfusate (5) passed through the separated extremity (21).
  9. The perfusion system according to one of the preceding claims, characterized in that the perfusion system (1) has at least one online blood gas analysis (BGA) measurement for real-time detection of arterial and venous parameters, in particular pO2, pCO2, pH, potassium, sodium, calcium, lactate and/or glucose, in the perfusate (5) passed through the separated extremity (21).

Description

The invention relates to a perfusion system for performing ex-vivo perfusion of a separated biological tissue body in form of an extremity of a human or an animal. The invention belongs to the technical field of ex-vivo organ perfusion. In recent years, so-called ex-vivo organ perfusion has been increasingly used in clinical practice in allogeneic transplantation of solid organs, especially for heart, lung, liver and kidney. Ex-vivo organ perfusion is an organ-specific, temporarily limited (<24 hours), storage option for donor organs until their transplantation, which is increasingly being used as an alternative to the still current gold standard - static, cold organ storage (4-10°C). Static, cold storage is associated with significant side effects, which ex-vivo organ perfusion is designed to minimize or prevent. Thus, the organism of the cold-stored organ is minimized, which reduces nutrient uptake and its metabolism, and the storage solution is neither continuously oxygenated (oxygen supply) nor decarboxylated (carbon dioxide release), resulting in certain storage damages (e.g., ischemia-reperfusion damage) that have a significant negative impact on the outcome after transplantation. WO 2019/141809 A1 discloses a perfusion loop assembly for ex vivo liver perfusion, comprising at least one pump for providing a fluid flow of a perfusion fluid through a line that branches into a first branch line and a second branch line downstream of the pump, the first branch line being configured to provide a first portion of the perfusion fluid to the hepatic artery and being coupled with at least one first gas exchanger and comprising at least one flow rate and/or pressure sensor, the second branch line being configured to provide a second portion of the perfusion fluid to the portal vein and comprising at least one first valve for controlling the flow of the perfusion fluid into the portal vein, the second branch line further comprising at least one flow rate and/or pressure sensor; a liver chamber assembly; and an outlet line connecting the liver chamber assembly and the pump. US 2021/0289771 A1 discloses a portable, ex vivo perfusion system for preserving detached biological tissue includes a receptacle for housing the tissue in a normothermic environment, a perfusion core to pump perfusate through the tissue via at least one conduit, at least one detection device to measure parameters during perfusion, and at least one parameter control device to maintain the parameter in a predetermined threshold. The system also includes a controller with instructions to receive the measured parameters, compare the parameters to predetermined thresholds, and when the parameters are outside the thresholds change an output of the at least one parameter control device to get the parameters within the threshold and alert a user that parameters were outside the thresholds. The invention is based on the object of providing an improved perfusion system that avoids such disadvantages. The fundamental difference to the gold standard is that the respective organs are perfused ex-vivo (outside the body), i.e. the respective separated biological tissue body, with a nutrient solution appropriately matched to the organ to be perfused, at different temperatures (depending on the protocol, from 37°C to hypothermic) and thus can maintain their physiological function within the ex-vivo system. In addition, the respective nutrient solution can be oxygenated and decarboxylated depending on the system, so that a physiological environment is established for the organ in the ex-vivo system, which ensures the exercise of the physiological organ function ex-vivo. Data generated for ex-vivo application in the context of allogeneic transplantation show that ex-vivo organ perfusion yields significantly better post-operative results compared with static, cold storage. Similarly, it has been shown that so-called marginal donor organs, which are initially of borderline organ quality for transplantation, can be regenerated and improved in quality by ex-vivo organ perfusion and then ultimately transplanted successfully. In addition, the ex-vivo organ perfusion system prolongs the "ischemia time" to be tolerated, since there is no real ischemia, i.e. a lack of oxygen, in the ex-vivo system, so that the so-called ischemia-reperfusion damage can also be significantly reduced. Such a system is advantageously suited for extremities. Such a system is currently not yet available for extremity perfusion, neither for use in the context of allogeneic transplantation, nor the other application possibilities that will be mentioned below. The invention is defined in the appended claims. Thus, proposed is a perfusion system for performing ex-vivo perfusion of a separated biological tissue body in form of an extremity of a human or an animal, comprising at least one basic system for providing a basic circuit of the ex-vivo perfusion with at least the following components: a) a