Systems and methods for liquid perfusion of body tissue

Abstract

The disclosure relates to systems and methods for liquid perfusion of body tissue. A system (10) comprises: a cell therapy element (100), which comprises a cell therapy portion (111) for containing cell therapy cells, a liquid perfusate portion (112) for receiving liquid perfusate, a semi-permeable separator (110) to separate the two portions, and thermal insulation (121) and / or a heater (122); and a liquid perfusion apparatus configured to circulate liquid perfusate through: (i) the liquid perfusate portion for interaction with cell therapy cells in the cell therapy portion via the semi-permeable separator, and (ii) the body tissue. The system may be for ex situ machine perfusion of body tissue, such as donor organs.

Description

[0001] SYSTEMS AND METHODS FOR LIQUID PERFUSION OF BODY TISSUE

[0002] Technical Field

[0003] The present disclosure relates to the field of systems and methods for liquid perfusion of body tissue. In particular, the present disclosure may relate to the field of systems and methods for ex- situ machine perfusion of body tissue, such as donor organs.

[0004] Background

[0005] When performing an organ transplant, there will usually be an extended period of time between an organ being removed from a donor body to that organ being inserted into a receiving body. During this time period, the quality and health of the organ may deteriorate due to spending time outside of the living body. As this intervening time period increases, the likelihood of that organ remaining a viable donor organ will decrease. It may be desirable to provide improved systems and methods which increase the likelihood of such a donor organ remaining viable despite this extended period of time out the body, or which recondition, treat or repair organs to otherwise improve their quality.

[0006] Summary

[0007] Aspects of the disclosure are set out in the independent claims and optional features are set out in the dependent claims. Aspects of the disclosure may be provided in conjunction with each other, and features of one aspect may be applied to other aspects.

[0008] Embodiments of the present disclosure relate to liquid perfusion systems which include a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion for receiving liquid perfusate; and a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion, and in which a thermal regulation element is included to regulate the temperature of the cell therapy cells in the cell therapy portion.

[0009] For instance, in an aspect, there is provided a system for liquid perfusion of body tissue, the system comprising: a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion for receiving liquid perfusate; a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion; and thermal insulation arranged to thermally insulate to the cell therapy portion; a liquid perfusion apparatus configured to circulate liquid perfusate through: (i) the liquid perfusate portion for interaction with cell therapy cells in the cell therapy portion via the semi-permeable separator, and (ii) said body tissue.

[0010] For instance, in an aspect, there is provided a system for liquid perfusion of body tissue, the system comprising: a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion for receiving liquid perfusate; a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion; and a heater for regulating a temperature of the cell therapy portion; a liquid perfusion apparatus configured to circulate liquid perfusate through: (i) the liquid perfusate portion for interaction with cell therapy cells in the cell therapy portion via the semi-permeable separator, and (ii) said body tissue.

[0011] Embodiments may enable liquid perfusate to interact with the cell therapy cells in the cell therapy portion via the semi-permeable separator, before that liquid perfusate is then delivered to the body tissue. This arrangement may provide benefits to the body tissue associated with the interaction between the liquid perfusate and the cell therapy cells in the cell therapy element. Moreover, by regulating a temperature of the cell therapy cells, the cell therapy cells themselves may operate more effectively, thereby further enhancing the beneficial effects of providing cell therapy treated liquid perfusate to the body tissue. For example, the system may be configured to deliver cellular therapy treated liquid perfusate to the body tissue. The cell therapy element may be configured to perform its own temperature regulation, e.g. using the thermal regulation element (the insulation and / or heater).

[0012] The two aspects may be combined, e.g. so that the cell therapy element comprises thermal insulation arranged to thermally insulate the cell therapy portion, as well as a heater for regulating a temperature of the cell therapy portion.

[0013] The insulation may be arranged to at least partially surround the cell therapy element. The insulation may surround one or more walls of the cell therapy element. The insulation may at least partially surround a surface of the cell therapy portion, such as an external surface of the cell therapy portion. For example, the insulation may completely surround the cell therapy element.

[0014] The heater may be configured to heat the cell therapy cells in the cell therapy portion. The heater may be coupled to a surface of the cell therapy portion, such as an external surface of the cell therapy element (e.g. to the cell therapy portion). The system may be configured to control operation of the heater based on an obtained indication of a temperature of the cell therapy portion. For example, the system may be configured to control operation of the heater to retain a temperature of the cell therapy portion within a selected range.

[0015] The liquid perfusion apparatus may comprise a liquid perfusion heater for heating a liquid perfusate to be delivered to the body tissue. The thermal regulation element (i.e. the heater for heating the cell therapy portion) may be a separate component to the liquid perfusion heater (or any other heater within the liquid perfusion apparatus).

[0016] The thermal regulation element (e.g. the insulation and / or the heater) may be arranged to retain a temperature of the cell therapy cells in the cell therapy portion within a threshold range. For example, the thermal regulation element may be configured so that the cell therapy cells are retained within a selected temperature range. The selected temperature range may be selected based on the type of the cell therapy cells in the cell therapy portion. The thermal regulation element may be arranged to inhibit thermal gradients across the cell therapy element exceeding a threshold level. For example, the thermal regulation element may be arranged to provide a uniform temperature distribution throughout the cell therapy cells in the cell therapy portion, e.g. so that the cell therapy cells are all kept within a threshold temperature range (irrespective of where in the cell therapy portion they are).

[0017] The liquid perfusate portion may comprise one or more liquid perfusate channels. Each of the one or more liquid perfusate channels may extend through the cell therapy portion. The semi- permeable separator may comprise one or more semi-permeable walls. Each semi-permeable wall may separate a liquid perfusate channel from the cell therapy portion. For example, each liquid perfusate channel may be surrounded by a semi-permeable wall which separates that liquid perfusate channel from the cell therapy portion. There may be a plurality of liquid perfusate channels extending across the cell therapy portion. The cell therapy element may be arranged for liquid perfusate to flow through each of the plurality of liquid perfusate channels across the cell therapy region. The semi-permeable walls are configured to permit (e.g. allow) liquid perfusate in the liquid perfusate region (e.g. in the liquid perfusate channels) to interact with cell therapy cells in the cell therapy portion. The thermal regulation element may be configured to regulate a temperature of the cell therapy portion throughout the volume of the cell therapy portion, e.g. also in regions away from the liquid perfusate channels.

[0018] The cell therapy element may comprise a hollow fibre element. For example, the cell therapy element may comprise a filter. The cell therapy element may comprise a hollow fibre bioreactor.

[0019] The semi-permeable separator may comprise a semi-permeable membrane. The semi-permeable membrane may comprise a plurality of pores. A size of the pores may be selected to permit exchange of material between the cell therapy portion and the liquid perfusate portion, e.g. non- cellular material. The semi-permeable separator may be arranged to permit two-way exchange between the cell therapy portion and the liquid perfusate portion. The semi-permeable separator may be configured to inhibit passage of cell therapy cells from the cell therapy portion into the liquid perfusate portion. The semi-permeable separator may be configured to allow exchange of non-cellular material between the cell therapy portion and the liquid perfusate portion. For example, the semi-permeable separator may be configured to permit exchange of smaller substances than the cell therapy cells such as secreted soluble factors and / or extracellular vesicles (e.g. from the cell therapy portion to the liquid perfusate portion, and from the liquid perfusate portion to the cell therapy portion). For example, a pore size of the pores of the semi-permeable separator may be selected to permit this exchange of material. Liquid perfusate may also interact with the cell therapy cells through the semi-permeable separator, e.g. to transmit a “turn on” signal from the body tissue to the cell therapy cells. For example, the liquid perfusate may interact with the cell therapy cells for priming or licensing.

[0020] Cell therapy cells may be provided in the cell receiving portion. The cell therapy element may be pre-loaded with cell therapy cells. The cell therapy element may be loaded with cells shortly prior to use, or during use, to provide point of care delivery of the cell therapy to body tissues or a human or animal body.

[0021] The system may comprise a pump coupled to the cell therapy element. The pump may be configured to control a flow rate of liquid perfusate through the cell therapy element. For example, the pump may be configured to vary a flow rate through the cell therapy element. The pump may be configured to control an amount and / or a proportion of liquid perfusate to be delivered to the body tissue which passes through the liquid perfusate portion. The pump may be configured to control the flow of liquid perfusate through the cell therapy element based on the body tissue and / or the cell therapy cells contained in the cell therapy portion (e.g. the cell therapy cell type and numbers). The pump may be configured to control an amount of liquid perfusate which is extracted from the liquid perfusion apparatus for passing through the cell therapy element. The remaining liquid perfusate may be delivered to the body without passing through the cell therapy element. For example, the system may comprise a first liquid perfusate flow path which bypasses the cell therapy element and a second liquid perfusate flow path which passes through the cell therapy element. The pump may be configured to select an amount (e.g. a flow rate and / or a pressure) of liquid perfusate which passes through the cell therapy element. In other words, the system may be configured to selectively control the amount of liquid perfusate which travels along the second liquid perfusate flow path (and thus which is cell therapy treated).

[0022] The system may comprise an oxygenator configured to oxygenate liquid perfusate. The oxygenator may be configured to oxygenate liquid perfusate which has passed through the cell therapy element (before it is delivered to the body tissue).

[0023] The system may comprise an ex-vivo liquid perfusion system. For this, the components of the system are to be located external to the human or animal body associated with the body tissue to which the system is coupled. The ex-vivo liquid perfusion system may comprise an ex-situ liquid perfusion system and / or an extracorporeal liquid perfusion system.

[0024] For example, the system may comprise an ex-situ liquid perfusion system. The system may comprise an ex-situ machine perfusion system for liquid perfusion of one or more pieces of body tissue, such as human or animal organs (or artificial organs). The ex-situ system may be configured to couple to body tissue away from (e.g. which has been removed from) the human or animal body (or which is artificial body tissue away from a human or animal body). The system may be configured to store and preserve said body tissue (ex-situ). Embodiments may facilitate improved storage and preservation of such body tissue, e.g. resulting in a greater likelihood of that tissue being viable for implantation into a recipient human or animal body. Embodiments may facilitate reconditioning, treatment, or reversal of previous injury to the body tissue to improve its viability for implantation into a recipient human or animal body.

[0025] For example, the system may comprise an extracorporeal liquid perfusion system. The extracorporeal liquid perfusion system may be configured to couple to a human or animal body. The system may be configured to provide thermally regulated cell therapy treatment of liquid perfusate which is to be delivered to that human or animal body.

[0026] In an aspect, there is provided an insert for a system for liquid perfusion of body tissue, the insert comprising: an inlet configured to couple to a liquid perfusion apparatus of a said system to receive liquid perfusate therefrom; a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion coupled to the inlet for receiving liquid perfusate therefrom; a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion; and thermal insulation arranged to thermally insulate the cell therapy portion; an outlet coupled to the liquid perfusate portion to receive cell therapy treated liquid perfusate therefrom and configured to couple to said liquid perfusion apparatus to provide the cell therapy treated liquid perfusate to said liquid perfusion apparatus. The insert may comprise a pump configured to control the flow of liquid perfusate through the insert.

[0027] In an aspect, there is provided an insert for a system for liquid perfusion of body tissue, the insert comprising: an inlet configured to couple to a liquid perfusion apparatus of a said system to receive liquid perfusate therefrom; a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion coupled to the inlet for receiving liquid perfusate therefrom; a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion; and a heater for regulating a temperature of the cell therapy portion; an outlet coupled to the liquid perfusate portion to receive cell therapy treated liquid perfusate therefrom and configured to couple to said liquid perfusion apparatus to provide the cell therapy treated liquid perfusate to said liquid perfusion apparatus. The insert may comprise a pump configured to control the flow of liquid perfusate through the insert.

[0028] In an aspect, there is provided a method of ex-situ liquid perfusion of body tissue, the method comprising: interacting liquid perfusate with cell therapy cells via a semi-permeable separator, wherein the cell therapy cells are contained within a thermally insulated housing; and delivering the cell therapy treated liquid perfusate to said body tissue. The method may comprise regulating a flow of liquid perfusate to interact with the cell therapy cells.

[0029] In an aspect, there is provided a method of ex-situ liquid perfusion of body tissue, the method comprising: interacting liquid perfusate with cell therapy cells via a semi-permeable separator; operating a heater to regulate a temperature of the cell therapy cells; and delivering the cell therapy treated liquid perfusate to said body tissue. The method may comprise regulating a flow of liquid perfusate to interact with the cell therapy cells.

[0030] Figures

[0031] Some examples of the present disclosure will now be described, by way of example only, with reference to the figures, in which:

[0032] Fig. 1 is a schematic diagram of an example system for liquid perfusion of body tissue.

[0033] Fig. 2 shows five graphs of numerical data obtained from preserving real human kidneys.

[0034] Fig. 3 shows three graphs of numerical data obtained from preserving real human kidneys.

[0035] Fig. 4 shows two sets of graphs of numerical data obtained from preserving real human kidneys. Fig. 5 shows three graphs of numerical data obtained from cell therapy elements.

[0036] In the drawings like reference numerals are used to indicate like elements.

[0037] Specific Description

[0038] Embodiments of the present disclosure are directed to systems and methods for liquid perfusion of body tissue in which cell therapy cells interact with a liquid perfusate that is to be delivered to said body tissue. The system is designed so that the liquid perfusate interacts with the cell therapy cells via a semi-permeable separator, such as a semi-permeable membrane. The separator may stop ingress of the cell therapy cells into the liquid perfusate, but it may permit transfer of smaller molecules from the cell therapy side to the liquid perfusate side, and vice-versa. The system includes one or more additional elements for regulating a temperature of the cell therapy cells. This may comprise an active element, such as a heater for regulating (e.g. heating or cooling) a temperature of the cell therapy cells (e.g. via a surface in contact with these cells), and / or it may comprise a passive element, such as thermal insulation for thermally insulating the portion containing the cell therapy cells. Through the provision of such systems, the liquid perfusate delivered to said body tissue may contain additional beneficial components to help prevent degradation and / or improve the viability of that body tissue.

[0039] An example system will now be described with reference to Fig. 1.

[0040] Fig. 1 shows a system 10. The system 10 is for liquid perfusion of body tissue. In Fig. 1 , body tissue 60 (i.e. the tissue which is to be perfused by system 10) is shown. In the example of Fig. 1 , the system 10 is an ex-situ machine perfusion system, and so the body tissue 60 is shown coupled to the system 10 away from the body from which it originated.

[0041] The system 10 includes a reservoir 20, a liquid perfusate pump 30, an oxygenator 40 and a liquid perfusate heater 50. These components may form part of a liquid perfusion apparatus for circulating liquid perfusate through the system 10 (and the body tissue 60).

[0042] The system 10 also includes a cell therapy element 100. The cell therapy element 100 is shown enlarged and in greater detail in Inset A. The cell therapy element 100 comprises a liquid inlet 101 and a liquid outlet 102. The cell therapy element 100 includes one or more semi-permeable walls 110, as well as one or more cell therapy portions 111 and one or more liquid perfusate channels 112. The cell therapy element 100 includes a thermal regulation element. Two options for this thermal regulation element are shown in Fig. 1 as thermal insulation 121 and cell therapy heater 122. Although not shown in Fig. 1, the cell therapy element 100 may also include inlet and outlet ports for the cell therapy cells (e.g. to allow cell therapy cells to be loaded into, and removed from, the cell therapy portion(s) 111).

[0043] The system 10 also includes components for coupling the cell therapy element 100 to the liquid perfusion apparatus. For this, an inlet connector 201 and outlet connector 202 are included. Also shown in Fig. 1 is a cell therapy pump 210 and an optional cell therapy liquid heater 220.

[0044] In Fig. 1 , two flow paths are shown for liquid perfusate through the system 10. The first liquid flow path is through the components of the liquid perfusion apparatus: reservoir 20 to liquid perfusate pump 30, oxygenator 40 and into body tissue 60, but not through the cell therapy element 100. The second flow path does pass through the cell therapy element 100 (as well as the cell therapy pump 210 and optional heater 220). The second flow path runs in parallel to a portion of the first flow path. In effect, the second flow path provides a detour for liquid perfusate flowing on the first flow path. The first flow path will now be described in more detail before describing the second flow path.

[0045] The system 10 is connected to provide the first flow path for liquid perfusate through the components of the liquid perfusion apparatus and through the body tissue 60. This flow path is circular so that liquid perfusate may be continuously pumped through the liquid perfusion apparatus and body tissue 60. It will be appreciated in the context of the present disclosure that the particular order of the different components along the flow path should not be considered limiting. As shown in Fig. 1 , the first flow path may start at the reservoir 20 before passing through the liquid perfusate pump 30, the oxygenator 40 (with associated liquid perfusate heater / cooler 50), then through the body tissue 60, and back to the reservoir 20.

[0046] To help illustrate the first flow path, four sections of flow path are shown in Fig. 1 , and these will be referred to as: first tube 71, second tube 72, third tube 73 and fourth tube 74.

[0047] The reservoir 20 is coupled to the first tube 71 and to the fourth tube 74. The liquid perfusate pump 30 is coupled to the first tube 71 and the second tube 72. The oxygenator 40 is coupled to the second tube 72 and the third tube 73. The body tissue 60 is coupled to the third tube 73 and the fourth tube 74. The first tube 71 couples the reservoir 20 to the liquid perfusate pump 30. The second tube 72 couples the liquid perfusate pump 30 to the oxygenator 40. The third tube 73 couples the oxygenator 40 to the body tissue 60. The fourth tube 74 couples the body tissue 60 to the reservoir 20.

[0048] The reservoir 20 comprises a store of liquid perfusate. The reservoir 20 is arranged to receive liquid perfusate from the body tissue 60 (via fourth tube 74) and to provide liquid perfusate to be delivered to the body tissue 60 (via first, second and third tubes 71 , 72, 73). In the example ordering shown in Fig. 1, the liquid perfusate pump 30 is coupled to the reservoir 20 (e.g. for receiving liquid perfusate therefrom). The liquid perfusate pump 30 is connected between the reservoir 20 and the oxygenator 40. The oxygenator 40 is connected between the liquid perfusate pump 30 and the body tissue 60. The body tissue 60 is connected between the oxygenator 40 and the reservoir 60.

[0049] The liquid perfusion heater 50 may be coupled to the oxygenator 50 (as shown in Fig. 1). Additionally, or alternatively, the liquid perfusion heater 50 may be coupled to the first liquid flow path at another region, e.g. somewhere upstream of the body tissue 60. As shown in Fig. 1, the system 10 may include a plurality of connectors, such as tubes 71, 72, 73 and 74, for connecting the different components of the liquid perfusion apparatus. Each tube may be provided to define the flow path through the system 10, e.g. to provide a conduit through which liquid perfusate flows. Although only one piece of tubing is shown for each connection in Fig. 1, it will be appreciated that multiple portions of tubing could be provided. For example, the connection to the body tissue 60 (e.g. from oxygenator 40 to body tissue 60 and / or from body tissue 60 to reservoir 20) may comprise a plurality of connectors, e.g. pieces of tubing. Each such piece of tubing may be coupled to the native vasculature of the body tissue 60 (e.g. to its veins and arteries), or other anatomical structures for example ureter, bile duct, heart atria or ventricles. One piece of tubing may be provided to couple to each such connection to the vasculature, or other anatomical structures, of the body tissue 60. Likewise, one piece of tubing may be provided for each such connection from the vasculature, or other anatomical structures, of the body tissue 60 towards the reservoir 20. For example, tubing may be connected to one or more arteries or veins (e.g. portal vein for liver perfusion), or other anatomical structures, of the body tissue 60 to couple the liquid perfusate pump 30 / oxygenator 40 to the body tissue 60. Likewise, tubing may be connected to one or more veins, or other anatomical structures, of the body tissue 60 and / or to a collecting container which the body tissue 60 drains into to couple the body tissue 60 to the reservoir 20.

[0050] The structure and function of the cell therapy element 100, and the components which couple it to the liquid perfusion apparatus, will be described in more detail further below with reference to Inset A of Fig. 1, but first the function of the other components of the system 10 will be described.

[0051] The system 10 is configured to circulate liquid perfusate through the body tissue 60. The system 10 may be configured to provide normothermic liquid perfusion of the body tissue 60. For example, the liquid perfusate heater 50 may be configured to regulate a temperature of the liquid perfusate (e.g. to heat it and / or to cool it) to be within a selected range. The liquid perfusate heater 50 may be configured to regulate the liquid perfusate temperature 50 to be within a normothermic range. Although not shown in Fig. 1, the system may optionally comprise a heater / cooler configured to regulate a temperature of the body tissue 60 itself, e.g. to regulate a temperature of a container in which the body tissue 60 is stored.

[0052] The reservoir 20 is configured to store liquid perfusate to be delivered to the body tissue 60. The reservoir 20 is coupled to receive liquid perfusate which has passed through the body tissue 60. The reservoir 20 is coupled to deliver stored liquid perfusate to the other components of the system 10 for further delivery to the body tissue 60. For example, the liquid perfusate pump 30 is configured to receive liquid perfusate from the reservoir 20 which it may pump towards the body tissue 60. The liquid perfusate pump 30 and oxygenator 40 are located downstream of the reservoir 20. That is, the liquid perfusate pump 30 and oxygenator 40 are configured to receive liquid perfusate from the reservoir 20. The liquid perfusate pump 30 may be upstream of the oxygenator 40. The liquid perfusate pump 30 may be configured to pump liquid perfusate (from the reservoir 20) towards the oxygenator 40 (and thus body tissue 60).

[0053] The liquid perfusate pump 30 is configured to regulate a pressure of the liquid perfusate. Although not shown in Fig. 1, the system 10 may comprise one or more pressure sensors configured to obtain an indication of a pressure of the liquid perfusate flowing through the system 10. The liquid perfusate pump 30 may be configured to control the pressure to be at a selected value, e.g. the pump 30 may be configured to operate according to a constant pressure. The liquid perfusate pump 30 may be configured to regulate the pressure to provide a desired flow rate through the body tissue 60. For example, the liquid perfusate pump 30 may control the pressure to be in a range between a maximum pressure associated with potential damage to the vasculature of the body tissue 60 and a minimum pressure associated with insufficient flow through the body tissue 60. Additional pressure sensors may be provided, e.g. for larger portions of body tissue, such as the liver, or for portions of body tissue which require different pressures for different areas of inflow (such as the liver which requires a different pressure in the hepatic artery and portal vein).

[0054] The oxygenator 40 is configured to oxygenate the liquid perfusate. Although not shown in Fig. 1 , the system 10 may comprise an oxygen sensor configured to obtain an indication of an oxygenation level of the liquid perfusate. The oxygenator 40 may be configured to regulate an oxygenation level of the liquid perfusate, e.g. to increase the oxygenation level of the liquid perfusate to be delivered to the body tissue 60.

[0055] The liquid perfusate heater 50 may be configured to regulate a temperature of the liquid perfusate. For simplicity, this is referred to as a “heater”, but the liquid perfusate heater 50 may be configured to selectively provide heating or cooling. That is, the liquid perfusate heater 50 is configured to regulate a temperature of the liquid perfusate by increasing or decreasing that temperature, as required. The liquid perfusate heater 50 may be configured to regulate the liquid perfusate temperature to be within a selected range e.g. a normothermic (body temperature) range. Additionally or alternatively, the liquid perfusate heater 50 may be configured to regulate liquid perfusate temperature to a hypothermic range, e.g. approximately 8 to 10 degrees Celsius.

[0056] The liquid perfusate pump 30, oxygenator 40 and / or liquid perfusate heater 50 may be configured to regulate properties of the liquid perfusate based on the body tissue 60 to which the liquid perfusate is to be delivered. They may be configured to control conditions of the liquid perfusate to mimic one or more ordinary living conditions of the body tissue 60. For example, the liquid perfusate heater 50 may be configured to regulate the liquid perfusate temperature to be normothermic. Likewise, the liquid perfusate pump 30 may be configured to control liquid perfusate pressure and / or flow rate to be at similar levels to that for the living body tissue. For example, they may be configured to regulate liquid perfusate to be similar in oxygenation, carbon dioxide content, pressure and / or temperature to that of blood when the body tissue 60 would be operating in normal conditions in the human or animal body. Additionally, or alternatively, they may be configured to control one or more conditions to be different to that during normal life. For example, the oxygenator 40 may be configured to elevate liquid perfusate oxygen levels to above normal values. Likewise, the liquid perfusate heater 50 may be configured to control the liquid perfusate temperature to be lower than body temperature. For example, they may be configured to control conditions of the liquid perfusate to specific non-physiological conditions, such as maintained hypothermia or increased oxygen contents.

[0057] In other words, the system 10 is configured to store liquid perfusate to be delivered in the reservoir 20, to condition that liquid perfusate accordingly before then delivering that liquid perfusate to the body tissue 60. The liquid perfusate which has passed through the body tissue 60 is then returned to the reservoir 20, before being re-conditioned for delivery the body tissue 60 again.

[0058] The present inventors have identified that body tissue 60 which is perfused by the system 100 may substantially benefit from enabling an interaction between the liquid perfusate to be delivered to the body tissue 60 and cell therapy cells. In particular, the present inventors have identified that the provision of a semi-permeable interface between the liquid perfusate and the cell therapy cells may be particularly advantageous, so that the cell therapy cells themselves do not pass through into the liquid perfusate, but other (e.g. smaller) molecules and cell products (e.g. extracellular vesicles), which may arise due to this semi-permeable interface between liquid perfusate and cell therapy cells, can pass through into the liquid perfusate.

[0059] As will now be described in more detail, this functionality may be provided by the cell therapy element 100. The cell therapy element 100 is shown larger and in greater detail in the cross- sectional view of Inset A of Fig. 1.

[0060] As already mentioned, the liquid perfusion apparatus defines a first flow path which does not pass through the cell therapy element 100, as well as a second liquid flow path which does pass through the cell therapy element 100. For this second liquid flow path, the inlet connector 201 and outlet connector 202 are connected to components of the liquid perfusion apparatus. In the example shown in Fig. 1, both the inlet connector 201 and the outlet connector 202 are connected between the reservoir 20 and the liquid perfusate pump 30, e.g. both the inlet connector 201 and the outlet connector 202 are connected to the first tube 71. In other words, this second liquid flow path runs parallel to the first liquid flow path between the reservoir 20 and the liquid perfusate pump 30, e.g. parallel to the first tube 71. The second flow path passes through the cell therapy pump 210, the cell therapy liquid heater 220 and the cell therapy element 100, before returning to the first flow path.

[0061] In other words, at least some of the liquid perfusate being circulated through the liquid perfusion apparatus and body tissue 60 (e.g. along the first liquid flow path) may pass through the second liquid flow path (and through the cell therapy element 100).

[0062] For the cell therapy element 100 itself, a liquid flow path is defined from the liquid inlet 101 through to the liquid outlet 102.

[0063] A portion of the cell therapy element 100 is for storing cell therapy cells (hereinafter referred to as the ‘cell therapy portion 111’), and a portion of the cell therapy element 100 is for passing liquid perfusate (hereinafter referred to as the ‘liquid perfusate portion’). The cell therapy portion 111 is separated from the liquid perfusate portion by a semi-permeable barrier. The semi-permeable barrier may be provided by one or more semi-permeable membranes.

[0064] The liquid perfusate portion comprises one or more liquid perfusate channels 112. Each liquid perfusate channel 112 is coupled to the liquid inlet 101 and to the liquid outlet 102, e.g. to provide a flow path therebetween. Each liquid perfusate channel 112 is at least partially bounded by semi- permeable wall 110. That is, at least a portion of the wall(s) which defines the liquid perfusate channel 112 is semi-permeable. For example, the majority, e.g. all, of each liquid perfusate channel 112 is bounded by a semi-permeable wall 110. The cell therapy element 100 may comprise a plurality of such liquid perfusate channels 112. The liquid perfusate channels 112 may be arranged in an array (e.g. grid-like) structure. For example, the liquid perfusate channels 112 may be parallel to each other.

[0065] The liquid perfusate channels 112 may be at least partially flexible. For example, the material which provides the semi-permeable wall 110 of a liquid perfusate channel 112 may itself a certain degree of inherent flexibility. As such, the arrangement of the channels 112 within the cell therapy element 100 may not be fixed in a rigid structure. Instead, the channels 112 themselves may move / bend due to movement of liquid perfusate through those channel 112 and / or due to movement in the cell therapy portion 111.

[0066] A portion of some, or all, of the liquid perfusate channels 112 may be separated from a neighbouring liquid perfusate channel 112 by a region of the cell therapy portion 111. For example, each liquid perfusate channel 112 may be at least partially surrounded (radially) by the cell therapy portion 111 of the cell. For example, the cell therapy element 100 may comprise a volume in which the cell therapy cells are provided (‘the cell therapy portion 11 T) and a plurality of liquid perfusate channels 112 extending across that volume from the liquid inlet 101 to the liquid outlet 102. Each liquid perfusate channel 112 may be cylindrical. One or more walls which define the liquid perfusate channel 112 along its length may be a semi-permeable wall 110. Each liquid perfusate channel 112 may be at least partially in contact with a region of the cell therapy portion 111.

[0067] In other words, an outer surface of at least some of the liquid perfusate channels 112 (as provided at least in part by a semi-permeable wall 110) may be in contact with a cell therapy portion 111 (and cell therapy cells contained therein). Each liquid perfusate channel 112 may be relatively long and relatively thin. For example, the length and thickness of each liquid perfusate channel 112 may be selected to provide a surface area to volume ratio for that channel of at least a threshold amount. Each liquid perfusate channel 112 may be longer than it is wide, e.g. it may be at least 5 or at least 10 or at least 50 or at least 100 times longer than its width (e.g. its cross-sectional width / diameter).

[0068] A plurality of such liquid perfusate channels 112 are shown in Fig. 1. As shown, each liquid perfusate channel 112 is bounded by a semi-permeable wall 110 which separates that liquid perfusate channel 112 from the cell therapy portion 111. The liquid perfusate channels 112 may run parallel to each other (or at least approximately parallel). The liquid perfusate channels 112 may be distributed in a regular and / or uniform pattern within the cell therapy element 100, e.g. the inlets / outlets of each channel may be spaced across the element 100 in a regular and / or uniform distribution.

[0069] Each of the liquid perfusate channels 112 couples the liquid inlet 101 to the liquid outlet 102. The cell therapy element 100 is arranged to separate liquid received through the liquid inlet 101 into each of the liquid perfusate channels 112. For example, one or more diverters or channel separators may be included so that the liquid flows into each of the different liquid perfusate channels 112. Likewise, liquid flowing through each of the liquid perfusate channels 112 is directed out through the liquid outlet 102.

[0070] The semi-permeable walls 110 may each be provided by a semi-permeable membrane. The semi- permeable wall 110 comprises a plurality of pores (e.g. it may be porous). A pore size may be selected based on the cell therapy cells in the cell therapy portion 111. For example, the pore size may be selected to inhibit passage of the cell therapy cells themselves, but to allow smaller molecules such as secreted soluble factors and / or extracellular vesicles to pass therethrough. For example, the pore size may be no more than 300 nm, such as between 200 and 400 nm (e.g. to permit transfer of extracellular vesicles including exosomes, but not cells themselves). A smaller pore size could be employed if only permitting secreted soluble factors (e.g. of the order of 100- 200 kDa), such as soluble paracrine factors (e.g. VEGF, vasodilatory molecules, indoleamine 2 3- dioxygenase, cytokines). The semi-permeable wall 110 may comprise a filter.

[0071] In other words, the cell therapy element 100 is arranged to keep the cell therapy cells and the liquid perfusate in separate compartments, but where smaller molecules than the cell therapy cells themselves may be transferrable between the cell therapy portion 111 and the liquid perfusate portion (e.g. from the cell therapy portion 111 into the liquid perfusate portion and from the liquid perfusate portion into the cell therapy portion 111).

[0072] The system 10 also includes a thermal regulation element arranged to regulate a temperature of cell therapy cells in the cell therapy portion 111 of the cell therapy element 100. In Fig. 1 , two thermal regulation elements are shown: (i) thermal insulation 121, and (ii) cell therapy heater 122.

[0073] The thermal insulation 121 at least partially surrounds the cell therapy element 100 (and the cell therapy portion 111 thereof). For example, the thermal insulation 121 may completely surround the cell therapy element 100. The cell therapy element 100 may comprise one or more outer walls which define an internal volume of the cell therapy element 100 therewithin. The liquid perfusate channels 112 may extend across this internal volume. The remainder of this internal volume may provide the cell therapy portion 111 and may be filled with cell therapy cells. The insulation 121 may at least partially, e.g. completely, surround the one or more outer walls of the cell therapy element 100. For example, an outer surface of the outer wall(s) may be covered by thermal insulation 121. The cell therapy element 100 may comprise one or more layers of thermal insulation 121 which surround the cell therapy portion 111 (as well as the liquid perfusate channel 112).

[0074] The cell therapy heater 122 may be coupled to the cell therapy portion 111 of the cell therapy element 100. For example, the cell therapy heater 122 may be coupled to one of the walls (e.g. the outer walls) of the cell therapy element 100 which defines the cell therapy portion 111. The cell therapy heater 122 may be coupled to an outside surface of the wall (as shown in Fig. 1) or it may be coupled to an inside surface. The cell therapy heater 122 is located in close proximity to (or in contact with) the cell therapy portion 111 of the cell therapy element 100 (and thus the cell therapy cells therein). The cell therapy heater 122 may be a component of the cell therapy element 100 and / or it may be in contact with a surface of the cell therapy element 100.

[0075] The cell therapy element 100 may comprise a hollow fibre element and / or a bioreactor. For example, the cell therapy element 100 may comprise a hollow fibre bioreactor. As will be appreciated in the context of the present disclosure, any suitable cell therapy cell may be provided in the cell therapy portion 111 of the cell therapy element 100. Although not shown in Fig. 1 , the cell therapy portion 111 may comprise a seeding inlet and / or outlet for providing cells into / out of the cell therapy portion 111. The cell therapy cells may comprise stem cells.

[0076] The particular choice of cell therapy cells to be used may be selected based on the intended application. For example, the choice of cell therapy cells may be selected based on the type of body tissue 60 (e.g. type of organ) to which the system is coupled. Some cell therapy cells may be capable of providing beneficial effects when applied to a majority of (or even any) different types of body tissue 60, whereas some cell therapy cells may be specific to particular types of body tissue 60.

[0077] For example, the cell therapy cells may comprise one or more of the following: (i) multipotent adult progenitor cells (such as the cell product sold under the registered trade mark ‘MultiStem’), (ii) mesenchymal stromal cells, including autologous, allogeneic or xenogeneic (sourced from any tissue of origin including e.g. bone marrow, adipose tissue, umbilical cord, placenta, peripheral blood), (iii) human amniotic epithelial cells, (iv) pluripotent stem cells (including induced pluripotent stem cells; iPSC), and any cell products derived from these, (v) adipose derived stem cells, (vi) endothelial progenitor cells, (vii) stem cells from umbilical cord blood, (viii) engineered cell lines, and / or immune cells including regulatory T-cells (TRegs). Such cell therapy cells may be broadly applicable to different types of body tissue 60. Additionally, or alternatively, cell therapy cells may be provided which are more specific to particular types of body tissue 60 (e.g. to specific organs). For example, such cell therapy cells may comprise one or more of the following organ specific stem or progenitor cells: (i) neonatal kidney stem / progenitor cells, (ii) renal stem / progenitor cells, (iii) liver stem / progenitor cells, (iv) cardiac stem / progenitor cells, (v) lung stem / progenitor cells, and / or (vi) mesenchymal stromal cells (MSCs) harvested from specific organs for example: kidney, liver, lung or cardiac derived MSCs.

[0078] The cell therapy element 100 is arranged to permit exchange of molecules, such as secreted soluble factors and / or extracellular vesicles, between the cell therapy portion 111 and the liquid perfusate channels 112 without permitting exchange of the cell therapy cells themselves. The cell therapy element 100 is configured to permit two-way exchange between the liquid perfusate channels 112 and the cell therapy portion 111 (e.g. from the cell therapy portion 111 to the liquid perfusate channels 112 and from the liquid perfusate channels 112 to the cell therapy portion 111).

[0079] The present inventors have identified that this arrangement may enable beneficial molecules released by the cell therapy cells to be included within the liquid perfusate which is to be provided to the body tissue 60. This may advantageously enable benefits associated with cell therapy to be provided without having to physically provide cell therapy cells in direct contact with the body tissue 60. As such, this arrangement may significantly reduce the risk of deleterious effects such as the formation of clots, antibodies and / or tumours as a result of contact (e.g. direct contact) with and / or engraftment of the cell therapy cells. Also, by not delivering the cell therapy cells themselves to the body tissue 60, there may be fewer regulatory limitations associated with this technology. Furthermore, communication from the liquid perfusate (which has circulated through the body tissue 60) and the cell therapy cells may enable a “turn on” signal to be provided to the cell therapy cells. In turn, this may lead to the cell therapy cells generating (more of) the beneficial molecules, or cell products, that may pass through the semi-permeable wall 110 and be delivered to the body tissue 60 with the liquid perfusate.

[0080] The cell therapy element 100 is configured to provide an interface between: (i) molecules and other cellular products in the cell therapy portion 111 , and (ii) liquid perfusate in the liquid perfusate channels 112. The semi-permeable walls 110 are arranged to provide an interface region between the liquid perfusate portion and the cell therapy portion 111. The semi-permeable walls 110 may be arranged to permit two-way transfer between liquid perfusate in the liquid perfusate channels 112 and molecules in the cell therapy portion 111. For example, the semi-permeable walls 110 may be configured to permit interaction of the liquid perfusate which has travelled through the body tissue 60 with the cell therapy cells in the cell therapy portion 111, e.g. to transmit a “turn on” signal to said cell therapy cells. Likewise, the semi-permeable walls 110 may be configured to permit transfer of smaller molecules through to the liquid perfusate channels 112, while inhibiting the transfer of cell therapy cells.

[0081] The cell therapy element 100 is configured to provide a large surface area of the contact surface between the liquid perfusate channels 112 and the cell therapy portion 111. For example, the liquid perfusate channels 112 may be configured to be relatively long and relatively narrow to maximise the surface area of each liquid perfusate channel 112 which is contact with the cell therapy portion 111.

[0082] As already mentioned, the system 10 comprises a second liquid flow path which passes through the cell therapy element 100. The second liquid flow path is coupled to the first liquid flow path to receive liquid perfusate therefrom and to provide liquid perfusate thereto. That is, the cell therapy element 100 is provided in a parallel arm to the first liquid flow path (to the first tube 71 in Fig. 1). For this, the inlet connector 201 is coupled to the first flow path of the liquid perfusion apparatus, and the outlet connector 202 is coupled to the first flow path of the liquid perfusion apparatus. The second flow path runs from through the inlet connector 201 , through the cell therapy element 100 and out through the outlet connector 202. The cell therapy pump 210 and cell therapy liquid heater 220 are provided in the second flow path.

[0083] In other words, the system 10 is arranged to define two liquid flow paths: (i) one which bypasses the cell therapy element 100, and (ii) one which passes through the cell therapy element 100. In Fig. 1 , the first flow path is the first tube 71 from the reservoir 20 to the liquid perfusate pump 30. In Fig. 1 , the second flow path comprises a portion of the first tube 71 before diverting through the inlet connector 201 , through the cell therapy element 100 and out trough the outlet connector 202.

[0084] The inlet connector 201 may comprise attachment means for connecting to an existing liquid perfusion apparatus. In Fig. 1, the inlet connector 201 is shown connected to the liquid perfusion apparatus (to first tube 71). The inlet connector 201 may comprise tubing to connect to said liquid perfusion apparatus. For example, the tubing may comprise a 1 / 8 inch tubing, a 1 / 4 inch tubing, a 3 / 8 inch tubing (3.175 mm, 6.35 mm and 9.525 mm, respectively), a barb connector to fit any of these tubing types, and / or a luer lock connector. Likewise, the outlet connector 202 may comprise attachment means for connecting to an existing liquid perfusion apparatus. In Fig. 1 , the outlet connector 202 is shown connected to the liquid perfusion apparatus (to first tube 71). The outlet connector 202 may comprise tubing to connect to said liquid perfusion apparatus. For example, the tubing may comprise a 1 / 8 inch tubing, a 1 / 4 inch tubing, a 3 / 8 inch tubing (3.175 mm, 6.35 mm and 9.525 mm, respectively), a barb connector to fit any of these tubing types, and / or a luer lock connector.

[0085] The inlet connector 201 is coupled to the cell therapy pump 210. The cell therapy pump 210 may comprise a peristaltic pump. The cell therapy pump 210 is connected between the inlet connector 201 and the cell therapy element 100 (the liquid inlet 101 of the cell therapy element 100). In other words, and as shown in Fig. 1, the cell therapy pump 210 is coupled to, e.g. in fluid communication with, the liquid perfusion apparatus (e.g. first tube 71) via the inlet connector 201. The cell therapy pump 210 is coupled between the first liquid flow path of the liquid perfusion apparatus and the cell therapy element 100.

[0086] If an optional cell therapy liquid heater 220 is included, the cell therapy liquid heater 220 may be located between the cell therapy pump 210 and the cell therapy element 100. Likewise, an optional oxygenator may be included in the second flow path. For example, the optional oxygenator may be downstream of the cell therapy pump 210 (e.g. between the cell therapy pump 210 and the cell therapy element 100). This oxygenator may regulate oxygen and / or carbon dioxide content of fluid entering the cell therapy element 100, and may itself be connected to a fluid heater.

[0087] The cell therapy element 100 is coupled to the outlet connector 202 (the liquid outlet 102 of the cell therapy element 100 is connected to the outlet connector 202). As shown in Fig. 1 , the outlet connector 202 is coupled to the liquid perfusion apparatus (to first tube 71), e.g. to couple the second flow path (through the cell therapy element 100) back to the first liquid flow path (which bypasses the cell therapy element 100).

[0088] This arrangement defines a second liquid flow path in which liquid perfusate is received in through the inlet connector 201, where that liquid then flows through the cell therapy pump 210, optional heater 220 and into the cell therapy element 100 (e.g. through the liquid inlet 101, the liquid perfusate channels 112, and out through the liquid outlet 102), before passing out through the outlet connector 202. This defines an additional or alternative path for liquid perfusate to flow through, as compared to the existing first liquid perfusate flow path for that liquid perfusate apparatus.

[0089] This second liquid flow path is arranged in parallel with the first liquid flow path of the liquid perfusion apparatus, e.g. with the second liquid flow path passing through the cell therapy element 100 and the first liquid flow path bypassing the cell therapy element 100.

[0090] The system 10 is arranged so that both flow paths may ultimately lead liquid perfusate to the body tissue 60. Only one of the flow paths (the second flow path) involves interaction with the cell therapy cells in the cell therapy element 100.

[0091] The inlet connector 201 is configured to couple to a flow path of the liquid perfusion apparatus. As shown in Fig. 1 , the inlet connector 201 is coupled to the first tube 71. The inlet connector 201 is configured to couple to said flow path to receive liquid perfusate therefrom. Likewise, the outlet connector 202 is configured to couple to a flow path of the perfusion apparatus (the outlet connector 202 is coupled to the first tube 71 in Fig. 1). The outlet connector 202 is configured to return cell therapy treated liquid perfusate (i.e. liquid perfusate which has passed through the cell therapy element 100) to the liquid flow path of the liquid perfusion apparatus (e.g. to the first tube 71 in Fig. 1).

[0092] The cell therapy pump 210 may be configured to regulate the flow of liquid perfusate through the cell therapy element 100. That is, the cell therapy pump 210 may be configured to control (or at least influence) an amount, e.g. a flow rate, of liquid perfusate received through the inlet connector 201 (e.g. from the first liquid flow path of the liquid perfusion apparatus). For example, the cell therapy pump 210 may be configured to actively draw liquid perfusate in through the inlet connector 201 from the first liquid perfusate flow path of the liquid perfusate apparatus (e.g. from the first tube 71).

[0093] The cell therapy pump 210 may be configured to provide a selected flow rate through the cell therapy element 100. The selected flow rate for liquid perfusate flowing through the cell therapy element 100 may be different to the flow rate for liquid perfusate flowing through body tissue 60. For example, the cell therapy pump 210 may operate differently to the liquid perfusate pump 30. Likewise, if an optional cell therapy liquid heater 220 or oxygenator is included, said component may be operated differently to the liquid perfusate heater 50 / oxygenator 40 to control temperature or oxygenation of liquid perfusate in the cell therapy element 100 to be at different values to that of liquid perfusate provided to body tissue 60. The cell therapy liquid heater 220 may be configured to regulate a temperature of the liquid perfusate passing through the cell therapy element. For example, the cell therapy liquid heater 220 may be configured to increase or decrease this temperature. Operation of the cell therapy liquid heater 220 may be controlled to regulate a temperature of the liquid perfusate based on a temperature selected for interaction with the cell therapy cells in the cell therapy element 100.

[0094] For example, the flow rate of liquid perfusate through the cell therapy element 100 may be selected based on a type of cell therapy cells in the cell therapy portion 111 , e.g. to provide a desired interaction between liquid perfusate and cell therapy cells. The cell therapy pump 210 may be additional to the liquid perfusate pump 30. The cell therapy pump 210 may be configured to provide a different flow rate (or pressure), as compared to the liquid perfusion pump 30. For instance, this may enable the conditions (e.g. pressure / flow rate) through the cell therapy element 100 to be tailored to providing a desired interaction between liquid perfusate and cell therapy cells (rather than to desired conditions for liquid perfusate to be delivered to the body tissue 60).

[0095] The cell therapy element 100 is coupled to the other components of the liquid perfusion apparatus to provide an interaction with the cell therapy cells for liquid perfusate to be delivered to the body tissue 60. The cell therapy element 100 may be configured to receive liquid perfusate from the reservoir 20, e.g. through the liquid inlet 101. The cell therapy element 100 may be configured to output cell therapy treated liquid perfusate, e.g. through the liquid outlet 102, to be delivered to the body tissue 60. That is, the system 10 is configured so that at least some of the liquid perfusate circulating from the reservoir 20 to the body tissue 60 may pass through the cell therapy element 100 (e.g. in via inlet connector 201 and back via outlet connector 202) on its way to the body tissue 60.

[0096] For example, at least some of the liquid perfusate received at the liquid perfusate pump 30 may be cell-treated liquid perfusate received from the cell therapy element 100. The liquid perfusate pump 30 may be configured to control the pressure of the cell-treated liquid perfusate to be delivered to the body tissue 60. For example, the liquid perfusate pump 30 may be configured to control a pressure of this liquid perfusate based on the body tissue 60 to which that liquid perfusate is to be delivered. The oxygenator 40 may be configured to oxygenate this cell-treated liquid perfusate (e.g. based on a selected oxygenation for the body tissue 60 to which it is to be delivered). The liquid perfusate heater may be configured to regulate a temperature of this cell-treated liquid perfusate (e.g. based on a selected temperature for the body tissue 60 to which it is to be delivered).

[0097] The system 10 is configured to deliver the cell therapy treated liquid perfusate to the body tissue 60. The system 10 is configured to deliver at least some of the liquid perfusate which has passed through the body tissue 60 back to the cell therapy element 100 (for example via the reservoir 20). In other words, the system 10 is configured to circulate liquid perfusate through the cell therapy element 100 (for cell therapy treatment thereof), to the body tissue 60, and back to the cell therapy element 100. This arrangement may enable liquid perfusate which has passed through the body tissue 60 to interface with the cell therapy cells (in the cell therapy element 100). Also, this arrangement may enable liquid perfusate to be delivered to the body tissue 60 which has interacted with the cell therapy treatment cells.

[0098] The present inventors have further identified that the inclusion of a thermal regulation element to regulate a temperature of the cell therapy cells may facilitate improved operating characteristics for the cell therapy cells. In particular, the system 10 may be configured to ensure that a temperature of the cell therapy cells remains within a selected range associated with improved operation of those cells.

[0099] The cell therapy element 100 comprises the thermal regulation element. That is, the thermal regulation element is a component of the cell therapy element 100 itself. The thermal regulation element may be arranged to retain a temperature of the cell therapy cells in the cell therapy portion 111 within a threshold range. The thermal regulation element may be configured to heat the cell therapy portion 111 of the cell therapy element 100 (e.g. using cell therapy heater 122). The thermal regulation element may be configured to thermally insulate the cell therapy portion 111 of the cell therapy element 100 (e.g. using insulation 121). The threshold range may be selected based on the particular cell therapy cells. For example, the cell therapy cells may have an associated desired (or optimal) temperature range, and the thermal regulation element may be configured to retain the temperature of the cell therapy element 100 within such a temperature range. For example, the thermal regulation element may be configured to retain the cell therapy cells at a normothermic temperature, e.g. between 35 and 39 degrees.

[0100] The system 10 may be configured to regulate a temperature of the liquid perfusate (using liquid perfusate heater 50 for heating / cooling the liquid perfusate), e.g. so that it is normothermic. Likewise, if the optional cell therapy liquid heater 220 is included, this may provide heating / cooling of liquid perfusate. As such, liquid perfusate passing through the liquid perfusate channels 112 may be at a different, e.g. elevated, temperature, e.g. as compared to ambient. The liquid perfusate heater 50 may be configured to heat the liquid perfusate to a temperature selected based on the type of body tissue 60 to which that liquid perfusate is to be delivered. For example, this may be body temperature. This temperature may be similar to, e.g. the same as, a temperature at which the cell therapy cells are to be kept. In which case, due to thermal conduction from liquid perfusate in the liquid perfusate channels 112, a temperature of the cell therapy portion 111 in the immediate vicinity of (e.g. immediately adjacent to) a liquid perfusate channel 112 may be within the selected temperature range for the cell therapy cells themselves. However, other regions of the cell therapy portion 111 may be in a sub-optimal temperature range.

[0101] The inventors have shown that having a thermal regulation element (thermal insulation 121 and / or cell therapy heater 122) as part of the cell therapy element 100 results in improved temperature control of the cell therapy portion 111, when compared with a liquid perfusate system 10 with temperature control via liquid perfusate heater 50 and / or optional cell therapy liquid heater 220 with cell therapy element 100 without specific thermal regulation of said cell therapy element 100 (e.g. lacking thermal insulation 121 and cell therapy heater 122).

[0102] The thermal regulation element may be configured to regulate a temperature of all of the cell therapy portion 111 (e.g. for all of the cell therapy cells therein). For this, the thermal regulation element may be configured to provide a substantially uniform temperature throughout the cell therapy portion 111. For example, the thermal regulation element may be arranged to inhibit thermal gradients across the cell therapy element 100 exceeding a threshold level. That is, the thermal regulation element may be configured to inhibit certain regions of the cell therapy portion 111 being at a temperature which is substantially different (e.g. colder) to other regions of the cell therapy portion 111.

[0103] For instance, the thermal regulation element may comprise use of the thermal insulation 121 to reduce an amount of thermal transfer away from the cell therapy portion 111 of the cell therapy element 100. For example, the insulation 121 may at least partially, e.g. completely, surround an outer surface of the cell therapy portion 111 of the cell therapy element 100. The insulation 121 may be configured to inhibit thermal transfer above a threshold amount away from the cell therapy portion 111. For example, the thermal insulation 121 may be configured to increase heat retention within the cell therapy portion 111. The thermal insulation 121 may be configured to retain heat arising due to heating provided by thermal transfer from the liquid perfusate (e.g. which was heated by the liquid perfusate heater) to retain the entire cell therapy portion 111 within the selected temperature range for cell therapy operation. For example, cell therapy cells in further away regions from the liquid perfusate channels 112, such as towards the outer extremities of the cell therapy element 100, may be retained within their threshold temperature range despite being further away from a source of thermal transfer (e.g. from the liquid perfusate channels 112 containing warmer liquid perfusate). In other words, the thermal regulation element may be passive and configured to retain a temperature of the cell therapy portion 111 within a selected range.

[0104] Additionally, or alternatively, the thermal regulation element may comprise use of the cell therapy heater 122. The cell therapy heater 122 may be a separate, e.g. additional, component to the liquid perfusate heater 50 (or the cell therapy liquid heater 220, if included). The cell therapy heater 122 may be configured to heat at least a portion of the cell therapy portion 111 of the cell therapy element 100. For example, the cell therapy heater 122 may be configured to heat a surface, such as an external surface, of the cell therapy element 100. The cell therapy heater 122 may be configured to provide heating of the cell therapy portion 111 to retain a temperature of the cell therapy cells therein within a selected range. For example, the cell therapy element 100 may comprise one or more sensors configured to obtain an indication of a temperature of the cell therapy cells in the cell therapy portion 111. The system 10 may be configured to control operation of the cell therapy heater 122 based on said obtained indication of temperature. For example, in the event that a temperature of the cell therapy portion 111 is below a lower threshold, the cell therapy heater 122 may be configured to increase heating thereof. Likewise, in the event that a temperature of the cell therapy portion 111 exceeds an upper threshold, the cell therapy heater 122 may be configured to decrease and / or stop heating thereof. The system 10 may be configured to control operation of the cell therapy heater 122 to retain a temperature of the cell therapy cells within the cell therapy portion 111 within a threshold temperature range. The threshold temperature range may be selected depending on the body tissue 60. The cell therapy heater 122 may be configured to adjust its controlled temperature range accordingly.

[0105] Both active and passive thermal regulation may be employed. For example, both thermal insulation 121 and cell therapy heater 122 may be included together. Additionally, or alternatively, the insulation 121 may be provided in combination with the cell therapy liquid heater 220, e.g. so that the cell therapy liquid heater 220 may provide heating / cooling of the liquid perfusate so that this is within a selected temperature range, and the thermal insulation 121 may be configured to retain the temperature of the cell therapy cells within the cell therapy portion 111 within the selected temperature range.

[0106] In other words, the system 10 is configured to provide liquid perfusate to a body tissue 60, where that liquid perfusate has interacted with cell therapy cells which are retained within a selected temperature range. This may provide improved transfer of beneficial material to the liquid perfusate from the cell therapy cells, which in turn may then be provided to the body tissue 60. Likewise, this may provide improved transfer of relevant material from the liquid perfusate to the cell therapy cells to instruct action of those cell therapy cells accordingly.

[0107] In operation, liquid perfusate to be delivered to the body tissue 60 is stored in the reservoir 20. Some of this liquid perfusate will be provided to the cell therapy element 100 where it will pass through the liquid perfusate channels 112. In so doing, the liquid perfusate will interact with the cell therapy cells via the semi-permeable walls 110. This interaction may be two-way, such that the liquid perfusate may receive beneficial components from the cell therapy portion 111 (e.g. extracellular vesicles and / or secreted soluble factors) and the liquid perfusate may instruct the cell therapy cells (e.g. by providing a “turn on” signal). As a result, the liquid perfusate passing out from the cell therapy element 100 may be of improved quality. This cell therapy treated liquid perfusate may then be oxygenated, heated and / or pumped so that it is at a suitable oxygenation level, carbon dioxide level, temperature and / or pressure to be provided to the body tissue 60. This liquid perfusate is then delivered to the body tissue 60, e.g. through the native vasculature, before being collected and returned to the reservoir 20. This process is repeated continuously so that liquid perfusate keeps being treated by cell therapy cells and provided to the body tissue 60.

[0108] While this cell therapy treated liquid perfusion is occurring, the cell therapy portion 111 of the cell therapy element 100 is thermally regulated. For this, the cell therapy element 100 will be thermally insulated (by insulation 121) and / or heated (by cell therapy heater 122). In so doing, the temperature of the cell therapy portion 111 is retained within a threshold range. The threshold range is selected based on the cell therapy cells in the cell therapy portion 111 and / or the body tissue 60. The cell therapy cells may be retained at a close to optimal temperature to increase their functionality for treating liquid perfusate, e.g. so that the cell therapy cells in the cell therapy portion 111 make more of their beneficial products, which then get into the liquid perfusate in the liquid perfusate channels 112. As such, the interaction between liquid perfusate (in the liquid perfusate channels 112) and cell therapy cells (in the cell therapy portion 111) may result in improved liquid perfusate being provided to the body tissue 60.

[0109] As shown in Fig. 1, some of the liquid perfusate travelling from reservoir 20 to body tissue 60 passes through the cell therapy element 100 (via the second flow path), and some of this liquid perfusate may bypass the cell therapy element 100. The cell therapy pump 210 controls the amount of liquid perfusate which passes through the cell therapy element 100, e.g. by actively drawing a selected amount of liquid perfusate into the second liquid flow path. Operation of the cell therapy pump 210 is controlled to provide a flow rate / pressure through the cell therapy element 100 selected based on the interaction between liquid perfusate and cell therapy cells in the cell therapy element 100.

[0110] To demonstrate some of the beneficial effects brought about through use of the system 10 in Fig. 1 , reference will now be made to Fig. 2.

[0111] Fig. 2 shows numerical data demonstrating the beneficial effects of this technology. In particular, Fig. 2 shows the benefits of applying this technology to preserve and repair human kidneys. This data was obtained from three separate pairs of human kidneys (which were initially retrieved for transplantation but then used for research). For these three pairs, one kidney from the pair was treated as a sample and the other kidney in the pair was treated as the control. For the sample kidney, this was provided in a manner similar to the body tissue 60 in the system 10 of Fig. 1 (e.g. coupled to a thermally regulated cell therapy element 100). Specifically, the cell therapy element 100 used to treat the sample kidneys contained cell therapy cells, as well as thermal insulation 121 for regulating a temperature of the cell therapy cells (but with no cell therapy heater 122). For the control kidney, this was provided in a corresponding system to the sample kidney, only without any cell therapy cells being included in the cell therapy portion 111 of the cell therapy element 100. For both sample and control kidneys, the cell therapy element 100 was connected to the circuit after 1 hour of normothermic preservation. This was to ensure that any changes seen were due to the cell therapy element 100, rather than inherent chance differences between the kidneys. After this initial

[0112] 1 hour, kidneys were preserved for a further 12 hours at normothermia using the system 10, with cell therapy element 100 either with cell therapy cells in the cell therapy portion 111 (sample kidney) or without cell therapy cells in the cell therapy portion (control kidney).

[0113] As can be seen, in all instances, the sample kidney (‘Cell therapy element’) performed much better than the control kidney (‘Sham cell therapy element’). As shown in the first graph, the sample kidney had improved urine production. This is important as the amount of urine the kidney produces during this normothermic preservation is known to predict how well a kidney will perform after transplant into a patient. The remaining graphs contain data from a technique demonstrating the quality of blood flow into key regions in the kidney (contrast-enhanced ultrasound). These demonstrate improved blood flow to both the cortex and medulla regions of the kidney, both of which play vital roles in the function of kidneys. These results were clearly evident for all sets of kidneys, and statistically significant in most cases. All of these improvements demonstrated in Fig.

[0114] 2 were not seen at 1 hour of normothermic preservation (prior to attachment of cell therapy element 100), confirming that improvements in preservation and repair seen in Fig. 2 are a result of the presence of cell therapy cells in the cell therapy portion. The difference in urine flow between each pair of kidneys gradually increased over the 13 hours of preservation.

[0115] Fig.3 shows graphs of tests performed on five pairs of kidneys performed under the same conditions as those tests described above in respect of Fig. 2. The graphs of Fig. 3 also show improved urine production and blood flow to both the cortex and medulla regions of the sample kidneys (cell therapy element) when compared to the control kidneys (sham cell therapy element). Further tests were performed, on the pairs of kidneys used to generate Fig. 3 to measure Neutrophil Gelatinase-Associated Lipocalin (NGAL) production following cell therapy and to measure concentrations of CXCL5 in the liquid perfusate of a system connected to a sham cell therapy element and a cell therapy element. The results of these tests are shown in the graphs of Fig. 4. The first graph of Fig. 4 shows a decreased production of NGAL which is indicative of improved kidney health in the sample kidney (‘Cell therapy element’) compared to the control kidney (‘Sham cell therapy element’). The second graph of Fig. 4 shows increased concentrations of CXCL5 (a key secreted protein) in the liquid perfusate of the cell therapy element system when compared to those concentrations in the liquid perfusate of the sham cell therapy system. CXCL5 is a key factor being produced by the specific cell therapy which was loaded into the cell therapy element for these experiments.

[0116] As with the graphs of Fig. 2, it can be seen from the graphs of Figs. 2, 3 and 4 that in all instances, the sample kidney (‘Cell therapy element’) performed much better than the control kidney (‘Sham cell therapy element’). In all of these experiments thermal regulation of the bioreactor was performed, in addition to heating of the liquid perfusate, via thermal insulation 121.

[0117] Fig. 5 shows three further graphs, the first graph demonstrates that without thermal regulation (for example the presence of a cell therapy heater 122 or thermal insulation 121) that the cell therapy element would be at a sub-optimum temperature (optimum temperature in this example being within 2.5°C of the liquid perfusate temperature). The second and third graphs shown in Fig. 5 show the difference in the secretion of two proteins (IL6 and VEGF) from cell therapy cells that have been grown at different temperatures. In both cases the cell therapy cells show increased secretion of the respective proteins when held within an optimal temperate range (in this test when held at 37°C), highlighting the importance of temperature regulation of cell therapy cells in respect of the production of key secreted proteins.

[0118] This therefore demonstrates the beneficial effects achieved due to this thermally regulated cell therapy treatment of the liquid perfusate delivered to the body tissue being preserved. Moreover, the results demonstrating improved kidney function for the thermally regulated cell therapy treatment showed a greater increase for the longer the kidney was receiving the cell therapy treated liquid perfusate. This shows that this technology may facilitate even longer storage and preservation of body tissue, e.g. ex-situ, before the body tissue may be implanted in a donor.

[0119] As described herein, and as demonstrated from the graphs of Fig. 2, using a thermally regulated cell therapy element 100 may provide beneficial effects to body tissue to which that cell therapy treated liquid perfusate is delivered. As such, it will be appreciated in the context of the present disclosure that the particular form or setting for the body tissue to which the system 10 is coupled should not be considered limiting. That is, this technology may be incorporated in any liquid perfusion system.

[0120] For example, the present disclosure may relate to ex-vivo liquid perfusion systems for perfusing a human or animal body. An ‘ex-vivo’ liquid perfusion system comprises a system in which the components for controlling the liquid perfusion are located outside of (e.g. external to) the human or animal body, e.g. as compared to said components being indwelling to the human or animal body. Ex-vivo liquid perfusion systems of the present disclosure may comprise ex-situ liquid perfusion systems and / or extracorporeal liquid perfusion systems. An ‘ex-situ’ liquid perfusion system comprises a system in which the body tissue to which the liquid perfusion system is coupled for liquid perfusion thereof is itself located outside of the human or animal body. An ‘extracorporeal’ liquid perfusion system comprises a system which is configured to provide liquid perfusate to a living human or animal body, in which liquid (blood) is taken from circulating the human / animal body, with a process applied to that liquid before it is returned to circulation within the body. In other words, for an extracorporeal system, the body tissue may be a living human or animal body, whereas for an ex-situ system, the body tissue is tissue (such as an organ or organs) which has been extracted from the human or animal body and which is kept in isolation from that body.

[0121] Systems of the present disclosure may comprise ex-situ liquid perfusion systems or extracorporeal liquid perfusion systems.

[0122] For an ex-situ liquid perfusion system, e.g. as shown in Fig. 1 , the body tissue to which the system is coupled is tissue which is to be stored in the system. Such a system is configured to preserve that body tissue. For example, such an ex-situ liquid perfusion system may be configured to store and preserve body tissue, such as an organ, before that organ is to be implanted in a living human or animal body. Ex-situ systems of the present disclosure, e.g. which utilise thermally regulated cell therapy cell treatment, may provide improved storage, preservation and / or repair of body tissue. For example, the body tissue which has been stored and preserved in such a system may be of greater quality and / or may have a greater viability for implantation into a subsequent human / animal body.

[0123] For an extracorporeal liquid perfusion system, the body tissue to which the system is coupled may be a living human or animal body. Such a system is configured to facilitate treatment of that human or animal body (e.g. rather than preserving that body for subsequent implant, as in the case of an ex-situ liquid perfusion system). For example, for extracorporeal liquid perfusion systems of the present disclosure, the liquid perfusate may be blood from the body, and wherein the system is configured to provide at least some of that blood to the cell therapy element (for cell therapy treatment thereof) before returning that cell therapy treated blood to the body. For example, the present disclosure may be utilised in haemodialysis and / or hemofiltration devices, e.g. for patients with kidney failure, apheresis devices and / or extracorporeal membrane oxygenators for takeover of the heart / lungs for patients.

[0124] Liquid perfusion systems of the present disclosure may find particular utility in the field of ex-situ machine perfusion. For this, one or more pieces of body tissue may be stored and preserved by the system (away from the human or animal body). This body tissue may comprise one or more organs. In particular, systems of the present disclosure may find particular utility for storing and preserving transplant organs after they have been removed from one human or animal body, and before they are to be implanted into another (‘donor organs’). Systems of the present disclosure may facilitate greater preservation or repair of such body tissue to increase the likelihood of that tissue being viable for implantation into a recipient, as well as to increase the length of time for which that body tissue may be retained ex-vivo while still being feasible for implantation. A non- exhaustive list of example body tissue includes replacement organs, such as lungs, kidneys, liver, heart, pancreas, small bowel etc.

[0125] While the above description has related to a complete system for liquid perfusion, the present disclosure also provides inserts for a liquid perfusion apparatus. Such an insert is configured to be included within an existing liquid perfusion apparatus (i.e. inserted into the liquid perfusion apparatus) to provide capability of incorporating thermally regulated cell therapy treatment into that existing liquid perfusion apparatus. That is, the insert is configured to provide the beneficial cell therapy treatment, and thermal regulation thereof, to an existing system, such as an existing ex- situ machine perfusion system. For example, the insert may be added to a system that includes a liquid perfusion apparatus (e.g. with reservoir, oxygenator, liquid perfusate heater and / or pump) to incorporate the beneficial cell therapy treatment into that existing system. In other words, the insert may be configured for retrofitting into an existing liquid perfusion apparatus, e.g. to incorporate thermally regulated cell therapy treatment functionality into that existing apparatus.

[0126] The insert comprises the cell therapy element 100. The insert may also comprise the inlet connector 201 and outlet connector 202, the cell therapy pump 210, the optional cell therapy liquid heater 220 and / or optional oxygenator. For example, the insert may comprise the components which provide the second flow path in the system 10 of Fig. 1.

[0127] The insert may comprise a standalone apparatus for coupling to an existing liquid perfusion apparatus. The insert may be configured to itself draw in liquid perfusate from the liquid perfusion apparatus to which it is coupled. The insert may be configured to utilise the cell therapy element 100 to provide cell therapy treatment for said liquid perfusate. The insert may be configured to return said cell therapy treatment to the liquid perfusion apparatus, e.g. for subsequent delivery to a body tissue to be treated. The cell therapy pump 210 may be configured to regulate the flow of liquid perfusate through the insert (and through the cell therapy element 100). The insert may optionally be configured to regulate a temperature of the liquid perfusate passing through the insert, e.g. using cell therapy liquid heater 220. For example, this may enable the liquid perfusate to be controlled to a temperature selected based on a desired interaction between that liquid perfusate and the cell therapy cells.

[0128] This insert arrangement may therefore enable the beneficial effects of the cell therapy treatment described herein to be incorporated into existing liquid perfusion apparatuses. The insert may be configured for insertion in parallel or series with the flow paths of the existing liquid perfusion apparatus. For example, in Fig. 1 , the flow path is provided in parallel. By providing the insert as an additional, parallel, limb to the liquid perfusion apparatus, the flow rate through the insert may be controlled based on selected operating conditions for the cell therapy element 100 and cells therapy cells it contains (rather than operating conditions stipulated by the required delivery of liquid perfusate to the body tissue, or the operating conditions stipulated by elements of the extracorporeal circuit e.g. minimum flow rate for through a haemofilter). This may further increase the efficacy of the cell therapy treatment being provided. However, the insert could also be provided in series. In which case, all liquid perfusate to be delivered to the body tissue will pass through the cell therapy element 100. The series arrangement may find particular utility for extracorporeal systems.

[0129] As will be appreciated, inserts of the present disclosure may be coupled to any suitable existing liquid perfusion apparatus. For example, the inlet connector 201 and / or the outlet connector 202 may comprise connections, such as universal connections, to facilitate connection to any existing liquid perfusion apparatus. The insert may be coupled to any extracorporeal circuit. The insert may be a cross-compatible device which may be used with a plurality of different systems. Also, the particular choice of cell therapy element 100 need not be considered limiting as the insert may be configured to couple any suitable cell therapy element 100 to any existing liquid perfusion apparatus or other suitable system.

[0130] It is to be appreciated in the context of the present disclosure that the examples described herein and shown in the figures should not be considered limiting. For instance, in Fig. 1, the cell therapy element 100 is shown as being connected in parallel with the remaining components of the system 10. That is, there are at least two flow paths liquid perfusate can take when circulating through the system 10: one which passes through the cell therapy element 100, and one which does not. As such, not all liquid perfusate to be delivered to body tissue 60 must pass through cell therapy element 100. However, this arrangement should not be considered limiting, as the cell therapy element 100 could be provided in series. In other words, the system may be arranged so that all liquid perfusate passing from the reservoir 20 to the body tissue 60 will pass through the cell therapy element 100. It will be appreciated that in such series arrangements, features such as the cell therapy pump 210 and / or the optional cell therapy liquid heater 220 may not be included. For example, existing components within the system may provide the relevant pumping / heating of liquid perfusate which passes through the cell therapy element 100. Likewise, connectors 201 , 202 may not be needed when the cell therapy element 100 is already incorporated within the flow path through the system.

[0131] It will also be appreciated that the order of the components within system 10 should not be considered limiting. For example, the liquid perfusate pump 30, oxygenator 40 and / or liquid perfusate heater 50 may be oriented differently. For example, the oxygenator 40 may be provided upstream of the cell therapy element 100, e.g. so that liquid perfusate passing therethrough will have been oxygenated. Likewise, the pump 30 or heater 50 may be in a different location to control pumping / heating in a different relative position, e.g. upstream of the cell therapy element 100.

[0132] Also, as will be appreciated, the particular design for the cell therapy element 100 may itself vary depending upon the body tissue to which it is to be coupled and / or the cell therapy cells to be used with that body tissue. For example, the particular choice of cell therapy cells should not be considered limiting, any suitable cell therapy cell could be used. Likewise, any suitable body tissue could be coupled to the system, and the choice of cell therapy cells, as well as other components of the system 10, may also vary depending on this body tissue. For example, for larger body tissue, the cell therapy element 100 may be larger and may comprise more cell therapy cells in the cell therapy portion 111 than for smaller body tissue. The flow rate through the cell therapy element 100 may be controlled based on the size of the body tissue or the type or number of cell therapy cells. For example, a higher flow rate may be used for larger body tissue or larger numbers of cell therapy cells. Similarly, a pore size for the semi-permeable membrane may be chosen based upon the particular choice of cell therapy cells. For instance, some cell therapy cells may be larger than others, or the products intended to pass across the semi-permeable membrane may be of different sizes, and so the pore size may be selected according to these details of the cell therapy cells in question.

[0133] Additionally, in examples described herein, one or more properties of the cell therapy element 100, such as temperature and / or pressure / flow rate of liquid perfusate through the liquid perfusate channels 112 may be controlled to be within a selected range of acceptable values. For example, the thermal regulation element may be configured to regulate a temperature of the cell therapy cells in the cell therapy portion 111 to be within a selected temperature range. It will be appreciated that this particular range should not be considered limiting. The range of values may depend upon the particular choice of cell therapy cells. This temperature range could be centred around normothermic temperatures, such as between 30 and 45 degrees Celsius, e.g. between 36 and 38 degrees, between 32 and 42 degrees, e.g. between 35 and 40 degrees, e.g. at or close to 37 degrees. For some cell therapy cells, this closeness to normothermia may be beneficial, but for others, the desired temperature may be greater or lower. Systems of the present disclosure may be configured to obtain an indication of a chosen temperature (or temperature range) and to thermally regulate the cell therapy cells according to that chosen temperature (or temperature range). For example, systems of the present disclosure may comprise a controller configured to control operation accordingly, e.g. to regulate a temperature to be within a selected range.

[0134] It will be appreciated from the discussion above that the examples shown in the figures are merely exemplary, and include features which may be generalised, removed or replaced as described herein and as set out in the claims. With reference to the drawings in general, it will be appreciated that schematic functional block diagrams are used to indicate functionality of systems and apparatus described herein. In addition, the processing functionality may also be provided by devices which are supported by an electronic device. It will be appreciated however that the functionality need not be divided in this way, and should not be taken to imply any particular structure of hardware other than that described and claimed below. The function of one or more of the elements shown in the drawings may be further subdivided, and / or distributed throughout apparatus of the disclosure. In some examples the function of one or more elements shown in the drawings may be integrated into a single functional unit.

[0135] As will be appreciated by the skilled reader in the context of the present disclosure, each of the examples described herein may be implemented in a variety of different ways. Any feature of any aspects of the disclosure may be combined with any of the other aspects of the disclosure. For example, method aspects may be combined with apparatus aspects, and features described with reference to the operation of particular elements of apparatus may be provided in methods which do not use those particular types of apparatus. In addition, each of the features of each of the examples is intended to be separable from the features which it is described in combination with, unless it is expressly stated that some other feature is essential to its operation. Each of these separable features may of course be combined with any of the other features of the examples in which it is described, or with any of the other features or combination of features of any of the other examples described herein. Furthermore, equivalents and modifications not described above may also be employed without departing from the invention.

[0136] Certain features of the methods described herein may be implemented in hardware, and one or more functions of the apparatus may be implemented in method steps. It will also be appreciated in the context of the present disclosure that the methods described herein need not be performed in the order in which they are described, nor necessarily in the order in which they are depicted in the drawings. Accordingly, aspects of the disclosure which are described with reference to products or apparatus are also intended to be implemented as methods and vice versa. The methods described herein may be implemented in computer programs, or in hardware or in any combination thereof. Computer programs include software, middleware, firmware, and any combination thereof. Such programs may be provided as signals or network messages and may be recorded on computer readable media such as tangible computer readable media which may store the computer programs in non-transitory form. Hardware includes computers, handheld devices, programmable processors, general purpose processors, application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), and arrays of logic gates.

[0137] Other examples and variations of the disclosure will be apparent to the skilled addressee in the context of the present disclosure.

Claims

Claims1. A system for liquid perfusion of body tissue, the system comprising: a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion for receiving liquid perfusate; a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion; and thermal insulation arranged to thermally insulate the cell therapy portion; a liquid perfusion apparatus configured to circulate liquid perfusate through: (i) the liquid perfusate portion for interaction with cell therapy cells in the cell therapy portion via the semi- permeable separator, and (ii) said body tissue.

2. A system for liquid perfusion of body tissue, the system comprising: a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion for receiving liquid perfusate; a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion; and a heater for regulating a temperature of the cell therapy portion; a liquid perfusion apparatus configured to circulate liquid perfusate through: (i) the liquid perfusate portion for interaction with cell therapy cells in the cell therapy portion via the semi- permeable separator, and (ii) said body tissue.

3. The system of claim 1, wherein the cell therapy element comprises a heater for regulating a temperature of the cell therapy portion.

4. The system of claim 1 or 3, wherein the thermal insulation at least partially surrounds an external surface of the cell therapy portion.

5. The system of claim 2 or 3, or any claim dependent thereon, wherein the heater is coupled to a surface of the cell therapy portion, optionally wherein the heater is coupled to an external surface of the cell therapy portion.

6. The system of claim 2 or 3, or any claim dependent thereon, wherein the heater comprises a heater-cooler operable to both increase and decrease a temperature of the cell therapy portion.

7. The system of claim 5 or 6, wherein the system is configured to control operation of theheater based on an obtained indication of a temperature of the cell therapy portion.

8. The system of any of claims 5 to 7, wherein the system is configured to control operation of the heater to retain a temperature of the cell therapy portion within a selected range.

9. The system of any preceding claim, further comprising a pump coupled to the cell therapy element.

10. The system of claim 9, wherein the pump is configured to control a flow rate of liquid perfusate through the cell therapy element.

11. The system of any preceding claim, wherein a first liquid perfusate flow path bypasses the cell therapy element and a second liquid perfusate flow path passes through the cell therapy element.

12. The system of claim 11 , wherein the system is configured to selectively control the amount of liquid perfusate which travels along the second liquid perfusate flow path.

13. The system of any preceding claim, wherein the system is arranged to: (i) retain a temperature of the cell therapy cells in the cell therapy portion within a threshold range, and / or (ii) inhibit thermal gradients across the cell therapy element exceeding a threshold level.

14. The system of any preceding claim, wherein the cell therapy element comprises a hollow fibre element.

15. The system of any preceding claim, wherein the semi-permeable separator is arranged to permit two-way exchange between the cell therapy portion and the liquid perfusate portion.

16. The system of any preceding claim, wherein the semi-permeable separator is configured to inhibit passage of cell therapy cells from the cell therapy portion into the liquid perfusate portion.

17. The system of any preceding claim, wherein the semi-permeable separator is configured to allow exchange of non-cellular material, such as secreted soluble factors and / or extracellular vesicles, between the cell therapy portion and the liquid perfusate portion.

18. The system of any preceding claim, comprising cell therapy cells in the cell therapy portion.

19. The system of any preceding claim, wherein the system is an ex-situ machine perfusionsystem.

20. An insert for a system for liquid perfusion of body tissue, the insert comprising: an inlet configured to couple to a liquid perfusion apparatus of a said system to receive liquid perfusate therefrom; a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion coupled to the inlet for receiving liquid perfusate therefrom; a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion; and thermal insulation arranged to thermally insulate the cell therapy portion; an outlet coupled to the liquid perfusate portion to receive cell therapy treated liquid perfusate therefrom and configured to couple to said liquid perfusion apparatus to provide the cell therapy treated liquid perfusate to said liquid perfusion apparatus.

21. An insert for a system for liquid perfusion of body tissue, the insert comprising: an inlet configured to couple to a liquid perfusion apparatus of a said system to receive liquid perfusate therefrom; a cell therapy element comprising: a cell therapy portion for containing cell therapy cells; a liquid perfusate portion coupled to the inlet for receiving liquid perfusate therefrom; a semi-permeable separator arranged to separate the cell therapy portion from the liquid perfusate portion; and a heater for regulating a temperature of the cell therapy portion; an outlet coupled to the liquid perfusate portion to receive cell therapy treated liquid perfusate therefrom and configured to couple to said liquid perfusion apparatus to provide the cell therapy treated liquid perfusate to said liquid perfusion apparatus.

22. The insert of claim 20 or 21, further comprising a pump configured to control the flow of liquid perfusate through the insert.

23. The insert of any of claims 20 to 22, further comprising a liquid heater for heating the liquid perfusate, optionally wherein the liquid heater is configured to heat the liquid perfusate before it passes through the cell therapy element.

24. A method of ex-situ liquid perfusion of body tissue, the method comprising: interacting liquid perfusate with cell therapy cells via a semi-permeable separator, wherein the cell therapy cells are contained within a thermally insulated housing; anddelivering the cell therapy treated liquid perfusate to said body tissue.

25. A method of ex-situ liquid perfusion of body tissue, the method comprising: interacting liquid perfusate with cell therapy cells via a semi-permeable separator; operating a heater to regulate a temperature of the cell therapy cells; and delivering the cell therapy treated liquid perfusate to said body tissue.

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