Perfusion bioreactor, perfusion device, artificial liver system and related methods

Abstract

A perfusion bioreactor and perfusion devices. Each perfusion device has a mesh structure and an encapsulated organ tissue (EOT) disposed in the mesh structure. The EOT has a body, the thickness of which is defined between a first surface of the body and a second surface of the body. The body has at least one channel extending from one of the first surface and the second surface into the body to receive a fluid therein. The at least one channel has a diameter selected to allow solutes to diffuse out of the fluid and enter the body. The perfusion devices are arranged adjacent to each other and spaced apart from each other along the length of the bioreactor to receive the fluid and perfuse the fluid into the EOT of each perfusion device and at least one channel therein. A method for processing plasma and an artificial liver system are also disclosed.

Description

[0001] Citations of Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 674,696, filed on May 22, 2018, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present application relates generally to organ replacement therapy, and more particularly to reactors, devices, and systems for performing organ replacement therapy. Background Art

[0004] Acute liver failure (ALF) is characterized by a sudden drop in liver function following severe liver injury in patients without pre-existing liver disease. The standard treatment for acute liver failure is liver transplantation, which should be performed within a few days of symptom onset to avoid progression to multi-organ failure. Liver transplantation is difficult, dangerous, and not widely available. The regenerative capacity of the liver is well documented in the literature. Since ALF patients usually do not have any underlying disease before the injury, it is possible to avoid approximately 80% of transplants if liver function can be replaced within the time required for liver regeneration, such as with an extracorporeal system.

[0005] Some extracorporeal systems for the treatment of liver failure are acellular liver support systems based on molecular adsorption and albumin dialysis for blood purification. The systems are often used in conjunction with hemodialysis to remove water-soluble solutes. However, clinical trials have shown no significant difference in patient survival between standard therapy and some approved extracorporeal systems.

[0006] Several cell-based dialysis systems are under investigation. The use of human hepatocytes has been favored because it circumvents the adverse effects associated with the use of xenogeneic hepatocytes. However, human hepatocytes are limited in availability, difficult to culture, and the liver-specific functions of some hepatocytes have been shown to decline rapidly over time. Another limitation of some devices is the limited exchange of substances between the patient's blood and the hepatocytes in vitro. Summary of the invention

[0007] The present disclosure provides a perfusion bioreactor, which includes: a shell having a length defined between a shell inlet and a shell outlet, the shell having an inner surface defining a shell lumen disposed between the shell inlet and the shell outlet and in fluid communication therewith; and perfusion devices disposed in the inner lumen of the shell, each perfusion device including: a mesh structure supported by the inner surface of the shell, the mesh structure having a first wall spaced apart from a second wall to define an inner mesh cavity, the first and second walls of the mesh structure each having an opening therein to allow fluid communication through the mesh structure; and an encapsulated organ tissue disposed in the inner mesh cavity between the first and second walls of the mesh structure, the encapsulated organ tissue having at least one at least partially enclosed biological phase. The invention relates to an organoid covered with a capacitive cross-linked polymer, the encapsulated organ tissue having a body defined by a first surface of the body adjacent to the first wall of the mesh structure and a second surface of the body adjacent to the second wall of the mesh structure, the body having at least one channel extending from one of the first surface and the second surface into the body to receive a fluid therein, the at least one channel having a diameter selected to diffuse solutes out of the fluid and into the body; the perfusion devices are arranged in the lumen of the housing, adjacent to each other and spaced apart from each other along the length of the housing to receive the fluid transmitted from the housing inlet to the housing outlet, and perfuse the fluid into the encapsulated organ tissue of each perfusion device and the at least one channel therein.

[0008] The present disclosure provides a perfusion device, comprising: a mesh structure having a first wall spaced apart from a second wall to define an internal mesh cavity, the first and second walls of the mesh structure each having an opening therein to allow fluid communication through the mesh structure; and an encapsulated organ tissue disposed in the internal mesh cavity between the first and second walls of the mesh structure, the encapsulated organ tissue having at least one organoid at least partially covered by a biocompatible cross-linked polymer, the encapsulated organ tissue having a body defined by a first surface of the body adjacent to the first wall of the mesh structure and a second surface of the body adjacent to the second wall of the mesh structure, the body having at least one channel extending from one of the first surface and the second surface into the body to receive a fluid therein, the at least one channel having a diameter selected to diffuse a solute out of the fluid and into the body.

[0009] The present disclosure provides an artificial liver system, which includes: a fluid network and a pump for circulating plasma through the fluid network; and a perfusion bioreactor in fluid communication with the fluid network to receive plasma therefrom, the perfusion bioreactor including: a shell having a length defined between the shell inlet and the shell outlet, the shell having an inner surface defining the shell lumen between the shell inlet and the shell outlet and in fluid communication with the shell inlet, the shell inlet receiving the plasma; and a plurality of perfusion devices arranged in the inner lumen of the shell, each of the perfusion devices including: a mesh structure supported by the inner surface of the shell, the mesh structure having a first wall spaced from a second wall to define an internal mesh cavity, the first and second walls of the mesh structure each having an opening therein to allow fluid communication through the mesh structure; and a first wall disposed on the mesh structure to encapsulate liver tissue. The housing is provided with a housing having at least one encapsulated liver tissue having at least one liver organoid at least partially covered by a biocompatible cross-linked polymer in an internal reticular cavity between a first wall and a second wall, the encapsulated liver tissue having a body defined by a first surface of the body adjacent to the first wall of the reticular structure and a second surface of the body adjacent to the second wall of the reticular structure, the body having at least one channel extending from one of the first surface and the second surface into the body to receive plasma therein, the at least one channel having a diameter selected to diffuse undesirable solutes out of the plasma and into the body; the perfusion devices are arranged in the lumen of the housing, adjacent to each other, and spaced apart from each other along the length of the housing to receive plasma transmitted from the housing inlet to the housing outlet and perfuse the plasma into the encapsulated liver tissue of each perfusion device and the at least one channel therein.

[0010] The present disclosure provides a method for processing plasma, comprising: delivering plasma to at least one channel formed in an encapsulated liver tissue, the encapsulated liver tissue having at least one liver organoid at least partially covered by a biocompatible cross-linked polymer, the at least one channel having a diameter selected to diffuse undesirable solutes out of the plasma and into the encapsulated liver tissue.

[0011] The present disclosure provides a method for making a perfusion device, comprising: providing at least one liver organoid at least partially covered by a biocompatible cross-linked polymer, the at least one liver organoid at least partially covered by a biocompatible cross-linked polymer having a body, at least one channel extending into the body, the at least one channel having a diameter selected to diffuse solutes out of a fluid and into the body; and positioning the body within a cavity of a mesh structure to allow fluid to enter the cavity and the at least one channel of the body, and to allow the fluid to leave the cavity. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Reference is now made to the accompanying drawings, in which:

[0013] Figure 1A is a schematic diagram of a perfusion bioreactor;

[0014] Figure 1B yes Figure 1A A schematic diagram of a shell and a perfusion device of a perfusion bioreactor;

[0015] Figure 2A yes Figure 1B A perspective view of a portion of a mesh structure of a perfusion device;

[0016] Figure 2B yes Figure 2A A stereogram of another portion of the mesh structure;

[0017] Figure 3 is used for Figure 1B A three-dimensional view of another mesh structure in the perfusion device;

[0018] Figure 4 Encapsulation of liver organoids and fabrication of encapsulated liver tissue for use Figure 1B The process of filling the device;

[0019] Figure 5A yes Figure 1B A perspective view of one of the perfusion devices;

[0020] Figure 5B yes Figure 5A A side elevational view of the encapsulated organ tissue of the perfusion device shown;

[0021] Figure 5C yes Figure 5A An end view of the encapsulated organ tissue of the perfusion device is shown;

[0022] Figure 5D are arranged adjacent to each other Figure 1B Side views of two perfusion devices encapsulating organ tissue;

[0023] Figure 6 is used for Figure 1B A side view of another encapsulated organ tissue in the perfusion device;

[0024] Figure 7 is used for Figure 1B A side view of another encapsulated organ tissue in the perfusion device;

[0025] Figure 8 Is has Figure 1A Schematic diagram of the artificial liver system with perfusion bioreactor;

[0026] Fig. 9 Is has Figure 1A Schematic diagram of another artificial liver system with a perfusion bioreactor;

[0027] Fig.10 Is has Figure 1A Schematic diagram of another artificial liver system with a perfusion bioreactor;

[0028] Fig.11A is a schematic diagram of another perfusion bioreactor;

[0029] Fig. 11B yes Fig.11A A perspective view of an internal support of a perfusion bioreactor; and

[0030] Fig. 11C With perfusion device Fig. 11B A three-dimensional view of the internal support member. DETAILED DESCRIPTION

[0031] Figure 1A A perfusion bioreactor 10 is illustrated. A perfusion bioreactor 10 is a device in which a perfusion operation is performed. Specifically, a perfusion bioreactor 10 (sometimes referred to herein simply as "bioreactor 10") allows for the exchange of particles between a liquid and cells and tissues embedded within a porous biomaterial. The bioreactor 10 is a container with a controlled environment that allows cells to survive and carry out metabolic activities. In the depicted embodiment, and as explained in more detail below, the bioreactor 10 has an aggregate of organ cells that perform at least a portion of the metabolic functions of a human organ. To achieve this function, the bioreactor 10 can be made of any suitable biocompatible plastic, metal, or a composite thereof, such as polycarbonate.

[0032] When in operation, the bioreactor 10 receives fluid and transports the fluid out of the bioreactor 10. Therefore, the bioreactor 10 has a suitable inlet and a suitable outlet connected to a suitable conduit. In the depicted embodiment, the bioreactor 10 has a shell 16, which is an elongated body extending a length L between a shell inlet 18A and a shell outlet 18B. The shell inlet 18A is configured to allow plasma, nutrients or other fluid materials to be infused into the shell 16. In the embodiment shown, the shell 16 is a cylinder extending along the longitudinal axis so that its length is greater than the width. Other shapes of the shell 16 are possible and are within the scope of the present disclosure. The shell inlet 18A and the outlet 18B are the tapered ends of the shell 16 and are used as funnels to input and output the main part of the shell 16. The shell 16 is hollow and therefore has an inner cavity 19, and the fluid is input into the inner cavity 19 to interact with the organ cells. The inner cavity 19 is defined by the wall of the shell, which is cylindrical in the embodiment shown and defines an inner surface 19A. Fluid passes through housing 16 by first entering housing inlet 18A, then passing through interior cavity 19, and then exiting through housing outlet 18B.

[0033] Reference Figure 1B The bioreactor 10 also includes a perfusion device 20. Each perfusion device 20 performs the work of the bioreactor 10 by facilitating the exchange of particles between liquid and cells and tissues embedded in the porous biomaterial of each perfusion device 20. The perfusion device 20 contains an aggregate of organ cells that performs at least part of the metabolic function of a human organ, as explained in more detail below. The perfusion device 20 is disposed in the inner cavity 19 of the housing 16. As shown in FIG. Figure 1B As shown, the irrigation devices 20 are disposed in the lumen 19 adjacent to each other and spaced apart from each other along the length L of the housing 16. The irrigation devices 20 form a stack of irrigation devices 20A. In the depicted embodiment, the stack of irrigation devices 20A has a vertical or perpendicular orientation. The irrigation devices 20 are stacked on top of each other in the stack of irrigation devices 20A. In alternative embodiments, the stack of irrigation devices 20A has a horizontal or inclined orientation. Regardless of their orientation, the irrigation devices 20 and their components interact with the fluid traveling through the lumen 19 of the housing 16 from the housing inlet 18A to the housing outlet 18B.

[0034] Still reference Figure 1B, each perfusion device 20 includes a mesh structure 30 and one or more encapsulated organ tissues 40. The mesh structure 30 constitutes the body of the perfusion device 20 and provides structure therefor. The mesh structure 30 is porous and supported by the inner surface 19A of the housing 16 to mount each perfusion device 20 to the housing 16. The encapsulated organ tissue 40 of each perfusion device is located within the mesh structure 30. Therefore, the mesh structure 30 is any suitable device for retaining the encapsulated organ tissue 40 and allowing the fluid within the housing 16 to engage with the encapsulated organ tissue 40.

[0035] Another embodiment of the bioreactor 600 is as follows Figure 11A-11C As shown. In the embodiment shown, the bioreactor 600 has a housing 616, which is an elongated body extending a certain length between a housing inlet 618A and a housing outlet 618B. In the embodiment shown, the housing 616 is a cylindrical body extending along the longitudinal axis so that its length is greater than the width. The housing 616 is transparent and allows light to pass through. The housing inlet 618A and the outlet 618B are the conical ends of the housing 616, and act as a funnel to input and output the main part of the housing 616. The housing 616 is hollow and therefore has an inner cavity 619, and the fluid is input into the inner cavity 619 to interact with the organ cells. The inner cavity 619 is defined by the transparent wall of the housing 616, and the housing 616 is cylindrical in the depicted embodiment. The fluid flows through the housing 616 by first entering the housing inlet 618A, then passing through the inner cavity 619, and being discharged via the housing outlet 618B.

[0036] Still refer to Figure 11A-11C , the bioreactor 600 has an internal support 617 for supporting the perfusion device 20. The internal support 617 is located within the inner cavity 619. The internal support 617 includes end plates 617A, which are drilled to allow fluid to pass therethrough. The end plates 617A are linked to each other by racks 617B extending between the end plates 617A. The racks 617B are spaced apart from each other. The racks 617B can be attached to the inner surface of the housing 616. Each rack 617B includes notches or grooves 617C spaced along the length of the rack 617B. The mesh structure 30 of each perfusion device 20 is removably mounted on the rack 617B by being placed in the groove 617C.

[0037] Bioreactor 10,400 provides a controlled environment. In the depicted embodiment, the internal temperature of bioreactor 10,400 is controlled by a heat exchanger to keep it constant at 37°C. The internal pH of bioreactor 10,400 is controlled by adjusting bicarbonate to keep it constant at about 7.4. Since the depicted bioreactor 10,400 is used to process plasma, there are no erythrocytes (i.e., red blood cells) in the plasma. Therefore, the oxygen content of the plasma in bioreactor 10,400 is controlled. Bioreactor 10,400 can be used with other types of corporeal fluids and can control fewer or other parameters.

[0038] The mesh structure 30 and the encapsulated organ tissue 40 will now be described in greater detail.

[0039] Reference Figure 2A and Figure 2B , the mesh structure 30 has a first wall 32 spaced apart from a second wall 34 to define an inner mesh cavity 36. Encapsulated organ tissue 40 ( Figure 2A and Figure 2B The mesh structure 30 is provided with an inner mesh cavity 36 between the first 32 and second walls 34 (not shown). The first wall 32 and the second wall 34 are porous to allow fluid to enter the inner mesh cavity 36 to interact with the encapsulated organ tissue 40. The porous nature of the mesh structure 30 is provided by openings 38 in each of the first and second walls 32, 34, which allow fluid to communicate through the mesh structure 30. Figure 2A and Figure 2B , the mesh structure 30 includes a base 30A and a cover 30B that can be mounted on the base 30A to close the mesh structure 30 and define an internal mesh cavity 36. The base 30A includes a first wall 32 of the mesh structure 30, and the cover 30B includes a second wall 34. The cover 30B is press-fitted onto the base 30A.

[0040] Other embodiments of the grid structure 30 are possible. For example, Figure 3 A one-piece mesh structure 130 is shown. The mesh structure 130 is cylindrical and shaped like a disk. A first wall 132 and a second wall 134 are shown spaced apart to define an inner mesh cavity 136. The first wall 132 and the second wall 134 also have openings 138 therein. Figure 3In the embodiment of the present invention, the mesh structure 130 has a side wall 131 with an aperture 133 therein. The aperture 133 is in fluid communication with an internal mesh cavity 136. The aperture 133 allows the components that make up the encapsulated organ tissue 40 to be introduced into the internal mesh cavity 136, as explained in more detail below. Regardless of its configuration, the mesh structure 30, 130 can have a thickness that can be about 1 mm to about 8 mm, and can have a diameter that can be about 10 mm to about 80 mm. The mesh size (i.e., the size of the opening 38, 138) can be about 500 μm to about 5 mm. Although in Figure 2A-Figure 3 Although shown as being substantially circular in shape, it should be understood that the mesh structures 30, 130 may have other shapes, including but not limited to rectangular, square, triangular, and the like.

[0041] Reference Figure 4 , encapsulated organ tissue 40 (sometimes referred to herein as "EOT 40") has one or more organoids 42 at least partially covered by a biocompatible cross-linked polymer 44. Each organoid 42 is a growth or culture mass of cells or tissue that resembles an organ. Figure 4 In the bioreactor 10,400, each organoid 42 is a liver organoid similar to the liver, so that the EOT40 is an encapsulated liver tissue (ELT). The fluid entering the bioreactor 10,400 exchanges compounds with the tissues or cells of the organoid 42 in the EOT 40, so that the toxic compounds are metabolized by the cells of the organoid 42 and eliminated in a non-toxic form, while the useful proteins are produced by the cells of the organoid 42 and released into the fluid. Therefore, albumin, ammonia and other plasma components that need to be processed by the liver can be metabolized by the liver organoid 42, which is similar to human liver function. The organoid 42 can also be cultured by cells or tissues of another organ. A non-limiting list of other organs whose functions can be simulated by the organoid 42 includes kidneys, endocrine tissues and any other tissues that can be perfused by blood and can aggregate into organoids 42. Therefore, it should be understood that the liver, liver organoids or encapsulated liver tissue referred to in the present disclosure are not limited to organoids 42 or EOT 40 formed only by liver cells or tissues.

[0042] Figure 4 A process for providing a plurality of monodispersed liver organoids 42 in a biocompatible and cross-linked polymer 44 is shown. As shown, hepatoblasts, endothelial progenitor cells, and mesenchymal progenitor cells are obtained by differentiating a single iPSC. These cells are mixed and co-cultured in suspension to form liver organoids 42. Figure 4 In the illustrated embodiment of the liver organoid 42, the hepatoblasts have differentiated into hepatocytes, which (prior to introduction of the liver organoid 42 into the encapsulated liver tissue 40) substantially cover a core of cells formed by mesenchymal and endothelial progenitor cells. Figure 4The embodiment of the liver organoid 42 shown in FIG. 1 is substantially spherical in shape and has a relative diameter of approximately 150 μm. The liver organoid 42 is then encapsulated in a first compatible and cross-linkable matrix using a cross-linking agent that is Figure 4 40 can be used as a transplantable liver tissue in regenerative medicine (e.g., having a size of 5 mm-10 cm). Alternatively, the liver organoid 42 can be designed as a multi-well plate and used in drug development to determine the metabolism or liver toxicity of the screened compound.

[0043] The polymer 44 (also referred to as a polymer matrix) that can be used to encapsulate the liver tissue 40 forms a hydrogel around the liver organoids 42. Hydrogel refers to hydrophilic polymer chains in which water is the dispersion medium. The hydrogel can be obtained from natural or synthetic polymer networks. In the context of the present disclosure, the encapsulation within the hydrogel prevents the embedded liver organoids 42 from leaking out of the polymer 44. In one embodiment, each liver organoid 42 is individually encapsulated, and in another embodiment, the encapsulated liver organoids 42 can be further included in the polymer matrix 44. In yet another embodiment, the liver organoids 44 are included in the polymer matrix 44 so as to encapsulate them. Figure 4 As shown, the liver organoid 42 encapsulated in the hydrogel material forms a disc or other cylindrical structure. Other shapes of the organoid 42 encapsulated in the hydrogel material are possible and are within the scope of the present disclosure. The hydrogel can be any biocompatible material. Some non-limiting examples of hydrogels include PEG, and any polyethylene glycol (PEG)-based material, such as PEG-vinyl sulfone (PEG-VS).

[0044] Figure 4 A process for making encapsulated organoid tissue 40 is shown, which is described in PCT patent application PCT / CA2017 / 051404 (published as WO 2018 / 094522), entitled "Encapsulated Liver Tissue" filed on November 23, 2017, the entire contents of which are incorporated herein by reference. Organoids 42 can be harvested from ultra-low attachment flasks and centrifuged at low speed (400g, 5 minutes) to form a pellet. The pellet (approximately 3,000 organoids) can be resuspended in a 5% 4-arm PEG-vinyl sulfone (20 kDa) solution in sterile PBS without calcium and magnesium and supplemented with 0.1% N-vinyl-2-pyrrolidone and 0.4 mg / mL Irgacure 2959. 50 μL droplets of such solutions (containing approximately 100 organoids 42 ) can be generated and placed in the wells of a 96-well plate and subsequently exposed to UV light (5 min, 1090 μW / cm2 , 4 cm away) for cross-linking. The resulting encapsulated liver tissue 40 can be maintained in complete William E medium / complete EMB2 (1:1) medium supplemented with 20 ng / mL OSM and 10 μM dexamethasone for 5 days. Five days after encapsulation, the OSM supplement may be suspended and the ratio of complete William E medium / complete EBM2 medium may be changed from 1:1 to 4:1. The tissue can be cultured in an environment of O2 / 5% CO2 at 37°C, and the medium can be changed every other day. Albumin secretion can be evaluated weekly in the finishing medium. Encapsulated organoids 42 are likely to retain their ability to secrete albumin through the hydrogel for more than 7 weeks of culture, thereby demonstrating their survival in the polymer 44 and the maintenance of their differentiated state, while confirming the diffusion of the secreted protein to its outside. The encapsulated liver tissue 40 can be strong enough to be manipulated with instruments without damaging its shape and integrity.

[0045] Figure 5A-Figure 5C One of the perfusion device 20 and the EOT 40 is shown. The EOT 40 has a body 46 that provides physical structure to the EOT 40. The body 46 defines a thickness T. The thickness T is defined between a first surface 48A of the body 46 adjacent to the first wall 32 of the mesh structure 30 and a second surface 48B of the body 46 adjacent to the second wall 34. Thus, the EOT 40 is "sandwiched" by the mesh structure 30. In the described embodiment, the body 46 takes the form of the mesh structure 30 and is therefore shaped as a cylinder or disk. Just like the mesh structure 30, the body 46 can have other shapes, which is part of the present disclosure. In one implementation, the thickness T of the body 46 is about 1 mm to about 3 mm. Other values ​​of the thickness T of the body 46 are also possible and are within the scope of the present disclosure.

[0046] refer to Figure 5B and Figure 5C , EOT 40 is a three-dimensional porous body. EOT 40 is embedded with spatially organized channels, which are perfused with fluid (e.g., plasma) supplied to housing 16. Figure 5B and Figure 5CAs shown, the body 46 has one or more channels 41 extending into the body 46. Each channel 41 extends into the body 46 from one or both of the first surface 48A and the second surface 48B so as to receive the fluid into the channel 41. Each channel 41 has a diameter D. The diameter D of each channel 41 is selected to allow the undesirable solutes in the fluid to diffuse out of the fluid and enter the surrounding tissue of the body 46 and be metabolized. Controlling the diameter D of the channel 41 can allow improved removal of molecules of a certain size from the fluid while allowing molecules of interest with different sizes to remain in the fluid. The diameter D of each channel 41 in the body 46 can be the same, or can be different. In one embodiment, the diameter D of one or more channels 41 is about 150 μm-about 750 μm. Other values ​​of the diameter D of the channel 41 are possible and are within the scope of the present disclosure.

[0047] Therefore, it can be understood that each EOT 40 has a blood vessel-like structure (i.e., channels 41) that can assist the permeation of fluids and their solutes within the EOT 40, and assist the diffusion of solutes from the fluid into the surrounding polymer 44 hydrogel of the body 46. This is in contrast to some conventional polymerized organ tissues that do not have channels, so that the diffusion of solutes is limited to the surface of the polymerized organ tissue.

[0048] The channel 41 can be formed using any suitable technique. Some possible techniques include photolithography, sacrificial molding, or any other suitable microfabrication technique. For example, when using photolithography, forming the channel 41 includes curing a portion of the cross-linked polymer 44 of biocompatibility using a UV light source, while the body 46 is retained in the internal mesh cavity 36 of the mesh structure 30. This can include covering the body 46 with a photomask having one or more opaque portions corresponding to the final position of the channel 41. The cross-linked polymer 44 of biocompatibility is then cured with a UV light source applied to the photomask. The portion of the body 46 covered by the opaque portion of the photomask will remain uncured, thereby forming the channel 41 in the body 46. The EOT 40 can therefore be photopolymerized within the mesh structure 30. If the channel 41 is generated when the polymer 44 is in the mesh structure 30, the photomask used for the photolithography may need to match the opaque portion with the opening 38 of the mesh structure 30 to allow the UV light to penetrate into the hydrogel for curing.

[0049] In another embodiment using photolithography within the mesh structure 30, forming the channel 41 includes injecting at least one liver organoid 42 and a biocompatible cross-linked polymer 44 into the inner mesh cavity 36 of the mesh structure, and then curing portions of the biocompatible cross-linked polymer 44 with a UV light source to solidify the mass. The uncured portions of the polymer 44 form the channel 41. One technique for achieving this result involves ... Figure 2A-Figure 3 ), the hydrogel polymer 44 and organoids 42 are pipetted into the inner mesh cavity 36. Both the first and second walls 32, 34 and their openings 38 can be sealed, such as with a light-transparent seal similar to a glass slide, before injecting the hydrogel polymer 44 and organoids 42. The mixture is then cured and photopolymerized in the mesh structure 30.

[0050] Other techniques for forming the channels 41 are possible and are within the scope of the present disclosure. In an alternative embodiment, the EOT 40 is added to the internal mesh cavity 36 of the mesh structure 30 after photopolymerization. In yet another embodiment, the body 46 is bioprinted, or formed using a fabrication mold containing the channels 41, or by sacrificial molding using polymers or sugars. In yet another embodiment, the endothelial progenitor cells of the liver organoid 42 are organized in a capillary or capillary-like configuration.

[0051] The shape, orientation and path of the channel 41 may vary, and at least some of them will now be described in greater detail.

[0052] Reference Figure 5B and Figure 5C , the body 46 includes a plurality of channels 41. Channels 41A extend through the body 46 between the first and second surfaces 48A, 48B. Thus, channels 41A communicate with fluid passing through the body 46. The length La of channels 41A is substantially equal to the thickness T of the body 46. Channels 41B also extend through the body 46 and also communicate with fluid passing through the body 46. The length Lb of channels 41B is greater than the thickness T of the body 46 because channels 41B are skewed or inclined relative to the first and second surfaces 48A, 48B.

[0053] refer to Figure 5C and Figure 5D, the through channels 41A, 14B allow fluid to communicate through the body 46 of one perfusion device 20 and flow to the body 46A of another adjacent perfusion device 20. The channels 41A, 41B of the body 46 are offset from the channels 41C, 41D of the adjacent body 46A. In an embodiment where the stack of perfusion devices 20A has a vertical orientation, the offset channels 41A, 41B, 41C, 41D of the bodies 46, 46A are not vertically aligned. The channels 41A, 41B, 41C, 41D of the bodies 46, 46A do not overlap. Therefore, the fluid is prevented from flowing directly between the bodies 46, 46A in a straight or non-offset path. Therefore, the offset channels 41A, 41B, 41C, 41D define a tortuous flow path P for the fluid, causing the fluid to deviate from the straight path between the bodies 46, 46A. In Figure 5D 4, a tortuous flow path P allows the fluid to enter channel 41A and flow through body 46, then flow along first surface 48A of body 46A until reaching channel 41C, at which point the fluid enters channel 41C and flows through body 46A. This deviation of the fluid from one perfusion device 20 to another can help increase the opportunity for solutes to diffuse out of the fluid by delaying diffusion and giving the fluid more time to interact with organoids 42 of EOT 40.

[0054] Figure 6Another configuration of the channel 141 of the EOT 40 is shown. The channel 141 includes a first or main channel 141A and one or more other channels 141, referred to as secondary channels 141B. The main channel 141A is a through channel that extends through the body 46 between the first and second surfaces 48A, 48B. The secondary channel 141B extends into the body 46 from a first end 149A at one of the first surface 48A and the second surface 48B to a second end 149B in the body 46 at the main channel 141A. The second end 149B of the secondary channel 141B leads to the main channel 141A, so that the secondary channel 141B is in fluid communication with the main channel 141A. Therefore, the fluid can be transported from the first or second surface 48A, 48B of the body 46, through the secondary channel 141B, and into the main channel 141A. The length La of the main channel 141A is substantially equal to or greater than the thickness T of the body 46. The length Lb of the secondary channel 141B is less than the thickness T of the body 46, or greater than the thickness T of the body 46. The length Lb' of the secondary channel 141B is less than the thickness T of the body 46. The length Lb" of the secondary channel 141B is greater than the thickness T of the body 46, causing such secondary channel 141B to travel along a tortuous, curved or winding path through the body 46. The secondary channel 141B'" is a "dead end" channel and extends from one of the first and second surfaces 48A, 48B into the body 46 to a second end 149B in the body 46 that is not connected to any other channel 141A, 141B fluid. The dead end secondary channel 141B'" allows the solvent to diffuse out of the fluid and enter the body 46.

[0055] Figure 7 Another configuration of the channel 241 of the EOT 40 is shown. The body 46 includes two main channels 241A. Each main channel 241A extends into the body 46 from one of the first surface 48A and the second surface 48B. Each main channel 241A is a "dead end" channel and does not extend through the body 46. One or more secondary channels 241B extend between the two main channels 241A to connect them fluidically. Therefore, the fluid can pass through the body 46 from each first and second surfaces 48A, 48B by flowing into one of the main channels 241A, passing through one or more secondary channels 241B, and flowing out of the other main channel 241A.

[0056] Reference Figure 1A and Figure 1B, the operation of the bioreactor 10 will be described in more detail. Fluid received at the housing inlet 18A of the housing 16 is delivered to the internal cavity 19 to perfuse the fluid to the EOT 40 of each perfusion device 20. Thus, the fluid is delivered to the organoid 42 and the channel 41 of each EOT 40 through the openings 38 in the first wall 32 and the second wall 34 of each mesh structure 30. In the illustrated embodiment, the fluid is delivered from the lower housing inlet 18A to the upper housing outlet 18B against gravity. Figure 1B As shown, the housing 16 has a plurality of supports 17 that are attached to the inner surface 19A and spaced apart along the length L of the housing 16. The mesh structure 30 of each perfusion device 20 is removably mounted to one of the supports 17. In the embodiment shown, the supports 17 are notches or grooves in parallel columns 17A that are attached to the inner surface 19A and extend along the length L of the housing 16. The columns 17A are supported by a mesh to prevent the organoids 42 from escaping from the EOT 40 into the processed fluid and leaving the fluid outlet 18B in the event of tissue rupture. Other configurations of the supports 17 are possible and are within the scope of the present disclosure. For example, in any alternative embodiments, each mesh structure 30 has one or more supports 17 for attachment to the inner surface 19A of the housing 16.

[0057] Still refer to Figure 1B , the stack of perfusion devices 20A can be cryopreserved. All materials used can withstand extremely low temperatures with no or minimal fatigue. Prior to commencing plasma therapy, the perfusion device 20 can be removed from cryopreservation and inserted into the bioreactor 10. The circulation of warm fluid (e.g., warm plasma) is able to thaw the organoids 42 in the bioreactor 10 and further maintain the temperature of the organoids 42 at body temperature, creating an optimal environment for the tissue. In one embodiment, approximately 0.1% to approximately 1% of a human liver mass is present in the perfusion device 20 of the housing 16. This is equivalent to approximately millions to billions of hepatocytes, and can also be equivalent to approximately 500 to approximately 10,000 organoids per perfusion device 20.

[0058] Figure 8An embodiment of an artificial liver system 300 having a bioreactor 10,400 as described herein is shown. The artificial liver system 300 helps to simulate human liver function and can therefore be referred to as a "biological artificial liver device (BALD)". The artificial liver system 300 (sometimes referred to herein simply as "system 300") includes a fluid network 302, which is a series of pipes, connectors and other components to communicate plasma between the features of the system 300. The system 300 has a peristaltic pump 304 to circulate plasma through the fluid network 302. In the depicted embodiment, the pump 304 pushes the plasma through the fluid network 302 at a flow rate of about 50mL / min-about 300mL / min. An infusion pump can be placed immediately after the pump 304 to insert saline and / or anticoagulant (heparin). The fluid network 302 can have a pressure sensor to determine the pressure within the system 300 and ensure that the plasma re-enters the patient's body at a pressure similar to that when the plasma was extracted.

[0059] System 300 may optionally have an adsorption cartridge, as in Figure 8 306 is shown as a molecular adsorption system 306 or MAS. MAS 306 is any suitable perfusion device or carbon adsorption system. MAS 306 is in fluid communication with fluid network 302 to remove certain undesirable solutes from the plasma. Undesirable solutes may include toxins and high levels of bilirubin. Undesirable solutes are removed from the plasma in MAS 306 using adsorption on activated carbon or hydrophobic resin. System 300 may also have an oxygenator (oxygen generator) 308 in fluid communication with fluid network 302, such as Figure 8 as shown. The oxygenator 308 operates to dissolve oxygen in the plasma to produce oxygenated plasma. The bioreactor 10,400 is shown as being in fluid communication with the oxygenator 308 and receiving the oxygenated plasma therefrom. The oxygenated plasma enters the bioreactor 10,400 and interacts with the ELT 40 of the perfusion device 20, which diffuses other remaining undesirable solutes that have not been removed by the MAS 306 out of the oxygenated plasma and into the body 46 of the ELT 40. In an alternative embodiment, the oxygenator 308 is a component of the bioreactor 10,400, and oxygenation is performed in the bioreactor 10,400 itself. In one embodiment, the system 300 is devoid of an oxygenator. In one embodiment, oxygenation is performed on the plasma downstream of the bioreactor 10,400. The processed plasma exiting the housing outlet 18B of the bioreactor 10,400 can be provided for attachment to a commercially available extracorporeal filtration system 310. Thus, Figure 8The system 300 in FIG. 4 can be an add-on device used with an existing extracorporeal filtration system 310. In an alternative embodiment, a dialyzer 416 (see FIG. 400 ) is placed after the bioreactor 10, 400. Fig. 9 ) is placed in system 300 for plasma dialysis.

[0060] Fig. 9 Another embodiment of an artificial liver system 400 having a bioreactor 10, 400 as described herein is shown. The system 400 is a stand-alone extracorporeal unit that includes a blood circuit 401A and a plasma circuit 401B. The blood circuit 401A includes a pump 402 for pumping blood into the system 400. An infusion pump 402A is placed after the pump 402 to insert saline and anticoagulant (heparin). Fig. 9 In the embodiment, MAS 406 is located in the blood circuit 401A before the plasma separation module 408, which separates plasma from blood and provides plasma to the plasma circuit 401B. In the plasma circuit 401B, the system 400 has a peristaltic pump 410 to circulate the plasma through the fluid network 412. There is a blood leak detector 414 before the dialyzer 416 of the plasma circuit 401B, and the dialyzer 416 removes some undesirable solutes from the plasma using a dialysate. The plasma circuit 401B also has an oxygenator 418 to dissolve oxygen in the plasma to produce oxygenated plasma. The bioreactor 10,400 is in fluid communication with the oxygenator 418 and receives oxygenated plasma from it. Oxygenated plasma enters the bioreactor 10,400 and interacts with the ELT 40 of the perfusion device 20, which operates to diffuse other remaining undesirable solutes that have not been removed by the MAS 406 or the dialyzer 416 out of the oxygenated plasma and into the body 46 of the ELT 40. The processed plasma leaving the housing outlet 18B of the bioreactor 10,400 is provided back to the blood circuit 401A, where it is recombined with the separated blood products and returned to the patient's blood, or further fluid processing can be performed. The blood circuit 401A has a bubble detector 420 to prevent the introduction of air into the blood. The system 400 may also include a temperature sensor, a flow meter, a cell filter, a heat exchanger to maintain a constant temperature, a clamp, a drip chamber, and any other suitable device.

[0061] Fig.10Another embodiment of an artificial liver system 500 with a bioreactor 10,400 as described herein is shown. System 500 is an independent extracorporeal unit comprising a blood circuit 501A and a plasma circuit 501B. Blood circuit 501A comprises a pump 502 for pumping blood into system 500. An infusion pump 502A is immediately after pump 502 to insert saline and anticoagulant (heparin). Plasma separation module 508 separates plasma from blood and provides plasma to plasma circuit 501B. In plasma circuit 501B, system 500 has a peristaltic pump 510 to circulate plasma through a fluid network 512. There is a blood leak detector 514 upstream of pump 510. Plasma circuit 501B also has an oxygenator 518 to dissolve oxygen in plasma to produce oxygenated plasma. Bioreactor 10,400 is in fluid communication with oxygenator 518 and receives oxygenated plasma from it. Oxygenated plasma enters the bioreactor 10,400 and interacts with the ELT 40 of the perfusion device 20, which operates to diffuse remaining undesirable solutes out of the oxygenated plasma and into the body 46 of the ELT 40. The processed plasma exiting the housing outlet 18B of the bioreactor 10,400 is provided back to the blood circuit 501A and then to the dialyzer 516, which uses a dialysate to remove some of the undesirable solutes from the plasma. The processed plasma is recombined with the separated blood products and returned to the patient's blood, or further fluid processing may be performed. The blood circuit 501A has a bubble detector 520 to prevent the introduction of air into the blood. The system 500 may also include temperature sensors, flow meters, cell filters, heat exchangers to maintain a constant temperature, clamps, drip chambers, and any other suitable devices. The system 500 may include, for example, Fig.10 A blood perfusion (HP) cartridge is shown, which may be located upstream of the bioreactor 10,400.

[0062] Embodiments disclosed herein include:

[0063] A. A perfusion bioreactor, comprising: a shell having a length defined between a shell inlet and a shell outlet, the shell having an inner surface defining a shell lumen disposed between the shell inlet and the shell outlet and in fluid communication therewith; and perfusion devices disposed in the lumen of the shell, each perfusion device comprising: a mesh structure supported by the inner surface of the shell, the mesh structure having a first wall spaced apart from a second wall to define an inner mesh cavity, the first and second walls of the mesh structure each having an opening therein to allow fluid communication through the mesh structure; and an encapsulated organ tissue disposed in the inner mesh cavity between the first and second walls of the mesh structure, the encapsulated organ tissue having at least one at least partially biocompatible The invention relates to an organoid covered with a cross-linked polymer having a thickness defined by a first surface of the body adjacent to the first wall of the mesh structure and a second surface of the body adjacent to the second wall of the mesh structure, the body having at least one channel extending from one of the first surface and the second surface into the body to receive a fluid therein, the at least one channel having a diameter selected to diffuse solutes out of the fluid and into the body; the perfusion devices are arranged in the inner cavity of the shell, adjacent to each other, and spaced apart from each other along the length of the shell to receive the fluid transmitted from the shell inlet to the shell outlet, and perfuse the fluid into the encapsulated organ tissue of each perfusion device and the at least one channel therein.

[0064] B. A perfusion device comprising: a mesh structure having a first wall spaced apart from a second wall to define an internal mesh cavity, the first and second walls of the mesh structure each having an opening therein to allow fluid communication through the mesh structure; and an encapsulated organ tissue disposed in the internal mesh cavity between the first and second walls of the mesh structure, the encapsulated organ tissue having at least one organoid at least partially covered by a biocompatible cross-linked polymer, the encapsulated organ tissue having a body having a thickness defined between a first surface of the body adjacent to the first wall of the mesh structure and a second surface of the body adjacent to the second wall of the mesh structure, the body having at least one channel extending from one of the first surface and the second surface into the body to receive a fluid therein, the at least one channel having a diameter selected to diffuse a solute out of the fluid and into the body.

[0065] C. An artificial liver system, comprising: a fluid network and a pump for circulating plasma through the fluid network; and a perfusion bioreactor in fluid communication with the fluid network to receive plasma therefrom, the perfusion bioreactor comprising: a shell having a length defined between the shell inlet and the shell outlet, the shell having an inner surface defining the shell lumen between the shell inlet and the shell outlet and in fluid communication therewith, the shell inlet receiving plasma; and a plurality of perfusion devices arranged in the lumen of the shell, each of the perfusion devices comprising: a mesh structure supported by the inner surface of the shell, the mesh structure having a first wall spaced from a second wall to define an internal mesh cavity, the first and second walls of the mesh structure each having an opening therein to allow fluid communication through the mesh structure; and encapsulating liver tissue, disposed on the first wall of the mesh structure. The housing is provided with a first reticular cavity between the first wall and the second wall, the encapsulated liver tissue having at least one liver organoid at least partially covered by a biocompatible cross-linked polymer, the encapsulated liver tissue having a body defined by a first surface of the body adjacent to the first wall of the reticular structure and a second surface of the body adjacent to the second wall of the reticular structure, the body having at least one channel extending from one of the first surface and the second surface into the body to receive plasma therein, the at least one channel having a diameter selected to diffuse undesirable solutes out of the plasma and into the body; the perfusion devices are arranged in the lumen of the housing, adjacent to each other, and spaced apart from each other along the length of the housing to receive plasma transmitted from the housing inlet to the housing outlet, and perfuse the plasma into the encapsulated liver tissue of each perfusion device and the at least one channel therein.

[0066] D. A method for processing plasma, comprising: delivering plasma to at least one channel formed in an encapsulated liver tissue, the encapsulated liver tissue having at least one liver organoid at least partially covered by a biocompatible cross-linked polymer, the at least one channel having a diameter selected to diffuse undesirable solutes out of the plasma and into the encapsulated liver tissue.

[0067] E. A method of making a perfusion device comprising: providing at least one liver organoid at least partially covered by a biocompatible cross-linked polymer, the at least one liver organoid at least partially covered by a biocompatible cross-linked polymer having a body with at least one channel extending into the body, the at least one channel having a diameter selected to diffuse solutes out of a fluid and into the body; and positioning the body within a cavity of a reticular structure to allow fluid to enter the cavity and at least one channel of the body, and to allow the fluid to leave the cavity.

[0068] Each of embodiments A, B, C, D and E may have one or more of the following additional elements in any combination.

[0069] Element 1: At least one channel of the body of each priming device extends through the body between the first and second surfaces.

[0070] Element 2: The length of the at least one channel is substantially equal to or greater than the thickness of the body.

[0071] Element 3: The at least one channel of one of the perfusion devices is offset from the at least one channel of an immediately adjacent perfusion device, and the fluid travels along a tortuous flow path between the channels of adjacent perfusion devices.

[0072] Element 4: The at least one channel of the body includes a first channel and at least another channel, the first channel extends through the body between the first and second surfaces, and the at least another channel extends into the body from a first end at one of the first surface and the second surface to a second end in the body at the first channel, and the at least another channel is fluidically connected to the first channel.

[0073] Element 5: The length of the first channel is substantially equal to or greater than the thickness of the body, and the length of the at least another channel is less than or greater than the thickness of the body.

[0074] Element 6: The length of the at least one other channel is greater than the thickness of the body.

[0075] Element 7: A plurality of support members spaced apart along the length direction of the housing, the mesh structure of each perfusion device being detachably mounted on one of the support members.

[0076] Element 8: The housing has an upright orientation and the perfusion devices are supported by the housing in a stack one on top of the other.

[0077] Element 9: The diameter of the at least one channel is 150 μm-750 μm.

[0078] Element 10: The at least one organoid encapsulating organ tissue includes a plurality of liver organoids.

[0079] Element 11: delivering oxygenated plasma includes delivering oxygenated plasma from the at least one channel to a second channel in another encapsulated liver tissue having at least one liver organoid at least partially covered by a biocompatible cross-linked polymer.

[0080] Element 12: delivering oxygenated plasma includes delivering oxygenated plasma from the at least one channel to a second channel in another encapsulated liver tissue having at least one liver organoid at least partially covered by a biocompatible cross-linked polymer, the second channel being misaligned with the at least one channel.

[0081] Element 13: delivering oxygenated plasma from at least one channel to a second channel includes delivering oxygenated plasma to the second channel, the second channel being vertically spaced apart from the at least one channel.

[0082] Element 14: The encapsulated liver tissue is cryopreserved prior to transporting the plasma through the fluidic network.

[0083] Element 15: Encapsulated liver tissue cryopreserved with oxygenated plasma.

[0084] Element 16: Providing at least one liver organoid at least partially covered by a biocompatible cross-linked polymer includes forming the at least one channel in the body using photolithography.

[0085] Element 17: Forming the at least one channel includes curing portions of the biocompatible cross-linked polymer with a UV light source while the body is retained in the cavity of the mesh structure.

[0086] Element 18: Forming the at least one channel includes injecting at least one liver organoid and a biocompatible cross-linked polymer into the cavities of the mesh structure and curing portions of the biocompatible cross-linked polymer using a UV light source.

[0087] Element 19: Forming the at least one channel includes covering the body with a photomask having at least one opaque portion; and curing the biocompatible cross-linked polymer with a UV light source applied to the photomask, wherein the portion of the body covered by the at least one opaque portion of the photomask remains uncured to form the at least one channel.

[0088] Element 20: Oxygenating the plasma to produce oxygenated plasma.

[0089] Element 21: Oxygenating the plasma includes oxygenating the plasma prior to delivering the plasma to the at least one channel.

[0090] Element 22: Oxygenation of plasma includes oxygenation of plasma in a perfusion bioreactor.

[0091] Element 23: An oxygenator in fluid communication with the fluid network diffuses oxygen into the plasma to produce oxygenated plasma.

[0092] The above description is exemplary only, and those skilled in the art will recognize that changes may be made to the described embodiments without departing from the scope of the disclosed invention. Other modifications falling within the scope of the invention will be apparent to those skilled in the art upon review of this disclosure, and these modifications are intended to fall within the appended claims.

Claims

1. A perfusion device, comprising: a mesh structure having a first wall spaced apart from a second wall to define an interior mesh cavity, each of the first wall and the second wall of the mesh structure having an opening therein to allow fluid communication through the mesh structure; and an encapsulated organ tissue disposed in the interior mesh cavity between the first wall and the second wall of the mesh structure, the encapsulated organ tissue having at least one organoid at least partially covered by a biocompatible cross-linked polymer, the encapsulated organ tissue having a body having a thickness defined between a first surface of the body adjacent to the first wall of the mesh structure and a second surface of the body adjacent to the second wall of the mesh structure, the body having at least one channel extending from one of the first surface and the second surface into the body to receive a fluid therein, the at least one channel having a diameter selected to diffuse a solute out of the fluid and into the body; The biocompatible cross-linked polymer is a hydrogel, the at least one channel of the body extends through the body between the first surface and the second surface, and the at least one channel has a diameter of 150 μm to 750 μm.

2. The perfusion device of claim 1, wherein the length of the at least one channel is equal to or greater than the thickness of the body.

3. The perfusion device of claim 1 , wherein the at least one channel of the body comprises a first channel and at least one other channel, the first channel extending through the body between the first surface and the second surface, the at least one other channel extending into the body from a first end of one of the first surface and the second surface to a second end within the body of the first channel, the at least one other channel being in fluid communication with the first channel.

4. The perfusion device of claim 3, wherein the length of the first channel is equal to or greater than the thickness of the body, and the length of the at least one further channel is less than or greater than the thickness of the body.

5. A perfusion device according to claim 4, wherein the length of the at least one further channel is greater than the thickness of the body.

6. The perfusion device of any one of claims 1-5, wherein the at least one organoid of encapsulated organ tissue comprises a plurality of liver organoids.

7. An artificial liver system, comprising: a fluid network and a pump for circulating plasma through the fluid network; and a perfusion bioreactor in fluid communication with the fluid network to receive plasma therefrom, the perfusion bioreactor comprising: a housing having a length defined between a housing inlet and a housing outlet, the housing having an inner surface defining a lumen of the housing between and in fluid communication with the housing inlet and the housing outlet, the housing inlet receiving the plasma; and A plurality of perfusion devices are arranged in the inner cavity of the housing, each of the perfusion devices comprising: a mesh structure supported by the inner surface of the housing, the mesh structure having a first wall spaced from a second wall to define an interior mesh cavity, each of the first and second walls of the mesh structure having an opening therein to allow fluid communication through the mesh structure; and an encapsulated liver tissue disposed in the interior mesh cavity between the first wall and the second wall of the mesh structure, the encapsulated liver tissue having at least one liver organoid at least partially covered by a biocompatible cross-linked polymer, the encapsulated liver tissue having a body having a thickness defined between a first surface of the body adjacent to the first wall of the mesh structure and a second surface of the body adjacent to the second wall of the mesh structure, the body having at least one channel extending from one of the first surface and the second surface into the body to receive plasma therein, the at least one channel having a diameter selected to diffuse undesirable solutes out of the plasma and into the body; The perfusion devices are arranged in the lumen of the housing, adjacent to each other, and spaced apart from each other along the length of the housing to receive plasma delivered from the housing inlet to the housing outlet, and to perfuse the plasma into the encapsulated liver tissue of each perfusion device and the at least one channel therein; The biocompatible cross-linked polymer is a hydrogel, the at least one channel of the body extends through the body between the first surface and the second surface, and the at least one channel has a diameter of 150 μm to 750 μm.

8. The artificial liver system of claim 7, wherein the length of the at least one channel is equal to or greater than the thickness of the body.

9. The artificial liver system of claim 7 or 8, wherein the at least one channel of one of the perfusion devices is offset from at least one channel of an immediately adjacent perfusion device, the fluid flowing along a tortuous flow path between the channels of adjacent perfusion devices.

10. The artificial liver system of claim 7, wherein the at least one channel of the body comprises a first channel and at least one other channel, the first channel extending through the body between the first surface and the second surface, the at least one other channel extending into the body from a first end of one of the first surface and the second surface to a second end within the body of the first channel, the at least one other channel being in fluid communication with the first channel.

11. An artificial liver system according to claim 7 or 8, comprising a plurality of supports spaced apart along the length of the housing, the mesh structure of each perfusion device being removably mounted to one of the supports.

12. The artificial liver system according to claim 7 or 8, wherein the housing has an upright orientation and the perfusion devices are supported by the housing in a stacked manner one on top of the other.

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