Liquid-tight case for tissue device and system having same - Patents.com

Abstract

The liquid-tight case includes a housing for enclosing a tissue device, the tissue device having a first channel network and a second channel network in fluid communication with the first channel network. The liquid-tight case also includes a first inlet port, a second inlet port, and at least one outlet port. The first inlet port is formed in or coupled to the housing and configured to be in fluid communication with the first channel network of the tissue device. The second inlet port is formed in or coupled to the housing and configured to be in fluid communication with the second channel network of the tissue device. The at least one outlet port is formed in or coupled to the housing. The liquid-tight case allows the tissue device to have more flexible and more complex designs with more suitable or modified materials for cell migration and tissue formation.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 333,905, entitled "Liquid-Tight Case for Tissue Device and System Having Same," filed April 22, 2022, which is incorporated by reference in its entirety for all purposes. This application also claims priority to U.S. Provisional Patent Application No. 63 / 495,046, entitled "Liquid-Tight Case for Tissue Device and System Having Same," filed April 7, 2023, which is incorporated by reference in its entirety for all purposes.

[0002] SUMMARY The present disclosure relates generally to a fluid-tight case for enclosing a tissue device, and a system having a tissue device enclosed within the fluid-tight case and controlling the flow of a medium therethrough. [Background technology]

[0003] Existing tissue devices face many challenges including leakage, cracking, and delamination, as well as further challenges with controlling flow through microchannel devices. For example, conventional approaches for utilizing tissue devices are susceptible to rupture or delamination when subjected to compressive forces, which gradually leads to undesirable collapsed structures.

[0004] Given the current state of the art, there remains a need for liquid-tight cases and systems that address the above-mentioned challenges.

[0005] The information disclosed in this "Background" section is provided for understanding the general background of the present invention, and is not acknowledged or implied that this information forms part of the prior art already known to those skilled in the art. Summary of the Invention

[0006] In one exemplary embodiment, the present disclosure describes a liquid-tight case for enclosing and protecting a tissue device. In various embodiments, the present disclosure also provides a system having a tissue device enclosed within the liquid-tight case.

[0007] In various embodiments, the present disclosure provides a liquid-tight case including a housing, a first inlet port, a second inlet port, and at least one outlet port. The housing is configured to enclose a tissue device therein. The tissue device includes a first channel network and a second channel network in fluid communication with the first channel network. The first inlet port is coupled to the housing and configured to be in fluid communication with the first channel network of the tissue device. The second inlet port is coupled to the housing and configured to be in fluid communication with the second channel network of the tissue device. The at least one outlet port is coupled to the housing.

[0008] In various embodiments, the present disclosure provides a liquid-tight case including a housing, a first inlet port, a second inlet port, and at least one outlet port. The housing is configured to enclose a tissue device therein. The first inlet port is coupled to the housing and configured to receive a first plurality of live cells and pass the first plurality of live cells to the tissue device. The second inlet port is coupled to the housing and configured to receive a second plurality of live cells and pass the second plurality of live cells to the tissue device. The at least one outlet port is coupled to the housing.

[0009] In some embodiments, the tissue device includes a first channel network and a second channel network. The first channel network is in fluid communication with a first inlet port of the liquid-tight casing for receiving a first plurality of live cells. The second channel network is in fluid communication with a second inlet port of the liquid-tight casing for receiving a second plurality of live cells. The first and second channel networks are in fluid communication with each other.

[0010] In some embodiments, the tissue device is a device that simulates arterial blood flow.

[0011] In some embodiments, the tissue device is a liver device.

[0012] In some embodiments, the at least one exit port includes a first exit port, a first portion of the first exit port in fluid communication with a second portion of the first inlet port, thereby providing fluid communication through the tissue device.

[0013] In some embodiments, the housing includes a base, a lid, and a seal. The base is formed with a hollow space configured to receive the tissue device. The lid is coupled to the base to enclose the tissue device within the hollow space. A seal is disposed between the base and the lid to enhance sealing of the liquid-tight case.

[0014] In some embodiments, the lid is coupled to the base by one or more fasteners, a snap fit, a press fit, one or more adhesives, tapes, or a combination thereof.

[0015] In some embodiments, the seal is made of an elastomeric material.

[0016] In some embodiments, the seal is an O-ring.

[0017] In some embodiments, the base includes a rim and a groove formed along the rim for receiving the seal.

[0018] In some embodiments, the first inlet port, the second inlet port, and the at least one outlet port are coupled to the lid or the base.

[0019] In some embodiments, the first inlet port, the second inlet port, or each of the first and second inlet ports includes a barbed outer connector or is coupled to the exterior of the lid or base to facilitate tubing.

[0020] In some embodiments, the at least one exit port includes a first exit port, and the base of the housing is monolithically formed with a sheath configured to allow the tubing of the first exit port to pass through the housing and be directly connected to a portion of the tissue device.

[0021] In some embodiments, the first and second inlet ports are in or coupled to a first portion of the base, and the at least one outlet port is in or coupled to a second portion of the base.

[0022] In some embodiments, each of the first and second inlet ports includes a barbed outer connector formed on the exterior of the first portion of the base to facilitate tubing. Additionally or optionally, a barbed inner connector is formed on the interior of the first portion of the base to facilitate tubing and direct connection to a tissue device.

[0023] In some embodiments, the first and second portions of the base are opposed to one another.

[0024] In some embodiments, the first and second inlet ports are coupled to the lid.

[0025] In some embodiments, each of the first and second entry ports includes a barbed outer connector coupled to the outside of the lid to facilitate tubing. Additionally or optionally, in some embodiments, a barbed inner connector is formed on or coupled to the inside of the lid to facilitate tubing and direct connection to a tissue device.

[0026] In various embodiments, the present disclosure provides a system including a liquid-tight case as disclosed herein and a tissue device enclosed within the liquid-tight case and in fluid communication with a first inlet port, a second inlet port, and at least one outlet port.

[0027] In some embodiments, the system is implantable in the body of a human subject or animal.

[0028] In some embodiments, the animal is a rat or a pig.

[0029] In some embodiments, the system is one of a cardiovascular left ventricular muscle patch, a face transplant, a limb, a finger, and a kidney.

[0030] In various embodiments, an apparatus is provided for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing. In some embodiments, the apparatus includes a plurality of pumps. In some embodiments, the apparatus includes a manifold interconnecting the plurality of pumps. In some embodiments, the apparatus includes outlet tubing coupled to the manifold.

[0031] The liquid-tight cases and systems of the present disclosure have other features and advantages that will become apparent from or be more fully described in the accompanying drawings, which are incorporated herein, and the following detailed description, which together serve to explain certain principles of exemplary embodiments of the present disclosure.

[0032] The foregoing summary as well as the following detailed description of embodiments of systems and devices will be better understood when read in conjunction with the accompanying drawings of illustrative embodiments, it being understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.

[0033] In the drawings: [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 is a perspective view that generally illustrates an exemplary system, in accordance with some exemplary embodiments of the present invention. [Diagram 2] 2 is a partial cross-sectional side view that diagrammatically illustrates the system of FIG. 1 in accordance with some exemplary embodiments of the present invention. [Diagram 3] FIG. 2 is an exploded view that generally illustrates the system of FIG. 1 in accordance with some exemplary embodiments of the present invention. [Figure 4] FIG. 1 is a perspective view that generally illustrates an exemplary system, in accordance with some exemplary embodiments of the present invention. [Diagram 5] 5 is a partial cross-sectional top view that diagrammatically illustrates the system of FIG. 4 in accordance with some exemplary embodiments of the present invention. [Figure 6] 5 is an exploded view that generally illustrates the system of FIG. 4 in accordance with some exemplary embodiments of the present invention. [Figure 7] 5 is a top view that illustrates, in schematic form, a variation of the system of FIG. 4, in accordance with some exemplary embodiments of the present invention. [Figure 8] FIG. 1 is a perspective view that generally illustrates an exemplary system, in accordance with some exemplary embodiments of the present invention. [Figure 9] 9 is a side view that diagrammatically illustrates the system of FIG. 8 in accordance with some exemplary embodiments of the present invention. [Figure 10A] 9 is a partial cross-sectional side view that diagrammatically illustrates the system of FIG. 8 in accordance with some exemplary embodiments of the present invention. [Figure 10B] FIG. 10B is an enlarged view of a portion of FIG. 10A. [Figure 11]9 is an exploded view that generally illustrates the system of FIG. 8, in accordance with some exemplary embodiments of the present invention. [Figure 12] 9 is a side view that diagrammatically illustrates the system of FIG. 8 in accordance with some exemplary embodiments of the present invention. [Figure 13] 9 is a partial cross-sectional side view that diagrammatically illustrates the system of FIG. 8 in accordance with some exemplary embodiments of the present invention. [Figure 14] 1 is a perspective view that generally illustrates a lip, according to some exemplary embodiments of the present invention; [Figure 15] 15 is another perspective view that generally illustrates the lip of FIG. 14 according to some exemplary embodiments of the present invention. [Figure 16] 1 illustrates a perfusion test according to some exemplary embodiments of the present invention. [Figure 17] 1 illustrates an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Figure 18] 1 illustrates an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Figure 19] 1 illustrates a first portion of an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Figure 20] 14 illustrates a second portion of an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Figure 21] 1 illustrates a manifold of an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Figure 22] 1 illustrates an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Diagram 23] 1 illustrates a side view of an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Figure 24] 24 illustrates a second side view of the device of FIG. 23. [Diagram 25] 1 illustrates a cross-sectional view of an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Figure 26] 1 illustrates a chart depicting various dimensions of an apparatus for controlling flow through a fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. [Figure 27] 1 illustrates a system including a fluid-tight casing and an apparatus for controlling flow through the fluid-tight casing and / or a tissue device housed by the fluid-tight casing, according to some exemplary embodiments of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Disclosed herein are systems and devices that include a liquid-tight case for enclosing and protecting a tissue device. Exemplary liquid-tight cases of the present invention generally include a housing configured to enclose a tissue device therein, and one or more ports configured to connect the tissue device to one or more components (e.g., other organs, devices, structures, or sources) outside the liquid-tight case, for example, to provide nutrients, living cells, other materials, or combinations thereof to the tissue device. Exemplary liquid-tight cases of the present invention can have any shape and any size that allows the liquid-tight case to accommodate tissue devices of various sizes.

[0036] The exemplary liquid-tight case of the present invention solves many of the problems of existing tissue devices, including leakage, cracking, and delamination. In some embodiments, the liquid-tight case of the present disclosure allows the tissue device to have a flexible and / or complex (e.g., fractal) design. For example, with the protection of the exemplary liquid-tight case of the present invention, the tissue device can be configured to achieve various functions with more suitable shapes, structures, and inner channels. By incorporating the exemplary liquid-tight case of the present invention into various systems, the tissue device can also be made with more suitable or modified materials (e.g., hydrogels) for cell migration and tissue formation. The exemplary liquid-tight case of the present invention allows the construction of various systems (system refers to the tissue device enclosed in the liquid-tight case of the present invention), such as cardiovascular left ventricular muscle patches, face transplants, limbs, fingers, and kidneys.

[0037] Referring now in detail to the drawings, in which like reference numbers denote like elements throughout, FIGS. 1-3 illustrate an exemplary system 100 in accordance with some exemplary embodiments of the present invention. System 100 generally includes a tissue device, such as tissue device 110, and a liquid-tight case, such as liquid-tight case 120. The exemplary liquid-tight case is configured to protect the tissue device and ensure that the tissue device receives nutrients, living cells, and / or other materials. The exemplary tissue device can be printed, for example, using an additive manufacturing method (e.g., high resolution), which allows for at least partially forming the tissue device as a three-dimensional monolithic structure. In some embodiments, the additive manufacturing method is selected from the group consisting of binder jetting, material extrusion, material jetting, polyjet, powder bed, sheet lamination, and vat photopolymerization. In some embodiments, the additive manufacturing method of vat photopolymerization includes stereolithography (e.g., projection stereolithography). In some such embodiments, by using additive manufacturing, the orientation of each layer of the liquid-tight case is formed in a first direction perpendicular to the direction of the force applied to the liquid-tight case. For example, in some embodiments, the orientation of the layers is not perpendicular to the direction of pulling the liquid-tight case. However, the present disclosure is not limited in this respect.

[0038] For example, in some embodiments, the liquid-tight casing includes a polymer selected at least in part based on the swelling degree of the polymer. In some embodiments, the swelling degree is based on one or more of the following parameters: one or more dimensional parameters of the liquid-tight casing (e.g., planar swelling, volumetric swelling), one or more mass parameters of the liquid-tight casing (e.g., mass swelling), one or more time parameters of the liquid-tight casing (e.g., per unit time), or a combination thereof. In some embodiments, the swelling degree is the ratio of the difference between the wet weight and the dry weight compared to the wet weight of the liquid-tight casing. For example, in some embodiments, the swelling degree is determined by Swelling ratio = Wwet - Wdry Wwet.

[0039] In some embodiments, the liquid-tight casing includes a polymer selected at least in part based on its porosity to allow the candidate target cells to attach to the pores of the liquid-tight casing (e.g., the pores of a tissue device) without exuding through the environment, thereby limiting the permeability of the liquid-tight casing. In some embodiments, the median size of the pores of the liquid-tight casing is about 5 microns (μm) to about 300 μm, about 19 μm to about 231 μm, about 25 μm to about 175 μm, or about 60 μm to about 100 μm. In some embodiments, the median size of the pores of the liquid-tight casing is at least 5 μm, at least 19 μm, at least 25 μm, at least 60 μm, at least 100 μm, at least 175 μm, at least 231 μm, or at least 300 μm. In some embodiments, the median size of the pores in the liquid-tight casing is at most 5 μm, at most 19 μm, at most 25 μm, at most 60 μm, at most 100 μm, at most 175 μm, at most 231 μm, or at most 300 μm.

[0040] As used herein, the term "about" or "approximately" can mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which may depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, as is customary in the art. "About" can mean within ±20%, ±10%, ±5%, or ±1% of a given value. When a particular value is described in this application and claims, unless otherwise stated, the term "about" means within an acceptable error range for the particular value. The term "about" can have the meaning commonly understood by a person of ordinary skill in the art. The term "about" can refer to ±10%. The term "about" can refer to ±5%.

[0041] In some embodiments, the polymeric material of the liquid-tight casing is polydimethylsiloxane (PDMS), polyglycerol sebacate (PGS), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), polyglycolide, polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), polydioxanone, polygluconate, polylactic acid-polyethylene oxide copolymer, modified cellulose, collagen, polyhydroxybutyrate, polyhydroxyprylamide, polyphosphoester, poly(alpha-hydroxy acid), polycaprolactone, polycarbonate, polyamide, polyanhydride, polyamino acid, polyorthoester, polyacetal. , polycyanoacrylate, degradable urethane, aliphatic polyester polyacrylate, polymethacrylate, acyl-substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, polyvinyl imidazole, chlorosulfonated polyolefin, polyethylene oxide, polyvinyl alcohol, Teflon (copyright), nylon silicone, shape memory materials such as poly(styrene-block-butadiene), polynorbornene, hydrogels, metal alloys, oligo(ε-caprolactone) diol as switching segment / oligo(p-dioxyanone) diol as physical crosslink, and combinations thereof. For example, in some embodiments, the case utilizes a PLGA polymer, which is a PLA / PGA polymer with a 50 / 50 ratio. An exemplary PLA / PGA polymer has a molecular weight of about 30,000 Da. However, the present disclosure is not limited thereto.

[0042] The liquid-tight case 120 generally includes a housing, such as housing 130, configured to encapsulate a tissue device therein. For example, in some embodiments, the housing 130 includes a base 131, a lid 132, and a seal 133. In some embodiments, the base, the lid, the seal, or a combination thereof are fabricated by a molding process, a printing process (e.g., additive manufacturing), or the like. In some embodiments, the base is formed to have a hollow space 134 configured to house (e.g., accommodate) the tissue device. In some embodiments, the lid is coupled to the base to encapsulate the tissue device within the hollow space. For example, in some embodiments, the base has an opening at the top, and the lip is coupled to the top of the base (e.g., by bonding with the opening in the base). In some embodiments, the housing, the base, the lid, the seal, or a combination thereof are formed as a three-dimensional monolithic device, which improves the material integrity and durability of the liquid-tight case. For example, in some embodiments, the housing, base, lid, seal, or combination thereof is integrally formed with another of the housing, base, lid, seal, or combination thereof, although the present disclosure is not limited in this respect.

[0043] In some embodiments, attachment of the lid and base is accomplished by any suitable means, including, but not limited to, screws, bolts, pins, rivets, adhesives, snap fits, press fits, tape, etc. For example, and by way of non-limiting example, in some embodiments, the lid is fastened to the base by a number of fasteners, such as one or more bolts 135 and / or one or more nuts 136. Note that while six pairs of bolts and nuts are illustrated, any number of fasteners (e.g., 2, 3, 4, 5, 6, 7, 8, or more than eight) can be used. Also, in some embodiments, the fasteners are evenly or non-uniformly spaced from one another.

[0044] In some embodiments, a seal is disposed between the base and the lid to enhance sealing of the liquid-tight case. In some embodiments, the seal is made of an elastomeric material, e.g., by molding, printing, etc. For example, in some embodiments, the seal is a mechanical seal that inhibits, retards, terminates, etc., fluid communication between the interior volume and the environment. For example, in some embodiments, the seal is placed between the lid and the base and compressed by a fastener mechanism, e.g., by tightening a bolt, thereby creating a liquid-tight (e.g., water-tight or waterproof) seal due to compression of the seal interposed between the lid and the base. Thus, in some such embodiments, the seal prevents flow of a medium between a first surface of the base and a second surface of the lid. Further, in some such embodiments, by compressing the seal between the first surface of the base and the second surface of the lid, the seal has an improved fit therebetween to maintain a flow-retarding condition therebetween, regardless of the type of medium, pressure, or temperature of the liquid-tight case. In some embodiments, the lid and / or the base include a groove configured to receive the seal. In some embodiments, the first width of the groove is greater than the second width of the seal in an uncompressed state and less than the third width of the seal in a compressed state, although the disclosure is not limited in this respect.

[0045] In some embodiments, fasteners are utilized to join the lid and the base of the housing. For example, in some embodiments, the fasteners include an adhesive layer (e.g., medical and / or surgical tape) that is used to encase (e.g., wrap around) the fasteners and the like to reduce sharp edges and corners of the liquid-tight case. Alternatively, in another embodiment, the lid and base are formed with countersinks so that the nuts and bolts are inserted flush with the surface of the lid or base. In further embodiments, the nuts are countersunk with holes or cuts that have a shape that simplifies fastening (e.g., no wrench is required if the nut is countersunk with a matching hexagonal hole or the like). In some embodiments, the liquid-tight case includes one or more radiused or chamfered edges, which provide a smooth exterior for the liquid-tight case. However, the present disclosure is not limited thereto. In some embodiments, the liquid-tight case includes.

[0046] In some embodiments, the fastener is flush with the housing surface such that an end portion of the fastener is in the same plane as a portion of the end housing. Thus, the fastener does not extend substantially beyond a portion of the end housing. However, the present disclosure is not limited thereto. For example, in some embodiments, the fastener is recessed from the housing surface and / or protrudes from the housing surface. In some embodiments, the fastener and the housing are flush. As used herein, the term "flush" is defined as a surface of a first component and a same respective surface of a second component having a distance or level that separates the first component and the second component within a tolerance of 0.0 cm, 50 μm, within a tolerance of 0.1 mm, within a tolerance of 0.1 cm, or within a tolerance of 0.25 cm. In some embodiments, the same respective surface of the second component is flush with a surface of the first component. For example, in some embodiments, a lid that is considered to be flush with a base may be disposed inside a portion of the base or may be integral with the base. However, the present disclosure is not limited thereto. Thus, in some embodiments, the housing includes one or more rounded edge portions, which allows for easier insertion, for example when the liquid-tight case is to be implanted in a subject.

[0047] In some embodiments, the housing is configured to minimize free space (e.g., one or more voids) within the liquid-tight case. For example, in some embodiments, the housing is configured to house the tissue device without causing decay of some or all of the cells housed by the tissue device. In some embodiments, the housing is configured to maximize the active area of ​​the tissue device. However, the present disclosure is not limited in this respect.

[0048] The liquid-tight casing 120 also includes one or more ports for connecting the tissue device with one or more components (e.g., organs, other devices, sources, etc.) outside the liquid-tight casing, for example, to provide nutrients, living cells, other materials, or a combination thereof to the tissue device. The one or more ports are formed in or coupled with the housing. For example, in some embodiments, the liquid-tight casing includes a first inlet port 140, a second inlet port 150, and at least one outlet port. In some embodiments, the one or more ports are integrally formed with the housing, for example, by forming a three-dimensional monolithic structure. In some embodiments, the at least one outlet port includes a first outlet port 160. In some embodiments, the at least one outlet port includes one or more additional or optional outlet ports in addition to the first outlet port. In some embodiments, the at least one outlet port includes one outlet port, two outlet ports, three outlet ports, or four outlet ports. In some embodiments, the at least one outlet port comprises no more than two outlet ports, no more than three outlet ports, or no more than four outlet ports. In some embodiments, the at least one outlet port comprises at least two outlet ports, at least three outlet ports, or at least four outlet ports. However, the present disclosure is not limited thereto.

[0049] In some embodiments, the first inlet port, the second inlet port, and the at least one outlet port have the same, similar, or different sizes, shapes, materials, structures, etc. Each of the first inlet port, the second inlet port, and the at least one outlet port can be formed in or coupled to the lid or base, independent of the other, separate from the other, or in cooperation with the other. For example, as a non-limiting example, the first inlet port and the second inlet port are formed in or coupled to the lid, and the first outlet port is formed in or coupled to the base. In some embodiments, each port is configured to exhibit laminar flow therein. In some embodiments, each port is sized based on Murray's Law.

[0050] In some embodiments, the base is monolithically (e.g., as a three-dimensional monolithic structure) formed with a sheath, such as sheath 161. The sheath is configured to allow a tube, generally indicated by reference numeral 170, to pass through the tissue device and be directly connected thereto (e.g., directly connected to the output of the first channel network of the tissue device), such as by adhesive(s). Examples of adhesives include, but are not limited to, silicone, cyanoacetate, styrene butadiene copolymer, and the like. In some such embodiments, the tube that passes through the sheath and is connected to the tissue device serves as the first exit port. The sheath with the tubing can be wrapped around with tape(s) or glued with adhesive(s) to provide an additional seal.

[0051] In some embodiments, the first inlet port includes a barbed outer connector (or barbs), such as barbed outer connector 141, formed on the outside of the lid or coupled with the lid. Barbed outer connector 141 is configured to facilitate tubing, e.g., to allow easy and / or tight connection of tubing. Similarly, in some embodiments, the second inlet port includes a barbed outer connector, such as barbed outer connector 151, formed on the outside of the lid or coupled with the outside of the lid to facilitate tubing. In some embodiments, a barbed inner connector, such as barbed inner connector 143, is formed on the inside of the lid or coupled with the inside of the lid to facilitate tubing. In some embodiments, the tubing connected with barbed inner connector 143 is directly connected to the tissue device (e.g., directly connected to the input of the first channel network of the tissue device), e.g., by adhesive(s) or the like.

[0052] In some embodiments, the barbed connectors for the different ports are configured the same or differently, e.g., having the same shape or different shapes, having the same size or different sizes, etc. Similarly, the tubing, generally indicated by reference number 170, can have the same or different configurations for the different barbed connectors and different ports. For example, in some embodiments, all the barbed outer connectors (or barbs) are configured substantially the same, and the tubing for the different barbed outer connectors and / or first outlet ports is the same. In some embodiments, all the tubing barbs are designed for tubing having an inner diameter (ID) of about 1 / 8 inch and an outer diameter (OD) of about 1 / 4 inch. In some embodiments, one or more barbs are designed for tubing having an ID less than 1 / 8 inch and / or an OD less than 1 / 4 inch. In some embodiments, one or more barbs are designed for tubing having an ID greater than 1 / 8 inch and / or an OD greater than 1 / 4 inch.

[0053] In some embodiments, the 3 barb Y-joint (i.e., barbed outer connector 141, barbed outer connector 151, and barbed inner connector 143) are monolithically formed with a lid, such as by molding or printing. In an alternative embodiment, the 3 barb Y-joint is made as a separate piece and coupled with a lip, such as by molding or printing. The separate 3 barb Y-joint can be made of a more durable plastic. In a further alternative embodiment, the first or second inlet port is constructed in a similar manner as the first outlet port 160, with a sheath rather than barbs.

[0054] In some embodiments, the first inlet port is configured to receive a first plurality of live cells and pass the first plurality of live cells to the tissue device. The second inlet port is configured to receive a second plurality of live cells and pass the second plurality of live cells to the tissue device. For example, in some embodiments, the first inlet port is a portal vein (PV) port that receives blood flow and passes it to a first channel network of the tissue device. The second inlet port is a hepatic bile (HB) port that provides bile inflow and / or outflow and is in fluid communication with a second channel network of the tissue device. The first outlet port is a PV outlet port and is in fluid communication with the first inlet port through the tissue device. The first outlet port allows blood flow to exit after it has been distributed throughout the tissue device to allow oxygen transport and cell nutrition of both networks.

[0055] 4-6, an exemplary system 200 is illustrated in accordance with some exemplary embodiments of the present invention. System 200 generally includes a tissue device, such as tissue device 110, and a liquid-tight casing, such as liquid-tight casing 220, for protecting the tissue device and ensuring that the tissue device receives nutrients, living cells, and / or other materials. Liquid-tight casing 220 is similar to liquid-tight casing 120, except that in liquid-tight casing 220, (i) the base has an opening on the side instead of the top, (ii) a lip is coupled to the side of the base, and (iii) the first inlet port, the second inlet port, and the first outlet port are all formed in or coupled to the base.

[0056] For example, in some embodiments, the liquid-tight case 220 includes a housing 230 configured to enclose a tissue device therein. The housing 230 includes a base 231, a lid 232, and a seal 233. The base, lid, and / or seal may be made by molding, printing, etc. The base has an opening on a side, and a lip is coupled to the side of the base.

[0057] In some embodiments, the liquid-tight casing 220 also includes a first inlet port 140, a second inlet port 150, and a first outlet port 160. The first and second inlet ports are formed in or coupled to the first portion of the base 231. Similar to the liquid-tight casing 120, in some embodiments, the first inlet port, the second inlet port, or the first and second inlet ports of the liquid-tight casing 220 each include a barbed outer connector formed on the outside of the first portion of the base to facilitate tubing. In some embodiments, a barbed inner connector, such as a barbed inner connector 143, is also formed on the inside of the first portion of the base to facilitate tubing and direct connection to a tissue device. However, the present disclosure is not limited thereto.

[0058] In some embodiments, the first exit port is formed in or coupled to the second portion of the base 231. Similar to the liquid-tight case 120, in some embodiments, the base 231 is monolithically formed with a sheath, such as sheath 161, in the second portion to allow tubing to pass through and be directly connected to a tissue device. In some embodiments, tubing that passes through the sheath and is connected to the tissue device serves as the first exit port. The sheath with the tubing can be wrapped around with tape(s) or adhered with adhesive(s) to provide an additional seal.

[0059] In some embodiments, the first and second portions of the base 231 are opposite one another. For example, in some embodiments, the first portion of the base 231 is the base wall on the right side of the figure and the second portion of the base 231 is the base wall on the left side of the figure.

[0060] Similar to liquid-tight casing 120, in some embodiments the three barb Y-joint of liquid-tight casing 220 is monolithically formed, such as by molding or printing, with the first portion of base 231. In an alternative embodiment, the three barb Y-joint is made as a separate piece and coupled, such as by molding or printing, with the first portion of base 231. In a further alternative embodiment, the first or second inlet port is constructed in a similar manner as first outlet port 160, but with a sheath rather than barbs.

[0061] In some embodiments, similar to the liquid-tight case 120, the lid is fastened to the base, for example, by bolts and nuts. The lid can be fastened to the base by any number of fasteners (e.g., any number of bolt and nut pairs), such as 2, 3, 4, 5, 6, 7, 8, more than 8, more than 10, more than 15, or more than 20, depending on the size and shape of the lid and base. As a non-limiting example, Figures 4-6 illustrate a lid fastened to a base by six fasteners. As another non-limiting example, Figure 7 illustrates a lid fastened to a base by eight fasteners, as indicated by the additional bolt holes shown in the figures.

[0062] 8-15, an exemplary system 300 is shown in accordance with some exemplary embodiments of the present invention. System 300 generally includes a tissue device, such as tissue device 110, and a liquid-tight casing, such as liquid-tight casing 320, for protecting the tissue device and ensuring that the tissue device receives nutrients, living cells, and / or other materials. Liquid-tight casing 320 is similar to liquid-tight casing 120, except that (i) liquid-tight casing 320 is fastened to a base by a snap fit, press fit, or the like, rather than by nuts and bolts, (ii) a first inlet port and a second inlet port of liquid-tight casing 320 are formed in or coupled to the base, and (iii) a first outlet port is formed in or coupled to the lid.

[0063] For example, in some embodiments, the liquid-tight case 320 includes a housing 330 configured to encapsulate a tissue device therein. The housing 330 includes a base 331, a lid 332, and a seal 333. The base, lid, and / or seal can be made by molding, printing, etc. The base has an opening at the top, and the base is formed to have a rim, such as rim 334. The lid is formed to have one or more snaps, such as snap 335, on at least one side of the lid for fastening to the rim of the base. In some embodiments, the lid is formed to have one or more snaps on all sides of the lid for fastening to the rim of the base. In another embodiment, a snap is formed on each side of the lid. In yet another embodiment, at least one side of the lid is formed to have more than one snap. In some embodiments, the lid is formed to have one or more notches, such as notch 336, on one or more corners of the lid to flexibly snap into an otherwise rigid material. In some embodiments, the lid is formed with a notch at each of the corners.

[0064] In some embodiments, a groove, such as groove 337, is formed along the rim to accommodate seal 333. In some embodiments, seal 333 is an O-ring that is printed. The seal can be placed in the groove in the base, glued in place, or the like.

[0065] In some embodiments, the liquid-tight casing 320 also includes at least one outlet port, such as the first inlet port 140, the second inlet port 150, and the first outlet port 360. The first inlet port and the second inlet port are formed in a portion of the base 331, for example, in the bottom of the base or are coupled to a portion of the base 331. Similar to the liquid-tight casing 120, in some embodiments, the first inlet port, the second inlet port, or the first and second inlet ports of the liquid-tight casing 320 each include a barbed outer connector formed on the outside of a portion of the base to facilitate tubing. In some embodiments, a barbed inner connector, such as the exposed inner connector 143, is also formed on the inside of a portion of the base to facilitate tubing and direct connection to a tissue device.

[0066] In some embodiments, the first exit port 360 is formed in or coupled to the lid 332. Similar to the first inlet port 140, in some embodiments the first exit port 360 includes a barbed outer connector, such as a barbed outer connector 361, formed on the outside of the lid 332 to facilitate tubing. In some embodiments, a barbed inner connector, such as an exposed inner connector 363, is also formed on the inside of the lid 332 to facilitate tubing and direct connection to a tissue device. The barbed inner and outer connectors isolate movement of the external tubing from components inside the liquid-tight case.

[0067] In some embodiments, similar to liquid-tight casing 120, in some embodiments the three barb Y-joint of liquid-tight casing 320 is monolithically formed with a portion (e.g., bottom) of base 331, such as by molding or printing. In an alternative embodiment, the three barb Y-joint is made as a separate piece and coupled with a portion of base 331, such as by molding or printing. In a further alternative embodiment, the first or second inlet port is constructed in a similar manner as first outlet port 160, with a sheath rather than barbs.

[0068] In some embodiments, the liquid-tight casing (e.g., casing 120, casing 220, casing 320) is illustrated as being substantially rectangular or cubic in shape, but it should be noted that these shapes are non-limiting examples. The liquid-tight casing can have any suitable shape and size depending on the application and / or shape / size / function of the tissue device. For example, the base (e.g., base 131, base 231, base 331) can have a shape that is substantially cubic, cylindrical, spherical, dome-shaped, etc. Similarly, the lid (e.g., lid 132, lid 232, lid 332) and the seal (e.g., seal 133, seal 233, seal 333) can have a shape that is substantially rectangular, circular, etc. to mate with the base. In some embodiments, the base includes a first polygonal shape and the lid includes a second polygonal shape that is different from the first polygonal shape.

[0069] Thus, the systems (e.g., System 100, System 200, System 300) can have any suitable shape and size depending on the application and / or shape / size / function of the tissue device. The systems can be configured small for implantation in small animals, such as rats. The systems can be configured large for implantation in larger animals, such as pigs. Other non-limiting examples of systems include, but are not limited to, cardiovascular left ventricular muscle patches, ears, bones, face transplants, limbs, fingers, and kidneys.

[0070] Referring to FIG. 16, a perfusion test is illustrated. The perfusion test is performed to evaluate any leaks through the assembled system and to confirm a secure connection between the tubes and ports. It is noted that while the figure shows system 100, the perfusion test can be performed with respect to system 200, system 300, or a similar system. The print resolution of the inner channels of the tissue device is evaluated prior to the perfusion test, for example by microscopic inspection. After verifying that all channels of the tissue device are open and perfusable, a flow (e.g., 100 ml of 1xPBS) is perfused through the assembled system at a specific flow rate (e.g., a flow rate of 192 ml / min) for a period of time (e.g., 1 hour) to evaluate the leak rate.

[0071] Thus, in some embodiments, the tissue device comprises a sponge or mesh that facilitates the culture of cells. For example, in some embodiments, the sponge of the insert is a type 1 collagen sponge, for example prepared from porcine dermis. In some embodiments, the tissue device comprises gelfoam, such as cylindrical gelfoam. In some embodiments, the tissue device is a gelfoam such as that provided by Pfizer (New York City, New York). Yet, in some embodiments, the tissue device is coated with gelatin. For example, in some embodiments, the tissue is coated with about 2% gelatin, about 1.5% gelatin, about 1% gelatin, about 0.5% gelatin, about 0.35% gelatin, about 0.2% gelatin, about 0.1% gelatin, or about 0.05% gelatin.

[0072] Thus, in some embodiments, a liquid-tight casing is utilized to flow culture medium through the system. In some embodiments, a plurality of cells are cultured two-dimensionally within each tissue device (e.g., cultured on a membrane of an insert of a tissue device). In some embodiments, a plurality of cells are cultured three-dimensionally within each tissue device (e.g., a plurality of cells are embedded within the tissue device and / or contained, e.g., suspended, within a hydrogel of the liquid-tight casing).

[0073] In some embodiments, the tissue device comprises a length (e.g., y-axis length) of about 31 millimeters (mm), a width (e.g., x-axis length) of about 11.4 mm, and a height (e.g., z-axis depth) of about 11 mm.

[0074] 17-27, in some embodiments, the present invention provides an apparatus for controlling flow through a fluid-tight casing and / or tissue device, in some embodiments, the apparatus includes or is in electronic communication with one or more processors, a memory coupled to the one or more processors, and a controller coupled to the memory and to the one or more processors.

[0075] In some embodiments, the flow of media within the system is at a flow rate of about 150 microliters per minute (μL / min), about 200 μL / min, about 250 μL / min, about 300 μL / min, about 350 μL / min, about 400 μL / min, about 450 μL / min, about 500 μL / min, about 550 μL / min, about 600 μL / min, about 650 μL / min, or about 700 μL / min. Generally, the flow of media within the system is at a flow rate that mimics the flow of fluids within an organ such that sufficient nutrients and waste removal are provided to the cells of the system without causing damage to the cells.

[0076] In some embodiments, the apparatus includes a pump configured to facilitate fluid flow through the fluid-tight casing and / or the tissue device based on one or more instructions provided by, for example, the controller.

[0077] In some embodiments, the systems and methods of the invention provide a device, known as a heparin delivery system (HDS), that includes a holder, collector manifold, outlet tubing connectors, or combinations thereof for up to a number of pumps (e.g., 4 pumps, 8 pumps, 12 pumps, 16 heparin pumps, 20 pumps, 25 pumps, etc.). In some embodiments, the holder includes a base with a manifold and a snap lid for securing the pumps.

[0078] In some embodiments, the fabrication of the systems and devices of the present invention uses higher resolution that may be required for the manifold channels and holes to mate with the pump needles, however, the present invention is not limited in this respect.

[0079] In some embodiments, the device is configured to be as light weight (eg, low mass) as possible, yet still ensure that the device is sufficiently rigid.

[0080] In some embodiments, the systems and devices of the present invention are configured to allow a needle to fit into a mating bore of the device.

[0081] It should be noted that while the tissue device is illustrated as being a block, this is for simplicity of example. The tissue device may have any suitable shape, size, and configuration. For example, in some embodiments, the tissue device is selected from a cylinder, a sphere, a dome, or other shape. Exemplary devices have dimensions of about 5mm to 10mm, 10mm to 20mm, 20mm to 30mm, 30mm to 40mm, greater than 40mm, greater than 50mm, greater than 60mm, greater than 70mm, greater than 80mm, greater than 90mm, greater than 100mm, or more. In some embodiments, the tissue device has dimensions of a first dimension of about 70mm, a second dimension of about 50mm, and a third dimension of about 35mm.

[0082] Exemplary tissue devices generally include one or more channel networks, such as channel network 112. It is noted that the tissue device may include one, two, three, four, or any suitable number of channel networks. It is also noted that each channel network may include one, two, three, four, five, six, or more than six levels of branches, and each branch may, but need not, be bifurcated. It is further noted that the channel network(s) may be structured the same, similarly, or differently than the illustrated embodiment. For example, in some embodiments, the tissue device includes two or more networks, where a first channel network is in fluid communication with a second channel network. The first channel network is configured to receive a first plurality of living cells through a liquid-tight casing, and the second channel network is configured to receive a second plurality of living cells through a liquid-tight casing. In some embodiments, the tissue device includes a first channel network in fluid communication with a third channel network, and a second channel network is formed interposed between the first channel network and the second channel network (e.g., the first channel network bypasses the second channel network, etc.).

[0083] In some embodiments, the tissue device is formed using a positive mold, thereby forming a void between the first and second channel networks. In some embodiments, the forming is by a negative mold, thereby forming a void between the first and second channel networks of the tissue device. However, the present disclosure is not limited thereto.

[0084] In some embodiments, the tissue device is a biomimetic network, a biomimetic structure, a biomimetic device, a vascular network device, an implantable living device, or the like. For example, in some embodiments, the tissue device is a device that stimulates arterial blood flow therethrough. For example, in some embodiments, the tissue device is configured to satisfy Murray's Law, which is a tool in optimizing the diameter of the branch channels of the tissue device. For example, each preceding channel before the smallest diameter channel of the tissue device has a diameter that increases by a predetermined factor derived from Murray's Law, which is based on biological observations of the ratio of inflow diameter to outflow diameter. Murray's Law states:

number

[0085] In some embodiments, the tissue device is a liver device. In some embodiments, the tissue device is the same as or similar to a biomimetic network, biomimetic structure, biomimetic device, vascular network device, or implantable living device described in any of U.S. Patent Application Publication Nos. 2015 / 0366651, 2019 / 0358367, 2018 / 0236134, and 2021 / 0071145, each of which is incorporated herein by reference in its entirety for all purposes.

[0086] Referring to FIG. 17, in some embodiments, the device includes a holder for up to 16 heparin pumps, a collector manifold, and an outlet tubing connector. The holder includes a base to house the manifold and a snap lid to secure the pump. In some embodiments, the outlet connects to 1 / 8 inch ID (hence 1 / 4 inch outer diameter (OD)) tubing with a 1 / 16 inch wall thickness. FIG. 17 illustrates a device including 16 pumps among the plurality of pumps. However, the disclosure is not limited thereto.

[0087] 18, in some embodiments, the device meets a threshold stiffness, a threshold needle fit, a threshold snap fit, or a combination thereof. For example, in some embodiments, the threshold snap fit considers whether the device is tight, sufficient, or loosely coupled. In some embodiments, the device meets a threshold ID (e.g., a dimensional threshold) of the metal needle hole, a curvature and tolerance threshold of the surface to be attached to the plurality of pumps, a stiffness threshold of the base and / or lid, a diameter threshold of the hole, a stiffness threshold of the outlet, a stiffness threshold of the side brace support, a thickness threshold, a circumferential band threshold (e.g., for additional support and protection of the pump), or a combination thereof. FIG. 18 illustrates a device including 25 pumps of the plurality of pumps.

[0088] 19, in some embodiments, the device includes a first portion (e.g., a lid portion) configured to couple to a second portion (e.g., a holder base portion) of the device. In some embodiments, the first portion is configured to snap-fit ​​couple to the second portion, for example, through a cantilever snap-fit ​​closure mechanism. In some embodiments, each cantilever snap-fit ​​closure mechanism is disposed on two or more sides of the first portion of the device.

[0089] Referring to FIG. 20, in some embodiments, the device includes a second portion configured to receive the first portion of the device. In some embodiments, the second portion is configured as a base. In some embodiments, the second portion includes one or more snap-fit ​​connections configured to receive corresponding snap-fit ​​features of the first portion of the device. In some embodiments, the second portion includes one or more inlets for one or more heparin pump needles. In some embodiments, the second portion includes a curved surface for mounting to a pump surface. In some embodiments, the second portion includes a heparin outlet tubing connection.

[0090] 21 and 22, in some embodiments, the device includes a manifold. In some embodiments, the manifold is a component of the second part. For example, in some embodiments, the manifold and the second part form a three-dimensional monolithic device. In some embodiments, the manifold is a collector coupled to a plurality of pumps. In some embodiments, the manifold is housed in the second part. In some embodiments, the manifold includes a plurality of holes for mating with the pump needles and terminates at an outlet tubing connection. In some embodiments, the manifold includes a 1 millimeter (mm) square collector channel that is 0.5 mm below the needle tip. In some embodiments, the outlet tubing connection is for 1 / 8 inch inner diameter (ID) tubing. In some embodiments, each pump is configured to provide a uniform flow rate of the medium (e.g., provide a constant pressure gradient). In some embodiments, each pump is in fluid communication with at least one pump of the plurality of pumps. However, the disclosure is not limited thereto. In some embodiments, each pump is configured to provide a flow rate to the liquid-tight casing and / or tissue device at a rate of about 100 milliliters (mL) / hour, about 300 mL / hour, about 500 mL / hour, about 700 mL / hour, about 900 mL / hour, about 1.5 L / hour, about 2 L / hour, about 5 L / hour, or about 30 L / hour. In some embodiments, each pump is configured to provide a flow rate to the liquid-tight casing and / or tissue device at a rate of at least about 100 milliliters (mL) / hour, at least about 300 mL / hour, at least about 500 mL / hour, at least about 700 mL / hour, at least about 900 mL / hour, at least about 1.5 L / hour, at least about 2 L / hour, at least about 5 L / hour, or at least about 30 L / hour. In some embodiments, each pump is configured to provide flow to the liquid-tight casing and / or tissue device at a rate of up to about 100 milliliters (mL) / hour, up to about 300 mL / hour, up to about 500 mL / hour, up to about 700 mL / hour, up to about 900 mL / hour, up to about 1.5 L / hour, up to about 2 L / hour, up to about 5 L / hour, or up to about 30 L / hour.

[0091] With reference to Figures 23-26, in some embodiments, the apparatus is configured to meet one or more dimensional thresholds, such as an XY plane tolerance, a Z plane tolerance, a minimum linear feature size, a minimum linear feature size, or a combination thereof.

[0092] Referring to FIG. 27, a system 100 is provided that includes a tissue device, such as tissue device 110, a fluid-tight casing, such as fluid-tight casing 120, and an apparatus for controlling flow through the fluid-tight casing and / or the tissue device.

[0093] It will be recognized by those skilled in the art that changes may be made to the exemplary embodiments shown and described without departing from the broad inventive concept thereof. It is to be understood that the embodiments and claims disclosed herein are not limited in their application to the details of construction and arrangement of components described in the specification and illustrated in the drawings. Rather, the description and drawings provide examples of contemplated embodiments. The embodiments and claims disclosed herein may further be in other embodiments and may be practiced and carried out in various ways.

[0094] Certain features of the exemplary embodiments may or may not be a part of the claimed invention, and various features of the disclosed embodiments may be combined. Thus, those skilled in the art will appreciate that the conception on which the present application and claims are based may be readily utilized as a basis for the designing of other structures, methods and systems for carrying out some of the purposes of the embodiments and claims presented herein. It is important, therefore, that the claims be regarded as including such equivalent structures.

[0095] Unless specifically stated herein, the terms "a," "an," and "the" should not be read as being limited to one element, but instead as meaning "at least one." The words "right," "left," "top," "bottom," "inside," and "outside" designate directions in the drawings to which reference is made.

[0096] Example 1 - Cultivation of hepatocytes The liquid-tight case of the system includes a plurality of hepatocytes housed in a tissue device. In response to the introduction of a medium, the hepatocytes generate a blood effluent and a bile effluent. Thus, the pump is coupled to the liquid-tight case such that the inlet of the channel of the tissue device is configured to receive the blood effluent, while the outlet of the channel is configured to receive the bile effluent. However, the present disclosure is not limited thereto. In some embodiments, this configuration allows for various experiments and determinations to be conducted regarding each effluent (e.g., determining whether each effluent kills or does not kill subsequent cells).

[0097] Thus, the disclosed systems, methods, and devices provide a means for directing flow within one or more fluid-tight enclosures. In some embodiments, these fluid-tight enclosures are utilized to simulate in vivo cell culture. In some embodiments, the fluid-tight enclosures are approximately 1000 mm 3 It is possible to culture cells having a volume of

[0098] The foregoing descriptions of certain exemplary embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and, of course, numerous modifications and variations are possible in light of the above teachings. The exemplary embodiments have been chosen and described in order to explain certain inventive principles and their practical applications, thereby enabling those skilled in the art to make and utilize the various exemplary embodiments of the present invention, as well as various alternatives and modifications. It is intended that the scope of the present invention be defined by the claims appended hereto, and their equivalents.

Claims

1. It is a liquid-tight case, A housing configured to enclose a tissue device, wherein the tissue device has a first channel network and a second channel network that is in fluid communication with the first channel network, and the housing has a base formed to have a hollow space configured to house the tissue device, and a lid coupled to the base to enclose the tissue device within the hollow space, A barbed internal connector configured to facilitate tubing and direct connection to the input of the first channel network of the organizational device, A first inlet port having a first barbed outer connector configured to facilitate tubing and to fluidly communicate with the first channel network of the tissue device through the barbed inner connector, A second inlet port having a second barbed outer connector configured to facilitate tubing and to be in fluid communication with the second channel network of the tissue device, The housing comprises at least one outlet port coupled to the housing, A liquid-tight case in which a three-spin Y-joint is formed by the barbed inner connector, the first barbed outer connector, and the second barbed outer connector, such that (i) the barbed inner connector is disposed on the inside of the lid and the first barbed outer connector and the second barbed outer connector are disposed on the outside of the lid, or (ii) the barbed inner connector is disposed on the inside of the base and the first barbed outer connector and the second barbed outer connector are disposed on the outside of the base.

2. The first inlet port is configured to receive a first plurality of living cells and to deliver the first plurality of living cells to the tissue device, The liquid-tight case according to claim 1, wherein the second inlet port is configured to receive a second plurality of living cells and to deliver the second plurality of living cells to the tissue device.

3. The liquid-tight case according to claim 1 or 2, wherein the tissue device is a device that stimulates arterial blood flow.

4. The liquid-tight case according to claim 3, wherein the tissue device is a liver device.

5. The liquid-tight case according to claim 1 or 2, wherein the at least one outlet port includes a first outlet port that is in fluid communication with the first inlet port through the tissue device.

6. The liquid-tight case according to claim 1 or 2, wherein the housing further comprises a seal disposed between the base and the lid to enhance the sealing of the liquid-tight case.

7. The liquid-tight case according to claim 6, wherein the lid is joined to the base by one or more fasteners, snap fasteners, press fasteners, one or more adhesives, tapes, or a combination thereof.

8. The liquid-tight case according to claim 6, wherein the seal is made of an elastomer material.

9. The liquid-tight case according to claim 6, wherein the seal is an O-ring.

10. The liquid-tight case according to claim 9, wherein the base comprises a rim and a groove formed along the rim to accommodate the seal.

11. The at least one outlet port includes a first outlet port, The liquid-tight case according to claim 10, wherein the base of the housing is monolithically formed to have a sheath configured to allow the tubing of the first outlet port to pass through and to be directly connected to the tissue device.

12. The liquid-tight case according to claim 10, wherein the first and second inlet ports are connected to the first portion of the base, and the at least one outlet port is connected to the second portion of the base.

13. The liquid-tight case according to claim 12, wherein the first and second portions of the base face each other.

14. The liquid-tight case according to claim 10, wherein the first and second inlet ports are coupled to the lid.

15. The liquid-tight case according to claim 1 or 2, wherein the tissue device is a three-dimensional monolithic structure.

Images