Macroencapsulation device for cell or tissue transplantation

Abstract

Macroencapsulation devices for transplanting cells or tissues are provided. In addition, macroencapsulation devices for local delivery of a drug to establish local immunosuppressive therapy are provided.

Description

Attorney Docket No. Georgetown.056.WOlTITLEMACROENCAPSULATION DEVICE FOR CELL OR TISSUE TRANSPLANTATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63 / 685,064, filed on August 20, 2024, which is incorporated herein by reference in its entirety.FIELD

[0002] Various embodiments described herein relate generally to transplantation systems, methods, and devices and, more specifically, relate to protecting transplanted tissues or cells from immune rejection.BACKGROUND

[0003] This section is intended to provide a background or context. The description may include concepts that may be pursued, but have not necessarily been previously conceived or pursued. Unless indicated otherwise, what is described in this section is not deemed prior art to the description and claims and is not admitted to be prior art by inclusion in this section.

[0004] There are no approved methods to transplant islet cells or other allogeneic cells without the use of high dose immunosuppressive therapy which is toxic. Even with this toxic therapy, the transplants have a limited life. Also, at present, islet cell transplantation also requires the administration of islet cells into the portal vein of the liver which also has potential surgical complications.

[0005] A technique to transplant cells using a device that locally delivers drug to establish local immunosuppressive therapy is needed.SUMMARY OF THE INVENTION

[0006] The above problems are overcome, and other advantages may be realized, by the use of the embodiments described herein.

[0007] As disclosed herein, improved devices for transplanting cells or tissues have been developed. Advantageously, the devices can locally deliver a drug to establish localAttorney Docket No. Georgetown.056.WOl immunosuppressive therapy. This enables the use of smaller doses over time and / or even distribution of the drug to the transplanted cells or tissue.

[0008] An aspect of the instant disclosure is a device for transplanting cells or tissues. The device includes a transplant unit (Unit A) configured to house tissues or cells for transplant; and a reservoir unit (Unit B) attached to the transplant unit. The reservoir unit is configured to selectively deliver at least one drug into the transplant unit. The reservoir unit stores the drug independently from the transplant unit. Unit B can be refillable.

[0009] In certain exemplary embodiments, the device further comprises at least one secondary reservoir unit, the secondary reservoir unit configured to deliver a second drug into the transplant unit.

[0010] In certain exemplary embodiments, the device further comprises at least one secondary transplant unit, wherein the reservoir unit is further configured to deliver at least one drug into the secondary transplant unit.

[0011] In certain exemplary embodiments, the transplant unit is pre-incubated in vitro with cells prior to placement.

[0012] In certain exemplary embodiments, the tissues or cells are at least one of: adhered to a wall of the transplant unit, adhered or coated to a substance inside the transplant unit, and suspended in a substance or substrate within the transplant unit.

[0013] In certain exemplary embodiments, the transplant unit comprises a cell matrix.

[0014] In certain exemplary embodiments, the device further comprises poly(lactic-co- glycolic acid (PLGA), serum, blood, a plastic polystyrene, a cell membrane, a hydrogel, or a non-competing cell type.

[0015] In certain exemplary embodiments, the reservoir unit is configured to deliver a specified amount of the drug into the transplant unit in response to a received signal from a remote controller.

[0016] In certain exemplary embodiments, the reservoir unit is configured to deliver a specified amount of the drug into the transplant unit at a set time interval.

[0017] In certain exemplary embodiments, the device further comprises a port configured to place or replenish the tissues or cells.Attorney Docket No. Georgetown.056.WOl

[0018] In certain exemplary embodiments, the reservoir unit further comprises a port configured to replace or replenish the drug.

[0019] In certain exemplary embodiments, the contents of the reservoir unit are stored independently from the transplant unit.

[0020] In certain exemplary embodiments, the device further comprises a pump configured to deliver the drug into the transplant unit via the reservoir unit. In certain exemplary embodiments, the pump is external to the device. In certain exemplary embodiments, the pump is disposed in the reservoir unit.

[0021] In certain exemplary embodiments, the reservoir unit comprises the at least one drug stored in a membrane-lined hollow or in a partially membrane-lined hollow. In certain exemplary embodiments, the membrane lined hollow comprises PLGA particles.

[0022] Another aspect of the instant disclosure is a device for transplanting cells or tissues. The tissue transplant device includes a transplant unit to house tissues or cells for transplant; and a pump attached to the transplant unit. The pump selectively delivers the drug into the transplant unit. The pump is configured to store the drug independently from the transplant unit and can also be refillable.

[0023] In certain exemplary embodiments, the pump is an osmotic drug delivery pump.

[0024] In certain exemplary embodiments, the pump is disposed within a hollow in the transplant unit.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Aspects of the described embodiments are more evident in the following description, when read in conjunction with the attached Figures.

[0026] FIG. 1A demonstrates blood glucose levels over time in transplanted mice using a pump device in accordance with an embodiment compared to other techniques.

[0027] FIG. IB depicts the ability of a subcutaneously transplanted chamber (Unit A), the cell reservoir, to support the survival and function of human islets when implanted subcutaneously in diabetic mice.

[0028] FIG. 2 illustrates a pump device to protect transplanted tissues or cells from immune rejection in accordance with one embodiment.Attorney Docket No. Georgetown.056.WOl

[0029] FIG. 3 illustrates another view of the pump device of FIG. 2.

[0030] FIG. 4 illustrates a further view of the pump device of FIG. 2.

[0031] FIG. 5 demonstrates blood glucose levels over time for an exemplary embodiment compared to other techniques.

[0032] FIG. 6 illustrates a pump device having two drug reservoir units in accordance with an exemplary embodiment.

[0033] FIG. 7 illustrates another view of the pump device of FIG. 6.

[0034] FIG. 8 illustrates a further view of the pump device of FIG. 6.

[0035] FIG. 9 shows a graph comparing the effect of pore size and hydrophobicity of the membrane device on the viability of MIN cells in vitro.

[0036] FIG. 10 illustrates a pump device where the PTFE-Tube is attached to the side of the transplant unit in accordance with an exemplary embodiment.

[0037] FIG. 11 illustrates another view of the pump device of FIG. 10.

[0038] FIG. 12 illustrates a pump device where the PTFE-Tube is inserted into the transplant unit in accordance with an exemplary embodiment.

[0039] FIG. 13 illustrates a sandwich pump device having multiple transplant units and reservoir units in accordance with an exemplary embodiment.

[0040] FIG. 14 illustrates another view of the sandwich pump device of FIG. 13.

[0041] FIG. 15 illustrates a further view of the sandwich pump device of FIG. 13.

[0042] FIG. 16 illustrates another sandwich pump device having multiple reservoir units adjacent to the transplant unit in accordance with an exemplary embodiment.

[0043] FIG. 17 illustrates another view of the sandwich pump device of FIG. 16.

[0044] FIG. 18 illustrates a further sandwich pump device in accordance with an exemplary embodiment.

[0045] FIG. 19 illustrates another view of the sandwich pump device of FIG. 16.

[0046] FIG. 20 illustrates a core pump device having multiple transplant units around a reservoir unit in accordance with an exemplary embodiment.Attorney Docket No. Georgetown.056.WOlDETAILED DESCRIPTION OF THE INVENTION

[0047] The practice of the present invention can employ, unless otherwise indicated, conventional techniques of tissue and cellular biology, bioengineering, polymer science, tissue and cellular transplantation, and immunology, which are within the skill of the art.

[0048] In order that the present invention can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention is related.

[0049] Any headings provided herein are not limitations of the various aspects or embodiments of the invention, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0050] All references cited in this disclosure are hereby incorporated by reference in their entireties. In addition, any manufacturers’ instructions or catalogues for any products cited or mentioned herein are incorporated by reference. Documents incorporated by reference into this text, or any teachings therein, can be used in the practice of the present invention. Documents incorporated by reference into this text are not admitted to be prior art.Definitions

[0051] The phraseology or terminology in this disclosure is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0052] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents, unless the context clearly dictates otherwise. The terms “a” (or “an”) as well as the terms “one or more” and “at least one” can be used interchangeably.

[0053] Furthermore, “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” is intended to include A and B, A or B, A (alone), and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intendedAttorney Docket No. Georgetown.056.WOl to include A, B, and C; A, B, or C; A or B; A or C; B or C; A and B; A and C; B and C; A (alone); B (alone); and C (alone).

[0054] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range, and any individual value provided herein can serve as an endpoint for a range that includes other individual values provided herein. For example, a set of values such as 1, 2, 3, 8, 9, and 10 is also a disclosure of a range of numbers from 1-10. Where a numeric term is preceded by “about,” the term includes the stated number and values ±10% of the stated number. The headings provided herein are not limitations of the various aspects or embodiments of the invention, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0055] Wherever embodiments are described with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are included.Macroencapsulation Devices

[0056] Various embodiments described herein provide a macroencapsulation device to transplant cells or tissues. The device is designed to be introduced to the transplant recipient and protect transplanted tissues or cells from immune rejection. The macroencapsulation device includes two distinct units, with a first unit, referred to as Unit A, containing a transplanted material (cells or tissues) and the second unit, referred to as Unit B, containing one or more drugs or bioactive substances to be released.

[0057] The one or more drugs or bioactive substances can locally inhibit the immune attack that rejects the transplanted cells or tissues (such as allogenic or xenogeneic cells) as well as prevent infection. Small amounts of drugs or bioactive substances may thus be administered directly to the area where the transplanted cells are located, e.g., within Unit A, in order to locally ward off immune rejection and / or infection.

[0058] By using two separate units, the device does not have both cells and drug encapsulated together. Rather, the drug can be delivered in smaller doses over time and / or even distributed to the cells. Unit A, which houses transplanted material, may include a portAttorney Docket No. Georgetown.056.WOl to allow introduction of the transplanted material. Unit B stores at least one drug for use to prevent rejection of the transplanted material in Unit A.

[0059] In some embodiments, the macroencapsulation device has a porous membrane for communication and / or drug delivery between Unit A and Unit B. In other embodiments, Unit B may be configured to evenly distribute the drug to Unit A, for example, through branching tubes. Between Unit A and Unit B may be one or more ports which allow the drug to be delivered to Unit A. In some embodiments, this may include a large permeable membrane.

[0060] In various embodiments, the device includes a port to deliver the transplanted cells or tissues through the skin into the device. This port may also be incorporated with a port in Unit A to allow direct access to the transplanted cells and / or tissues. Likewise, the device may include a port to allow drug to be added to Unit B.

[0061] The device may be composed or partially composed of a membrane material and in some cases a supportive scaffold. Device materials can include: polytetrafluoroethylene (PTFE), polyvinylidenes (PDVF), ethylene tetrafluoroethylene (ETFE), polysulfone, nylon, cellulose composites, polychromates, alumina oxide, track etched polyethylene or another suitable material. Different pore sizes may be used for each type of material depending on where the membrane is located. The device-supportive structure can be a scaffold made of medical grade silicone or another suitable substance.

[0062] In some embodiments, the pore size that separates Unit A and Unit B, the sides of the Units where A and B are together (touching), may be 0.4 microns. The pore size for at least part of the outer membrane for Unit A could be within a range of 2-50 microns, such as about 10 microns. For xenotransplants, the pore size may be very small (0.02 to 0.2 microns) to inhibit immunoglobulins and the drugs used would include complement inhibitors. In various embodiments, the outside of Unit B ideally may be impermeable.

[0063] There are many methods for drug delivery which can be used, including but not limited to, drug releasing material such as silicone and PLGA particles, and pumps. The device may include a pump, for example, located on the side of Unit B or inserted into Unit B. In other embodiments, the pump may be proximal to the device, such as through a perforated tube. In some embodiments, the reservoir for the pump may be located on or beneath the skin.Attorney Docket No. Georgetown.056.WOl

[0064] A device described herein was used with minimal amounts of at least one drug to inhibit the rejection of transplanted mouse insulinoma cells (MIN) and to successfully cure diabetes in recipient diabetic mice. Furthermore, repeat transplantation of a device described herein was shown to successfully restore euglycemia in diabetic mice and this underscores the robustness of the device since previously transplanted animals more aggressively reject subsequent transplants.

[0065] The device described herein allows many different kind of cells or tissues to be successfully transplanted with minimal risk and without the use of significant systemic amounts of toxic drug therapy. Some of the uses include treating type 1 diabetes by transplanting islet cells or tissue either subcutaneously or to other sites in the body including but not limited to the peritoneum, and treating liver failure by transplanting hepatocytes or liver tissue. Other suitable cells for transplantation include, but are not limited to: pancreatic cells including, but not limited to, islet of Langerhans cell subtypes a, 0, 5, 8 and PP; insulinsecreting 0 cells from a cell line such as RIN cells, HIT cells, MIN, INS-1, TC cells and the like; and liver cells including, but not limited to hepatocytes, stellate fat storing cells, Kupffer cells and liver endothelial cells; and stem cells including, but not limited to, pluripotent stem cells, adult stem cells such as, e.g., liver progenitor cells. Treatment of neurological conditions may also be performed by transplanting the device in or around the brain.

[0066] Suitable tissues include, but are not limited to: pancreatic tissue; islets of Langerhans tissue; and liver tissue from zone 1, zone 2, zone 3 or any combinations of zones.

[0067] In some embodiments, the transplanted tissues may be placed in various locations, for example, in the eye. Furthermore, the reservoir may be attached to a specific location, for example, an organ, or a tumor or growth in the case of treatment of such tumor or growth. Likewise, the device may be used for osteomyelitis, transplant of renal cells for artificial kidneys, chondrocytes for cartilage repair, skin cells for skin grafting, embryonic stem cells for various diseases and / or for treatment of neurological disorders. The transplanted cells may include parathyroid cells, cells that produce immune modulators and / or cells that have anticancer properties.

[0068] As used herein, the term “drug” refers to a pharmaceutical composition or medication that is useful to: inhibit or lessen the degree of transplant rejection, such as, e.g., immunomodulators; to inhibit or lessen the probability of infection in the recipient at the siteAttorney Docket No. Georgetown.056.WOl of transplant such as, e.g., antibiotics; and / or to inhibit fibrosis. Suitable immunomodulators include, but are not limited to, prednisone, prednisolone, KINERET®, ENBREL® (etanercept), abatacept, tacrolimus, sirolimus, everolimus, belatacept, cyclosporine, mycophenolate mofetil, imuran, rapamycin, and the like. Suitable antibiotics include, but are not limited to, cefuroxime, piperacillin, tazobactam, amoxicillin, clavulanic acid, cefamandole, tobramycin, ceftriaxone, cefotaxime, cephalosporin trimethoprim, sulfamethoxazole and the like and any combinations thereof.

[0069] Traditional methods of transplantation require systemic administration of one or more immunomodulators and / or antibiotics. The device described herein allows reduced amounts of one or more immunomodulators and / or antibiotics to be administered locally. In certain exemplary embodiments, the amount of immunomodulators and / or antibiotics used with the device described herein is about 5%, about 10%, about 15%, about 20%, about 25% of the amount of one or more immunomodulators and / or antibiotics that would typically be administered systemically. In some embodiments, the amount of immunomodulators and / or antibiotics used with the device described herein is less than 5% of the amount of one or more immunomodulators and / or antibiotics that would typically be administered systemically.

[0070] The device described herein may also contain one or more suitable growth factors, e.g., growth factors suitable for pancreatic or hepatic cell and / or tissue growth. Suitable growth factors include, but are not limited to, granulocyte colony stimulating factor (G-CSF), mesenchymal cells, granulocyte-macrophage colony-stimulating factor (GM-CSF), insulinlike growth factor 1 (IGF-1), platelet derived growth factor (PDGF), transforming growth factor-beta (TGF-P), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and the like.

[0071] In certain exemplary embodiments, the device is transplanted subcutaneously without significant surgical problems as found with islet transplantation into the hepatic vein of the liver. The device may also be delivered into another area of the body, including but not limited to viscera, the peritoneum or subcapsular space.

[0072] A PLGA based drug-delivery system may be used to deliver drug at small doses over long periods of time. These PLGA drug-laden spheres are enclosed within theAttorney Docket No. Georgetown.056.WOl membrane device and successfully prevent rejection of allotransplants and with a likelihood of success in xenotransplants. This drug-delivery system can be used in allotransplants and xenotransplants.

[0073] In one, non-limiting embodiment, MIN cells in a matrigel matrix were placed in Unit A and a cocktail of 10% of the systemic dose of rapamycin, tacrolimus, and KINERET® was introduced into separate Pump Unit B. The device was introduced to MIN cell pre-sensitized NOD mice. The device prevented allotransplant rejection by local immunotherapy for more than 35 days. FIG. 1A is a graph comparing the ability of the local immunotherapy device (‘NOD-osmotic Pump-Rap-Tac-Kinneret-10% sys’) to inhibit allotransplant rejection with other control group techniques. As shown, the blood glucose levels are shown over time (days).

[0074] The mean blood glucoses of mice in the ‘NOD-osmotic Pump-Rap-Tac-Kinneret- 10% sys’ group, transplanted with a device, which were administered 10% of the systemic dose of Rapamycin, Tacrolimus, and Kinneret were lower than mean blood glucose levels of the control mice ‘No-drug-NOD- Large pore bag with cells’ for 50 days. Further, the mice in the ‘NOD-Osmotic Pump-Rap-Tac-Kinneret-10% sys’ group had lower mean blood glucose levels up until 50 days than the mice in the other control group given contralateral devices, a device with MIN cells in a unit on one side of the animal and drug containing unit on the other side of the animal which does not provide local immunotherapy.

[0075] In addition to MIN cells, various embodiments can be used to enable other cells such as human islets cells (which ordinarily have difficultly to surviving in the subcutaneous space), to survive in a reservoir A in conditions where the animal cannot reject them. FIG. IB depicts the ability of a subcutaneously transplanted chamber (Unit A), the cell reservoir, to support the survival and function of human islets when implanted subcutaneously in diabetic mice. As shown, mean blood glucose levels were significantly lower in diabetic mice having a transplanted device than in control nude mice not transplanted with an islet device.

[0076] FIG. 2 - FIG. 4 show a pump device such as used in this non-limiting embodiment. The pump device includes a first unit, Unit A, which contains the transplanted MIN cells. Unit B houses the drug cocktail used. A pump is connected to Unit B by the Perforated PTFE-Tube. The pump may be used to deliver the cocktail in Unit B to the MIN cells in Unit A.Attorney Docket No. Georgetown.056.WOl

[0077] In various embodiments, many types of pumps can be used, such as, an osmotic drug delivery pump. The pump can be designed to be adjustable and can be programmed to release a given amount of drug. Some pumps can be externally controlled via Bluetooth, for example, to activate / deactivate the pump and / or to program the pump to run on a set cycle. In some, non-limiting embodiments, the pumps are located externally outside the body. In others, the pumps are incorporated into the implanted device.

[0078] In a further, non-limiting embodiment, a device is provided which can help prevent or inhibit allorej ection by local immunotherapy which is demonstrated by normalized blood glucoses or lower mean blood glucoses than control mice, as depicted in FIG. 5. In this embodiment, the test device included a chamber or unit filled with MIN cells and a chamber or unit containing a cocktail of 10% of the typical systemic dose of ENBREL® and abatacept within PLGA placed at ‘0’ time and at 38 days in allo pre-sensitized NOD mice.

[0079] From 3 to 90 days, mean blood glucose levels of mice in Group 1, the test animals with local immunotherapy devices, were lower than the control mice receiving contralateral devices, a device with MIN cells in a unit on one side of the animal and a drug containing unit on the other side of the animal, which do not provide local immunotherapy. Thus, the inhibition of allorej ection was due to the local effect of the drug in the test device. Blood glucose levels reached non-diabetic levels at 27 days in test device mice but always remained in the diabetic levels in mice transplanted with a contralateral control devices.

[0080] FIG. 6 - FIG. 8 show the pump device such as used in this non-limiting embodiment. The device includes a first unit, Unit A, which contains the transplanted MIN cells. In this embodiment, there are two Unit B’s which house the drug cocktail used. Each Unit B includes a Perforated PTFE-Tube. A pump may be used to deliver the cocktail in a Unit B to the MIN cells in Unit A.

[0081] In some embodiments, both Unit B’s may have the same drug / cocktail. In other embodiments, each Unit B may house a different drug / cocktail. Each Unit B may be used independently or together (e.g., if connected to the same pump or synchronized pumps).

[0082] As shown, the Unit B’s are located on opposite sides of the Unit A. In alternative embodiments, different geometrical layouts are possible, for example, the Unit B’s may be located at 90° from each other.Attorney Docket No. Georgetown.056.WOl

[0083] FIG. 9 is a graph that depicts pore size and hydrophobicity of unit A membrane on MIN cell viability. MIN (mouse insulinoma cells) were placed in different Unit A devices constructed from different types of membranes and incubated in media for 50 days. No matrix was added with the cells in the Units. The viability and growth of the cells were assessed by Alomar Blue and are recorded as absorbance on the Y axis. The best cell growth occurred in Units with hydrophobic membranes. MIN cell viability was equally supported with its membrane that had pore sizes of 0.4, 1, and 5 microns.

[0084] Accordingly, in some embodiments, unit A may include Matrigel or another matrix for the transplant cells. In such embodiments, the device, having Matrigel, may be used to transplant human islets or MIN cells in order to reduce blood sugars, such as in diabetic animals. In other embodiments, no matrix is provided.

[0085] In one alternative embodiment, the pump and PTFE-Tube may be connected to the Unit A. As shown in FIG. 10 and FIG. 11, the PTFE-Tube is attached to the side of the Unit A.

[0086] FIG. 12 shows another alternative where the PTFE-Tube attached to a hollowed- out Unit A. In this embodiment, Unit A may be structure to define a space which can receive the PTFE-Tube without disrupting the tissues or cells for transplant. This space may be an opening in a support matrix and / or may be lined with a permeable membrane / surface.

[0087] In a further alternative, the macroencapsulation device is a sandwich device. FIG. 13 - FIG. 15 show the sandwich device. The Unit A’s are positioned with multiple walled Unit B’s in a two-tiered pattern. Some of the walls on the Unit B’s may be silicone scaffolding which can provide support for the macroencapsulation device and prevent systemic drug leakage. The walls can be fabricated from biologically acceptable materials which do not cause an immune response. This can include polymers and polymer blends as well as other biocompatible materials.

[0088] FIG. 16 and FIG. 17 show another embodiment of the sandwich device. In this, non-limiting embodiment, one Unit A is disposed between two walled Unit B’s. Each walled Unit B has a PTFE-Tube port and scaffold walls. It should be noted that other material besides PTFE can be used for the tube ports, including but not limited to silicone.

[0089] FIG. 18 and FIG. 19 show a further embodiment of the sandwich device made of silicone and membrane. In this, non-limiting embodiment, two walled Unit B’s are located onAttorney Docket No. Georgetown.056.WOl opposite sides of the Unit A. As shown, a drug-filled PLGA rod has been placed into the walled Unit B’s through their tube ports. For clarification, Unit B may also contain drug without the PLGA rod. Unit B may define a hollow which is a membrane line defining a perimeter of the Unit B that allows the PLGA rod to be inserted. In this embodiment, the sides of the Unit B’s that are not tangent to reservoir A are impermeable to drug to prevent the drug from leaking out systemically.

[0090] FIG. 20 illustrates another alternative embodiment. In this embodiment, a single Unit B, the core, is surrounded by multiple Unit A’s (five shown here).

[0091] In one embodiment, a device is provided which includes: a) at least one unit (unit A) having tissue or hormone secreting cells; and b) at least one walled unit (unit B) attached to the unit A which serves as a reservoir to hold and release drug. In some embodiments, the reservoir (Unit B) does not use hydrogel. Unit A may be pre-incubated in vitro with cells prior to placement or directly placed in vivo with Unit B.

[0092] Cells placed into Unit A may be: a) directly placed in the Unit; b) adhered to the wall of the encapsulation unit; c) adhered or coated to a substance or substrate inside the unit; and / or d) suspended in a substance or substrate within unit A. Substances in Unit A adhered to the wall of the encapsulation unit may include PLGA, serum, blood, plastic polystyrene, cell membrane, and other non-competing cell types. Substances in Unit A in which cells are adhered or coated to a substance or substrate inside the unit may include PLGA, serum, blood, plastic polystyrene, cell membrane, and other non-competing cell types. Substances suspended in Unit A may include hydrogel, PLGA, serum, blood, plastic polystyrene, cell membrane, and other non-competing cell types which can be alive or dead. Cells may be grown in vitro with or without substance prior to implantation into Unit A. These substances may include PLGA, serum, blood, plastic, polystyrene, cell membrane, and other noncompeting cell types which may be alive or dead.

[0093] An embodiment provides a device for transplanting cells or tissues. The device includes a transplant unit (Unit A) configured to house tissues or cells for transplant; and a reservoir unit (Unit B) attached to the transplant unit. The reservoir unit is configured to selectively deliver at least one drug into the transplant unit. The reservoir unit stores the drug independently from the transplant unit.Attorney Docket No. Georgetown.056.WOl

[0094] In a further embodiment of the device above, one or more secondary reservoir units are also included. The secondary reservoir unit(s) can deliver a second drug into the transplant unit. In an alternative embodiment, the secondary reservoir unit(s) can provide additional storage of the first drug.

[0095] In another embodiment of any one of the devices above, the reservoir unit is configured to actively release the drug to the transplant unit, for example, using a pump. In an alternative embodiment, the reservoir unit is configured to passively deliver the drug to the transplant unit, for example, using osmotic delivery or diffusion.

[0096] In a further embodiment of any one of the devices above, the device includes at least one secondary transplant unit. The reservoir unit is further configured to selectively deliver at least one drug into the secondary transplant unit as well.

[0097] In another embodiment of any one of the devices above, the transplant unit is preincubated in vitro with cells prior to placement.

[0098] In a further embodiment of any one of the devices above, the tissues or cells are at least one of: adhered to a wall of the transplant unit, adhered or coated to a substance inside the transplant unit, and suspended in a substance or substrate within the transplant unit.

[0099] In another embodiment of any one of the devices above, the transplant unit comprises hydrogel, PLGA, serum, blood, plastic polystyrene, a cell membrane, or a noncompeting cell type. In some embodiments, the transplant unit includes other forms of support matrices for the tissues or cells for transplant (or no matrix). For instance, a cell matrix may comprise natural materials such as collagen, laminin, and / or fibronectin; may comprise synthetic materials; or may comprise a combination thereof. One particular example of a cell matrix is Matrigel®.

[0100] In a further embodiment of any one of the devices above, the reservoir unit is configured to release a specified amount of the drug into the transplant unit in response to a received signal, such as from a radio control unit.

[0101] In another embodiment of any one of the devices above, the reservoir unit is configured to release a specified amount of the drug into the transplant unit at a set time interval.

[0102] In a further embodiment of any one of the devices above, the device includes a port configured to place or replenish the tissues or cells for transplant.Attorney Docket No. Georgetown.056.WOl

[0103] In another embodiment of any one of the devices above, the contents of the reservoir unit are stored independently from the transplant unit.

[0104] In a further embodiment of any one of the devices above, the reservoir unit may include a port to allow additional drug to be provided.

[0105] In another embodiment of any one of the devices above, the pump may be disposed within the reservoir unit. In other embodiments, the pump may be connected to the reservoir unit via an extension or tube (e.g., a perforated PTFE-Tube).

[0106] In a further embodiment of any one of the devices above, the transplant unit includes at least one membrane which allows blood vessel access to the tissues or cells for transplant.

[0107] Another embodiment provides a device for transplanting cells or tissues. The tissue transplant device includes a transplant unit to house tissues or cells for transplant; and a pump attached to the transplant unit. The pump selectively delivers the drug into the transplant unit. The pump is configured to store the drug independently from the transplant unit.

[0108] In a further embodiment of the device above, the pump is an osmotic drug delivery pump.

[0109] In another embodiment of any one of the devices above, the pump is disposed within a hollow in the transplant unit.

[0110] The foregoing description has been directed to particular embodiments. However, other variations and modifications may be made to the described embodiments, with the attainment of some or all of their advantages. Modifications to the above-described systems and methods may be made without departing from the concepts disclosed herein. Accordingly, the disclosure should not be viewed as limited by the disclosed embodiments. Furthermore, various features of the described embodiments may be used without the corresponding use of other features. Thus, this description should be read as merely illustrative of various principles, and not in limitation of the disclosure.

Claims

Attorney Docket No. Georgetown.056.WOlCLAIMSWhat is claimed is:

1. A device comprising: a transplant unit configured to house tissues or cells for transplant; and a reservoir unit attached to the transplant unit, wherein the reservoir unit is configured to deliver at least one drug into the transplant unit; and wherein the reservoir unit is configured to store the drug independently from the transplant unit.

2. The device of claim 1, further comprising at least one secondary reservoir unit, the secondary reservoir unit configured to deliver a second drug into the transplant unit.

3. The device of claim 1, further comprising at least one secondary transplant unit, wherein the reservoir unit is further configured to deliver at least one drug into the secondary transplant unit.

4. The device of claim 1, wherein the transplant unit is pre-incubated in vitro with cells prior to placement.

5. The device of claim 1, wherein the tissues or cells are at least one of: adhered to a wall of the transplant unit, adhered or coated to a substance inside the transplant unit, and suspended in a substance or substrate within the transplant unit.

6. The device of claim 1, wherein the transplant unit comprises a cell matrix.

7. The device of claim 1, wherein the transplant unit comprises poly(lactic-co- glycolic acid (PLGA), serum, blood, a plastic polystyrene, a cell membrane, a hydrogel, or a non-competing cell type.Attorney Docket No. Georgetown.056.WOl8. The device of claim 1, wherein the reservoir unit is configured to deliver a specified amount of the drug into the transplant unit in response to a received signal from a remote controller.

9. The device of claim 1, wherein the reservoir unit is configured to deliver a specified amount of the drug into the transplant unit at a set time interval.

10. The device of claim 1, further comprising a port configured to place or replenish the tissues or cells.

11. The device of claim 1, wherein the reservoir unit further comprises a port configured to replace or replenish the drug.

12. The device of claim 1, wherein contents of the reservoir unit are stored independently from the transplant unit.

13. The device of claim 1, further comprising a pump configured to deliver the drug into the transplant unit via the reservoir unit.

14. The device of claim 13, wherein the pump is external to the device.

15. The device of claim 13, wherein the pump is disposed in the reservoir unit.

16. The device of claim 1, wherein the reservoir unit comprises the at least one drug stored in a membrane-lined hollow or in a partially membrane-lined hollow.

17. The device of claim 15, wherein the membrane-lined hollow or the partially membrane-lined hollow comprises poly(lactic-co-glycolic acid) particles.

18. A tissue transplant device comprising:(a) a transplant unit configured to house tissues or cells for transplant; andAttorney Docket No. Georgetown.056.WOl(b) a pump attached to the transplant unit, the pump configured to deliver the drug into the transplant unit, wherein the pump is configured to store the drug independently from the transplant unit.

19. The tissue transplant device of claim 18, wherein the pump is an osmotic drug delivery pump.

20. The tissue transplant device of claim 18, wherein the pump is disposed within a hollow in the transplant unit.

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