Macroencapsulation devices including immunomodulatory compounds

Abstract

Macroencapsulation devices and their methods of use are disclosed. In one embodiment, a macroencapsulation device may include one or more membrane layers configured to encapsulate a population of cells, and at least one immunomodulatory compound. The immunomodulatory compound may be contained in an immunomodulatory material including, for example, a matrix. The immunomodulatory material or compound, in certain cases, may mitigate undesirable foreign body responses during implantation of the device, gives rise to a low cytotoxicity, and / or the ability to promote cell viability.

Description

MACROENCAPSULATION DEVICES INCLUDING IMMUNOMODULATORY COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No.: 63 / 445,517, filed February 14, 2023, which is incorporated by reference in its entirety for all purposes.FIELD

[0002] Disclosed embodiments are related to macroencapsulation devices including immunomodulatory compounds.BACKGROUND

[0003] Therapeutic devices that deliver biological products can be used to treat various metabolic disorders, such as diabetes. Some of these devices include macroencapsulation devices that can be used to house cells capable of producing a desirable biological product, such as insulin. The devices may be implanted to a location in a subject to provide the desirable biological product.SUMMARY

[0004] In some aspects, a macroencapsulation device is provided. In some embodiments, a macroencapsulation device comprises a first membrane layer; a second membrane layer disposed on the first membrane layer, wherein the first membrane layer and the second membrane layer are bonded together to form a seal extending at least partially around an internal volume disposed between the first membrane layer and the second membrane layer, wherein the first membrane layer and / or the second membrane layer includes pores; and at least one immunomodulatory compound associated with the first membrane layer and / or the second membrane layer, wherein the at least one immunomodulatory compound includes at least one selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain- enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor.

[0005] In some aspects, a method for delivering a therapeutic composition produced by a population of cells is provided. In some embodiments, the method comprises diffusing the therapeutic composition across at least one membrane layer that at least partially encapsulates the population of cells; and exposing tissues surrounding the at least one membrane layer to at12154210.1least one immunomodulatory compound selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domaincontaining protein 3 (NLRP3) inflammasome inhibitor.

[0006] In some aspects, an immunomodulatory material is provided. In some embodiments, the immunomodulatory material comprises a matrix; and at least one immunomodulatory compound selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor, a colonystimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor included in the matrix.

[0007] In some aspects, a composition is provided. In some embodiments, the composition comprises a population of cells; and at least one immunomodulatory compound selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain- enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor.

[0008] It should be appreciated that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying figures.BRIEF DESCRIPTION OF DRAWINGS

[0009] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. In the drawings:

[0010] FIG. 1A shows a side view of a macroencapsulation device prior to loading, according to one embodiment;

[0011] FIG. IB shows a top view of the macroencapsulation device of Fig. 1A, according to one embodiment;

[0012] FIG. 1C shows a side view of the macroencapsulation device of Fig. 1A after loading with a desired material, according to one embodiment;

[0013] FIG. 2 shows a perspective view of a section of a portion of a first exemplary macroencapsulation device after filling with a desired material, according to one embodiment;

[0014] FIG. 3 shows a flow diagram of a method for delivering a therapeutic composition produced by a population of cells contained within a macroencapsulation device, according to one embodiment;

[0015] FIG. 4 shows a schematic of immunomodulatory materials associated with the macroencapsulation device, according to one embodiment;

[0016] FIG. 5 is a graph showing ratio of IL- 10 to IL-ip secreted by M0 macrophages in the presence of a panel of compounds, according to one embodiment;

[0017] FIG. 6 is a graph showing the amount of IL-ip per cell secreted by M0 macrophages in the presence of a panel of compounds, according to one embodiment;

[0018] FIG. 7 is a graph showing the amount of IL-ip per cell secreted by M0 macrophages in the presence of MCC950, according to one embodiment;

[0019] FIG. 8A-8D show schematics of molecular structures of tannic acid (FIG. 8A), pexidartinib (FIG. 8B), MCC950 (FIG. 8C), and TAK242 (FIG. 8D), according to one embodiment;

[0020] FIG. 9A-9B are graphs showing the fold change in IL-ip secreted by the M0 macrophages (FIG. 9A) or the Ml macrophages (FIG. 9B) at each compound condition with respect to the control (control of DMSO without any compound), according to one embodiment;

[0021] FIG. 10 is a graph showing the fold change in cell viability of rat islets in the presence of a panel of immunomodulatory compounds, according to one embodiment;

[0022] FIG. 11 is a graph showing cell number fluctuations when the cells are cultured in the presence of various compounds, according to one embodiment;

[0023] FIGS. 12A-12B are microscopy images showing endothelial network formation of HUVECs in the presence of EGM-2 control (FIG. 12A) and EGM-2 with DMSO (FIG. 12B), according to one embodiment;

[0024] FIGS. 12C-12E are microscopy images showing endothelial network formation of HUVECs in the presence of tannic acid at various concentrations, according to one embodiment;

[0025] FIGS. 12F-12H are microscopy images showing endothelial network formation of HUVECs in the presence of pexidartinib at various concentrations, according to one embodiment;

[0026] FIGS. 12L112L are microscopy images showing endothelial network formation of HUVECs in the presence of TAK242 at various concentrations, according to one embodiment;

[0027] FIGS. 12M-12Q are microscopy images showing endothelial network formation of HUVECs in the presence of MCC9550 at various concentrations, according to one embodiment;RECTIFIED SHEET (RULE 91) ISA / EP

[0028] FIGS. 12R-12T are microscopy images showing endothelial network formation of HUVECs in the presence of GDC-2394 at various concentrations, according to one embodiment;

[0029] FIGS. 13A-13B are photographs of lyophilized fibrin glue containing immunomodulatory compounds before (FIG. 13A) and after swelling with PBS (FIG. 13B), according to one embodiment;

[0030] FIGS. 14A-14B are SEM images of fibrin glue containing 50% fibrinogen (FIG. 14A) and 100% fibrinogen (FIG. 14B), according to one embodiment;

[0031] FIGS. 15A-15B are graphs showing release profiles of tannic acid from fibrin glues containing 100% fibrinogen (FIG. 15A) and 50% fibrinogen (FIG. 15B), according to one embodiment;

[0032] FIGS. 16A-16C are graphs showing release profiles of MCC950 from fibrin glue (FIG. 16A), TAK242 from fibrin glue (FIG. 16B), and pexidartinib from fibrin glue (FIG. 16C), according to one embodiment;

[0033] FIG. 16D is a graph showing stability of MCC950, pexidartinib, and TAK242 in aqueous media, according to one embodiment;

[0034] FIGS. 17A-17B show cross-sectional views of set-ups where fibrin glue containing immunomodulatory drugs in indirect contact (FIG. 17 A) versus in direct contact (FIG. 17B) with the macrophages, according to one embodiment;

[0035] FIG. 18 is a graph showing the fold change in IE-ip amount when the M0 macrophages are in direct contact or indirect contact with the fibrin glue containing various immunomodulatory drugs after 4 days and 7 days, according to one embodiment;

[0036] FIGS. 19A-19B are graphs of fold change in dead cells for SC islets (FIG. 19A) and percentage of dead cells (FIG. 19B) for various immunomodulatory compounds, according to one embodiment;

[0037] FIG. 19C is a graph that shows the percent viability of SC-islets following exposure to MD2-IN-1 or GDC-2394 at various concentrations, according to one embodiment; and

[0038] FIGS. 20A-20B are graphs of accumulative release of tannic acid from a sintered membrane (FIG. 19A) and from an unsintered membrane (FIG. 19B) at various concentrations, according to one embodiment.DETAILED DESCRIPTION

[0039] Driven by a rising need to deliver biological products to treat metabolic disorders, such as diabetes, different types of implantable therapeutic devices have been engineered.However, in certain circumstances, implantation of therapeutic devices may result in undesirableRECTIFIED SHEET (RULE 91) ISA / EPforeign body responses. Macrophages play a key role in foreign body response (FBR). While the classically activated macrophages (Ml) may be associated with generating a pro- inflammatory response (e.g., via generation of pro-inflammatory cytokines such as IL-ip), the alternatively activated macrophages (M2) may be associated with generating an antiinflammatory response (e.g., via generation of anti-inflammatory cytokines such as IL-10). During use, the therapeutic device may oftentimes trigger an undesirable pro-inflammatory response (e.g., via excessive production of pro-inflammatory cytokines), which may drive the formation of an undesirable collagen layer around device, which may subsequently cause the encapsulated cells within the device to suffer from oxygen deprivation. In addition, it may be difficult to modulate the foreign body response (e.g., pro-inflammatory response versus antiinflammatory response) of the implantable therapeutic devices during use.

[0040] In view of the above, the Inventors have recognized the benefits associated with attenuating the potential foreign body response associated with the use of macroencapsulation devices while promoting angiogenesis and vascularization. For example, the macroencapsulation devices of the present disclosure may comprise or otherwise be associated with at least one immunomodulatory compound capable of inhibiting or reducing a pro- inflammatory response associated with exposing the device to tissues. In some embodiments, the at least one immunomodulatory compound may be provided in the form of an immunomodulatory material as elaborated on further below. The immunomodulatory compounds, in certain cases, may have a particularly advantageous composition that gives rise to a low cytotoxicity and / or the ability to promote cell viability. The at least one immunomodulatory compound may be capable of inhibiting a pro-inflammatory response of the macrophage (e.g., MO and / or Ml macrophage). For example, the at least one immunomodulatory compound may be selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domaincontaining protein 3 (NLRP3) inflammasome inhibitor. These immunomodulatory compounds may either be used individually and / or two or more of the immunomodulatory compounds may be used in combination with one another. As described in more detail below, the immunomodulatory compounds may be associated with the macroencapsulation device and portion(s) thereof in any of a variety of appropriate fashions including, for example: being applied to tissue a macroencapsulation device is positioned proximate to; disposed within the macroencapsulation device; disposed in or on the one or more membrane layers of the macroencapsulation device; and / or in any other manner.

[0041] In some embodiments, the immunomodulatory compounds and materials described herein may be associated with a macroencapsulation device. For example, in one set of embodiments, the macroencapsulation device may comprise multiple membrane layers, such as a first membrane layer and a second membrane layer disposed on the first membrane layer. The first membrane layer and the second membrane layer, according to some embodiments, may be bonded together to form a seal extending at least partially around an internal volume disposed between the first membrane layer and the second membrane layer. In some cases, the first membrane layer and the second membrane layer may be bonded together to form a seal that extends completely around the internal volume disposed between the first membrane layer and the second membrane layer. The seals may be formed in any appropriate location on the membrane layers, such as along the perimeters of the membrane layers. In some embodiments, the internal volume may be configured to house a population of cells. The first and second membrane layers may be configured to block passage of the population of cells out of the device. Any of a variety of appropriate types of cells described elsewhere herein may be disposed within the internal volume of the device.

[0042] In some embodiments, the membrane layers may be porous in nature. For example, the first membrane layer and / or the second membrane layer may include a plurality of pores. The pores, according to some embodiments, may allow for transport of a biological product and / or one or more immunomodulatory compounds through the membrane layer(s). The membrane layer(s) may have any of a variety of appropriate material properties, including a particular material composition, membrane thickness, pore size, etc., as described in more details below.

[0043] In some aspects, a method for delivering a therapeutic composition produced by a population of cells is provided. In some cases, a macroencapsulation device described herein containing the population of cells within its internal volume may be employed for delivering the therapeutic composition produced by the cells.

[0044] In some embodiments, the method further comprises exposing tissues surrounding the macroencapsulation device to an immunomodulatory material and / or compound described herein. The immunomodulatory material and / or compound may be exposed to the tissues via any of a variety of appropriate methods. For example, in embodiments in which the immunomodulatory material is disposed on the surface(s) and / or within the pores of one or more membrane layers, the immunomodulatory compound described herein may be released from the surface(s) and / or the pores of the one or more membrane layers prior to being exposed to the tissues surrounding the at least one membrane layer.

[0045] In some embodiments, a method of treating a subject having a disease is provided. In some embodiments, the method of treating a disease comprises administering to a patient in need thereof a composition described herein. In some embodiments, the disease is type 1 diabetes. In some embodiments, the method of treating type 1 diabetes comprises administering to the patient in need thereof a composition comprising SC-P cells and one or more immunomodulatory compounds described herein. In some embodiments, the method of treating type 1 diabetes comprises administering to the patient in need thereof SC-P cells housed in a device described herein and one or more immunomodulatory compounds described herein. In some embodiments, the method of treating type 1 diabetes comprises administering to the patient in need thereof SC-P cells and one or more immunomodulatory compounds in the absence of a device.

[0046] In embodiments in which the immunomodulatory material or compound is immobilized to the one or more membrane layers via one or more linker molecules, the immunomodulatory compound may be released from the one or more membrane layers upon degradation of the linker molecules at the site of implantation. The one or more linker molecules, according to some embodiments, may undergo certain types of stimuli responsive degradation, such as enzymatic degradation, hydrolysis, temperature and / or pH induced degradation, etc. The released immunomodulatory material or compound may in turn be exposed to the tissues surrounding the one or more membrane layers.

[0047] In some embodiments, the immunomodulatory material or compound may be directly applied to tissues at an area of implantation surrounding the one or more membrane layers as opposed to being released from the one or more membrane layers. In some such embodiments, the immunomodulatory material or compound may be released to the surrounding tissues upon direct application to the site of implantation. Upon the release, the immunomodulatory material or compound may be exposed to the tissues surrounding the at least one membrane layer and generate a favorable foreign body response.

[0048] It should be understood that the exposure of immunomodulatory material or compound and the diffusion of the therapeutic composition to the surrounding tissues at the site of implantation may occur in any appropriate order, depending on parameters such as the location of the immunomodulatory material or compound with respect to the one or more membrane layers, the type of matrix used to encapsulate the compound, etc. For example, in one set of embodiments, both the therapeutic composition and the immunomodulatory material or compound may be simultaneously exposed or released to the surrounding tissues. Alternatively, the therapeutic composition may be diffused to the surrounding tissues prior to exposing the immunomodulatory material or compound to the tissues, or vice versa.

[0049] As described above, the methods and devices disclosed herein may include any of a variety of appropriate immunomodulatory compounds. The immunomodulatory compounds, according to some embodiments, may be configured to promote generation of one or more antiinflammatory cytokines (e.g., IL- 10) while inhibiting generation of one or more pro- inflammatory cytokines (e.g., IL-ip). Non-limiting examples of appropriate immunomodulatory compounds may include at least one selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, a NOD-, LRR- and pyrin domaincontaining protein 3 (NLRP3) inflammasome inhibitor, as well as combinations of the forgoing. In other embodiments, the immunomodulatory compounds may include Janus kinase inhibitor (JAK) inhibitor (e.g., baricitinib, ruxolitinib), a phosphodiesterase-4 (PDE4) inhibitor (e.g., roflumilast, apremilast), a CC-chemokine receptor-2 (CCR2) inhibitor (e.g., PF-04136309), a phenolic compound (e.g., polyphenol), a toll-like receptor antagonist, an IL-ip receptor antagonist (e.g., Anakinra), an apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) inhibitor, a caspase inhibitor, a Gasdermin D (GSDMD) inhibitor, a potassium and chloride channel inhibitor, and / or a nuclear factor erythroid 2-related factor 2 (NFR2) agonist. In particular, without wishing to be bound by any particular theory, it is believed that a macroencapsulation device used with and / or comprising (a) certain type(s) of immunomodulatory compound (e.g., CSF1R inhibitor, NLRP3 inflammasome inhibitor, TLR4 inhibitor, and / or NF-KB inhibitor) may exhibit an enhanced reduction in foreign body response compared to other types of immunomodulatory compounds, under otherwise identical conditions. In some embodiments, the macroencapsulation device may advantageously include one or more immunomodulatory compounds described elsewhere herein, such as a CSF1R inhibitor (e.g., pexidartinib), a NLRP3 inflammasome inhibitor (e.g., MCC950), a TLR4 inhibitor (e.g.,TAK242 and / or tannic acid), and / or a NF-kB inhibitor (e.g., TAK242 and / or tannic acid).

[0050] The at least one immunomodulatory compound may be present in the macroencapsulation device or portion(s) thereof in any of a variety of appropriate concentrations. For example, the at least one immunomodulatory compound may be present in the matrix, the at least one membrane layer, and / or the device at a concentration of greater than or equal to 0.005 mmol / L, greater than or equal to 0.01 mmol / L, greater than or equal to 0.02 mmol / L, greater than or equal to 0.04 mmol / L, greater than or equal to 0.1 mmol / L, greater than or equal to 0.2 mmol / L, greater than or equal to 0.3 mmol / L, greater than or equal to 0.8 mmol / L, greater than or equal to 2 mmol / L, greater than or equal to 4 mmol / L, greater than or equal to 6 mmol / L, greater than or equal to 8 mmol / L, greater than or equal to 10 mmol / L, or greater than or equal to12 mmol / L. In some embodiments, the at least one immunomodulatory compound may be present in the matrix, the at least one membrane layer, and / or the device at a concentration of less than or equal to 20 mmol / L, less than or equal to 15 mmol / L, less than or equal to 12 mmol / L, less than or equal to 10 mmol / L, less than or equal to 8 mmol / L, less than or equal to 6 mmol / L, less than or equal to 4 mmol / L, less than or equal to 2 mmol / L, less than or equal to 1 mmol / L, less than or equal to 0.8 mmol / L, less than or equal to 0.3 mmol / L, less than or equal to 0.1 mmol / L, less than or equal to 0.04 mmol / L, less than or equal to 0.02 mmol / L, or less than or equal to 0.01 mmol / L. Combinations of the above-referenced ranges are possible (e.g., greater than or equal to 0.005 mmol / L and less than or equal to 12 mmol / L). For example, in some embodiments, the at least one immunomodulatory compound may be present in the matrix, the at least one membrane layer, and / or the device at a concentration of between 0.005-15 mmol / L, 0.005-12 mmol / L, 0.005-6 mmol / L, 0.005-4 mmol / L, 0.005-2 mmol / L, 0.005-1 mmol / L, 0.005- 0.8 mmol / L, 0.01-15 mmol / L, 0.01-12 mmol / L, 0.01-6 mmol / L, 0.01-4 mmol / L, 0.01-2 mmol / L, 0.01-1 mmol / L, 0.01-0.8 mmol / L, 0.02-15 mmol / L, 0.02-12 mmol / L, 0.02-6 mmol / L, 0.02-4 mmol / L, 0.02-2 mmol / L, 0.02-1 mmol / L, 0.02-0.8 mmol / L, 0.04-12 mmol / L, 0.04-6 mmol / L, 0.04-4 mmol / L, 0.04-2 mmol / L, 0.04-1 mmol / L, 0.04-0.8 mmol / L, 0.1-15 mmol / L, 0.1-12 mmol / L, 0.1-6 mmol / L, 0.1-4 mmol / L, 0.1-2 mmol / L, 0.1-1 mmol / L, 0.1-0.8 mmol / L, 0.3-15 mmol / L, 0.3-12 mmol / L, 0.3-6 mmol / L, 0.3-4 mmol / L, 0.3-2 mmol / L, 0.3-1 mmol / L, or 0.3-0.8 mmol / L. In some embodiments, the at least one immunomodulatory compound may be present in the matrix, the at least one membrane layer, and / or the device at a concentration of greater than or equal to 0.01 mmol / L and less than or equal to 0.8 mmol / L. In some embodiments, the at least one immunomodulatory compound may be present in the matrix, the at least one membrane layer, and / or the device at a concentration of greater than or equal to 0.04 mmol / L and less than or equal to 4 mmol / L. In some embodiments, the at least one immunomodulatory compound may be present in the matrix, the at least one membrane layer, and / or the device at a concentration of greater than or equal to 0.02 mmol / L and less than or equal to 2 mmol / L. In some embodiments, the at least one immunomodulatory compound may be present in the matrix, the at least one membrane layer, and / or the device at a concentration of greater than or equal to 0.3 mmol / L and less than or equal to 12 mmol / L. Other ranges are also possible.

[0051] The at least one immunomodulatory compound may be used in any of a variety of appropriate therapeutic doses. For example, in some embodiments, therapeutic doses may be measured as the amount (e.g., in micromoles) of immunomodulatory compounds per volume (e.g., per liter of tissue). In some embodiments, the immunomodulatory compound may be used in a therapeutic dose of greater than or equal to 0.05 pM, greater than or equal to 0.1 pM, greater than or equal to 0.125 pM, greater than or equal to 0.15 pM, greater than or equal to 0.25 pM,greater than or equal to 0.5 pM, greater than or equal to 1 p M, greater than or equal to 2 p M, greater than or equal to 4 pM, or more, and / or less than or equal to 10 pM, less than or equal to 6 pM, less than or equal to 4 pM, less than or equal to 2 pM, less than or equal to 1 pM, less than or equal to 0.5 pM, less than or equal to 0.25 pM, less than or equal to 0.15 pM, less than or equal to 0.125 pM, less than or equal to 0.1 pM, or less. Combinations of the above-referenced ranges are possible (e.g., greater than or equal to 0.1 pM and less than or equal to 4 pM). For example, in some embodiments, the immunomodulatory compound may be used in a therapeutic dose of between 0.1-6 pM, 0.1-4 pM, 0.1-3.5 pM, 0.1-3 pM, 0.1-2.5 pM, 0.1-2 pM, 0.1-1.5 pM, 0.1-1 pM, 0.1-0.5 pM, 0.1-0.25 pM, 0.25-6 pM, 0.25-4 pM, 0.25-3.5 pM, 0.25-3 pM, 0.25-2.5 pM, 0.25-2 pM, 0.25-1.5 pM, 0.25-1 pM, 0.25-0.5 pM, 0.5-6 pM, 0.5-4 pM, 0.5-3.5 pM, 0.5-3 pM, 0.5-2.5 pM, 0.5-2 pM, 0.5-1.5 pM, 0.5-1 pM, 1-6 pM, 1-4 pM, 1-3.5 pM, 1-3 pM, 1-2.5 pM, 1-2 pM, 1-1.5 pM, 2-6 pM, 2-4 pM, 2-3.5 pM, 2-3 pM, or 2-2.5 pM. In some embodiments, the immunomodulatory compound may be used in a therapeutic dose greater than or equal to 0.125 pM and less than or equal to 0.25 pM. In some embodiments, the immunomodulatory compound may be used in a therapeutic dose greater than or equal to 0.25 pM and less than or equal to 4 pM. In some embodiments, the immunomodulatory compound may be used in a therapeutic dose greater than or equal to 2 pM and less than or equal to 4 pM. In some embodiments, the immunomodulatory compound may be used in a therapeutic dose greater than or equal to 0.25 pM and less than or equal to 0.50 pM. Other ranges are also possible.

[0052] In one set of embodiments, the immunomodulatory compound comprises a colony stimulating factor 1 receptor (CSF1R) inhibitor. Any of a variety of CSF1R inhibitors may be employed, including, but not limited to pexidartinib, or salts, analogs or derivatives thereof. In one set of embodiments, the immunomodulatory compound comprises pexidartinib. According to some embodiments, the presence of a particular type of CSF1R inhibitor (e.g., pexidartinib) in the macroencapsulation device may result in a relatively high reduction in foreign body response compared to other types of CSF1R inhibitors, under otherwise identical conditions. In some embodiments, the one or more CSF1R inhibitors may be present in a matrix in a concentration that is between or equal to 0.01 mmol / L and less than or equal to 0.8 mmol / L. In some embodiments, the one or more CSF1R inhibitors may be present in a matrix in a concentration that is between or equal to 0.005 mmol / L and less than or equal to 1 mmol / L. In some embodiments, the one or more CSF1R inhibitors may be present in a matrix in a concentration that is between or equal to 0.005 mmol / L and less than or equal to 1.5 mmol / L. Additionally, the one or more CSF1R inhibitors may be used in a therapeutic dose between or equal to 0.25 pM and less than or equal to 4 pM. In some embodiments, the one or more CSF1R inhibitors maybe used in a therapeutic dose between or equal to 0.125 pM and less than or equal to 0.25 pM. In some embodiments, the one or more CSF1R inhibitors may be used in a therapeutic dose between or equal to 0.1 pM and less than or equal to 0.35 pM. In some embodiments, the one or more CSF1R inhibitors may be used in a therapeutic dose between or equal to 0.05 pM and less than or equal to 0.5 pM. Of course, the use of CSF1R inhibitors with concentrations and / or therapeutic doses both greater than or less than those noted above, including the ranges described above for a generic immunomodulatory compound, are also contemplated as the disclosure is not so limited.

[0053] Alternatively or additionally, according to some embodiments, the immunomodulatory compound comprises a NLRP3 inflammasome inhibitor. Any of a variety of NLRP3 inhibitors may be employed, including, but not limited to MCC950, GDC-2394,YQ128, NLRP3 Inflammasome Inhibitor I, Muscone, 4’ -Methoxyresveratrol, CY-09, INF39, Dapansutrile, Shionone, Licochalcone B, and Dimethyl itaconate, or salt, analogs or derivatives thereof. In one set of embodiments, the immunomodulatory compound comprises MCC950. In some embodiments, the immunomodulatory compound comprises GDC-2394. In some embodiments, the immunomodulatory compound comprises YQ128. In some embodiments, the immunomodulatory compound comprises NLRP3 Inflammasome Inhibitor I. In some embodiments, the immunomodulatory compound comprises Muscone, 4’ -Methoxyresveratrol. In some embodiments, the immunomodulatory compound comprises CY-09. In some embodiments, the immunomodulatory compound comprises INF39. In some embodiments, the immunomodulatory compound comprises Dapansutrile. In some embodiments, the immunomodulatory compound comprises Shionone. In some embodiments, the immunomodulatory compound comprises Licochalcone B. In some embodiments, the immunomodulatory compound comprises Dimethyl itaconate. According to some embodiments, the presence of a particular type of NLPR3 inhibitor (e.g., MCC950) in the macroencapsulation device may result in a relatively high reduction in foreign body response compared to other types of NLPR3 inhibitors, under otherwise identical conditions. In some embodiments, the one or more NLRP3 inflammasome inhibitors may be present in a matrix in a concentration that is between or equal to 0.04 mmol / L and less than or equal to 4 mmol / L. In some embodiments, the one or more NLRP3 inflammasome inhibitors may be present in a matrix in a concentration that is between or equal to 0.02 mmol / L and less than or equal to 6 mmol / L. In some embodiments, the one or more NLRP3 inflammasome inhibitors may be present in a matrix in a concentration that is between or equal to 0.01 mmol / L and less than or equal to 8 mmol / L. Additionally, the one or more NLRP3 inflammasome inhibitors may be used in a therapeutic dose between or equal to 0.25 pM and less than or equal to 4 pM. In some embodiments, the one or moreNLRP3 inflammasome inhibitors may be used in a therapeutic dose between or equal to 0.2 p M and less than or equal to 5 pM. In some embodiments, the one or more NLRP3 inflammasome inhibitors may be used in a therapeutic dose between or equal to 0.15 pM and less than or equal to 6 pM. Of course, the use of NLRP3 inflammasome inhibitors with concentrations and / or therapeutic doses both greater than or less than those noted above, including the ranges described above for a generic immunomodulatory compound, are also contemplated as the disclosure is not so limited.

[0054] Alternatively or additionally, in some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising GDC-2394. In some embodiments, the immunomodulatory comprises a NLRP3 inhibitor comprising YQ128. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising NLRP3 Inflammasome Inhibitor I. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising muscone. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising 4'-methoxyresveratrol. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising CY- 09. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising INF39. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising dapansutrile. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising shionone. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising Licochalcone B. In some embodiments, the immunomodulatory compound comprises a NLRP3 inhibitor comprising dimethyl itaconate.

[0055] Alternatively or additionally, according to some embodiments, the immunomodulatory compound comprises a toll-like receptor 4 (TLR4) inhibitor. Any of a variety of TLR4 inhibitors may be employed, including, but not limited to TAK242, tannic acid, MD2-IN-1, TLR4-IN-C34, IAXO-102, and / or MD2-TLR4-IN-1, or salt, analogs or derivatives thereof. In one set of embodiments, the immunomodulatory compound comprises TAK242. In some embodiments, the immunomodulatory compound comprises tannic acid. In some embodiments, the immunomodulatory compound comprises MD2-IN-1. In some embodiments, the immunomodulatory compound comprises TLR4-IN-C34. In some embodiments, the immunomodulatory compound comprises IAXO-102. In some embodiments, the immunomodulatory compound comprises MD2-TLR4-IN-1. According to some embodiments, the presence of a particular type of TLR4 inhibitor (e.g., TAK242 and / or tannic acid) in the macroencapsulation device may result in a relatively high reduction in foreign body response compared to other types of TLR4 inhibitors, under otherwise identical conditions. In someembodiments, the one or more TLR4 inhibitors may be present in a matrix in a concentration that is between or equal to 0.3 mmol / L and 12 mmol / L. In some embodiments, the one or more TLR4 inhibitors may be present in a matrix in a concentration that is between or equal to 0.2 mmol / L and 15 mmol / L. In some embodiments, the one or more TLR4 inhibitors may be present in a matrix in a concentration that is between or equal to 0.02 mmol / L and 2 mmol / L. In some embodiments, the one or more TLR4 inhibitors may be present in a matrix in a concentration that is between or equal to 0.01 mmol / L and 4 mmol / L. Additionally, the one or more TLR4 inhibitors may be used in a therapeutic dose between or equal to 2 pM and less than or equal to 4 pM. In some embodiments, the one or more TLR4 inhibitors may be used in a therapeutic dose between or equal to 1 pM and less than or equal to 6 pM. In some embodiments, the one or more TLR4 inhibitors may be used in a therapeutic dose between or equal to 0.25 pM and less than or equal to 0.5 pM. In some embodiments, the one or more TLR4 inhibitors may be used in a therapeutic dose between or equal to 0.15 pM and less than or equal to 1 pM. Of course the use of TLR4 inhibitors with concentrations and / or therapeutic doses both greater than or less than those noted above, including the ranges described above for a generic immunomodulatory compound, are also contemplated as the disclosure is not so limited.

[0056] Alternatively or additionally, in some embodiments, the immunomodulatory compound comprises a TLR4 inhibitor comprising TLR4-IN-C34. In some embodiments, the immunomodulatory compound comprises a TLR4 inhibitor comprising IAXO-102. In some embodiments, the immunomodulatory compound comprises a TLR4 inhibitor comprising MD2- TLR4-IN-1.

[0057] Alternatively or additionally, according to some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor. Any of a variety of NF-KB inhibitors may be employed, including, but not limited to TAK242, tannic acid, sitagliptin, comuside, SM-7368, NF-KB-IN-1, IQ 3, sulfasalazine (NSC 667219), erdosteine, evodiamine, UCB-9260, triptolide (PG490), curcumenol, SN50, INH14, SC75741, JSH-23, xanthatin, maslinic acid, mulberroside A, eleutheroside E, and / or madecassic acid, or salt, analogs or derivatives thereof. In one set of embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising TAK242. In one set of embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising tannic acid. In one set of embodiments, the immunomodulatory compound comprises TAK242 and / or tannic acid. According to some embodiments, the presence of a particular type of NF-KB inhibitor (e.g., TAK242 and / or tannic acid) in the macroencapsulation device may result in a relatively high reduction in foreign body response compared to other types of NF-KB inhibitors, under otherwise identical conditions. In some embodiments, the one or more NF-KB inhibitors may be present in a matrix in aconcentration that is between or equal to 0.3 mmol / L and 12 mmol / L. In some embodiments, the one or more NF-KB inhibitors may be present in a matrix in a concentration that is between or equal to 0.2 mmol / L and 15 mmol / L. In some embodiments, the one or more NF-KB inhibitors may be present in a matrix in a concentration that is between or equal to 0.02 mmol / L and 2 mmol / L. In some embodiments, the one or more NF-KB inhibitors may be present in a matrix in a concentration that is between or equal to 0.01 mmol / L and 4 mmol / L. Additionally, the one or more NF-KB inhibitors may be used in a therapeutic dose between or equal to 2 pM and less than or equal to 4 pM. In some embodiments, the one or more NF-KB inhibitors may be used in a therapeutic dose between or equal to 1 pM and less than or equal to 6 pM. In some embodiments, the one or more NF-KB inhibitors may be used in a therapeutic dose between or equal to 0.25 pM and less than or equal to 0.5 pM. In some embodiments, the one or more NF- KB inhibitors may be used in a therapeutic dose between or equal to 0.15 pM and less than or equal to 1 pM. Of course, the use of NF-KB inhibitors with concentrations and / or therapeutic doses both greater than or less than those noted above, including the ranges described above for a generic immunomodulatory compound, are also contemplated as the disclosure is not so limited.

[0058] Alternatively or additionally, in some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising sitagliptin. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising cornuside. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising SM- 7368. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising NF-KB-IN- 1. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising IQ 3. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising sulfasalazine (NSC 667219). In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising erdosteine. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising Evodiamine. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising UCB-9260. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising triptolide (PG490). In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising curcumenol. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising SN50. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising INH14. In some embodiments, the immunomodulatory compound comprises a NF- KB inhibitor comprising SC75741. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising JSH-23. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising xanthatin. In some embodiments, theimmunomodulatory compound comprises a NF-KB inhibitor comprising maslinic acid. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising mulberroside A. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising eleutheroside E. In some embodiments, the immunomodulatory compound comprises a NF-KB inhibitor comprising madecassic acid.

[0059] Alternatively or additionally, according to some embodiments, the immunomodulatory compound comprises a TLR-4 and / or NF-KB inhibitor (e.g., TAK242 and / or tannic acid). In some embodiments, the immunomodulatory compound comprises a TLR-4 and a NF-KB inhibitor, such as TAK242. In some embodiments, the immunomodulatory compound comprises a TLR-4 and a NE-KB inhibitor, such as tannic acid. According to some embodiments, the TLR-4 and / or NE-KB inhibitor comprises a polyphenol having antiinflammatory and / or redox scavenging properties. In one set of embodiments, the immunomodulatory compound comprises tannic acid. In some embodiments, tannic acid may be present in a matrix in a concentration that is between or equal to 0.02 mmol / L and 2 mmol / L. Additionally, tannic acid may be used in a therapeutic dose between or equal to 0.25 pM and less than or equal to 0.5 pM. In one set of embodiments, the immunomodulatory compound comprises TAK242. In some embodiments, TAK242 may be present in a matrix in a concentration that is between or equal to 0.3 mmol / L and 12 mmol / L. Additionally, TAK242 may be used in a therapeutic dose between or equal to 2 pM and less than or equal to 4 pM. Of course, the use of tannic acid and / or TAK242 with concentrations and / or therapeutic doses both greater than or less than those noted above, including the ranges described above for a generic immunomodulatory compound, are also contemplated as the disclosure is not so limited.

[0060] In some embodiments, the immunomodulatory compound comprises a Janus kinase inhibitor (JAK) inhibitor (e.g., baricitinib, ruxolitinib). In some embodiments, the immunomodulatory compound comprises a phosphodiesterase-4 (PDE4) inhibitor (e.g., roflumilast, apremilast). In some embodiments, the immunomodulatory compound comprises a CC-chemokine receptor-2 (CCR2) inhibitor (e.g., PE-04136309). In some embodiments, the immunomodulatory compound comprises a phenolic compound (e.g., polyphenol). In some embodiments, the immunomodulatory compound comprises a toll-like receptor antagonist. In some embodiments, the immunomodulatory compound comprises an IL-ip receptor antagonist (e.g., Anakinra). In some embodiments, the immunomodulatory compound comprises an apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) inhibitor. In some embodiments, the immunomodulatory compound comprises a caspase inhibitor. In some embodiments, the immunomodulatory compound comprises a Gasdermin D (GSDMD) inhibitor. In some embodiments, the immunomodulatory compound comprises apotassium and chloride channel inhibitor. In some embodiments, the immunomodulatory compound comprises a nuclear factor erythroid 2-related factor 2 (NFR2) agonist.

[0061] In some embodiments, an immunomodulatory material may comprise a matrix that the at least one immunomodulatory compound is dispersed or otherwise included in. The matrix, according to some embodiments, may comprise a hydrogel, a microparticle, a nanoparticle, a biodegradable material, and / or a swellable polymer. The at least one immunomodulatory compound may be associated with the matrix in any of a variety of appropriate manners, such as being contained within the matrix and / or conjugated to the matrix. The matrix may comprise any of a variety of suitable compositions described elsewhere herein.

[0062] The immunomodulatory materials may be present in a macroencapsulation device in any of a variety of appropriate locations. The immunomodulatory materials, according to some embodiments, may be associated with the one or more membrane layers (e.g., the first membrane layer and / or the second membrane layer) of the macroencapsulation device in any of a variety of appropriate manners described herein. In one set of embodiments, the immunomodulatory material is disposed on the one or more of the membrane layers, such as on the first membrane layer and / or the second membrane layer. For example, the immunomodulatory material may be disposed on the surface one or more membrane layers as a surface coating, according to one embodiment. The immunomodulatory material may be surface coated on the one or more membrane layers as either a matrix containing the immunomodulatory compound or as the immunomodulatory compound itself (without the matrix). In some cases, the surface coating may be applied to either the interior and / or the exterior surface of the one or more membrane layers. Without wishing to be bound by any particular theory, it be believed that it may be advantageous to apply the immunomodulatory material to an exterior surface of the one of more membrane layers. This may allow for direct contact of the immunomodulatory material with surrounding tissues during implantation and contribute to a more favorable foreign body response.

[0063] Alternatively or additionally, the immunomodulatory material may be disposed on the one or more membrane layers via chemical immobilization to a surface of the one or more membrane layers. For example, in one embodiment, the immunomodulatory compound(s) described herein may be immobilized to a surface (e.g., an exterior surface) of the one or more membrane layers via chemical conjugation. In some instances, one or more linker molecules may be used to immobilize the immunomodulatory compound(s) to the one or more membrane layers. In some embodiments, the one or more linker molecule may be biodegradable and may be prone to degradations such as enzymatic degradation, hydrolysis, pH and / or temperature induced degradation, etc. The immunomodulatory compound(s) may be directly conjugated tothe one or more membrane layers and / or contained within a matrix that is in turn conjugated to the one or more membrane layers. Alternatively or additionally, the immunomodulatory material may be disposed (e.g., impregnated) in the pores of at least one of the one or more membrane layers, such as in the pores of the first membrane layer and / or the second membrane layer. Alternatively or additionally, the immunomodulatory material may be disposed within an internal volume of the device formed between the one or more membrane layers.

[0064] Alternatively or additionally, the immunomodulatory material may be disposed adjacent to the one or more membrane layers, such as adjacent to the first membrane layer and / or the second membrane layer. In one embodiment, the immunomodulatory material may be disposed around at least a portion of the one or more membrane layers. For instance, the immunomodulatory material may be disposed around at least a portion of the perimeter of the one or more layers. In some cases, the immunomodulatory material may be applied to tissue(s) within a surgical field (during implantation) that may be located adjacent to, and potentially disposed against, the macroencapsulation device after implantation. According to some embodiments, it may be advantageous to apply the immunomodulatory material using a method described above to a location on and / or adjacent the membrane, e.g., on an exterior surface of the membrane layer(s) and / or direct application to a tissue region surrounding the macroencapsulation device, such that the immunomodulatory compound(s) may be in direct contact with the tissues during implantation. Such methods of application may lead to favorable foreign body responses described elsewhere herein.

[0065] As noted above, in some embodiments, an immunomodulatory material comprises a matrix that the immunomodulatory compound may be dispersed within. The matrix, in some cases, comprises a hydrogel. According to some embodiments, the term hydrogel may refer to gels in which a cross-linked polymer matrix is fully or partially swollen with water, one or more water-compatible alcohols, or combinations thereof. The polymer matrix may be cross-linked either via chemical or physical means. As non-limiting examples, the hydrogel may be crosslinked through covalent bonds, ionic interactions, hydrogen bonding, chain entanglement, or self-association of microphase segregating moieties. Additionally, it should be understood that such hydrogels may exist and be used in a dehydrated (e.g., unswollen or lyophilized) state.

[0066] In some embodiments, the hydrogel may include a polymer matrix selected from at least one water-compatible organic polymer, alcohol-compatible organic polymer, and combinations thereof. The polymer may be homopolymeric, heteropolymeric (including, but not limited to, cross -polymers or co-polymers of any co-monomer distribution), and may be linear, branched, hyperbranched, dendrimeric, or crosslinked to any extent. Examples of suitable polymers include, but are not limited to, gelatin, methylcellulose, hydroxyethyl methyl cellulose,hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, polyacrylamides, polyacrylic acid, polymethacrylic acid, salts of polyacrylic acid, salts of polymethacrylic acid, poly (2-hydroxy ethyl methacrylate), polycaprolactone, polylactic acid, poly glycolic acid, polylactic-co-glycolic acid, polyvinylalcohol, polyanhydrides such as poly(methacrylic) anhydride, poly(acrylic) anhydride, polysebasic anhydride, collagen, keratin, poly(hyaluronic acid), hyaluronic acid-containing polymers and copolymers, polypeptides, dextran, dextran sulfate, chitosan, chitin, agarose gels, fibrin gels, soy-derived hydrogels and alginate-based hydrogels such as poly(sodium alginate), and combinations thereof.

[0067] In some embodiments, the hydrogel polymer matrix may include any of a variety of biodegradable and / or biocompatible polymers, such as a biopolymer (or natural polymer) and / or a biodegradable and / or biocompatible synthetic polymer. Examples of suitable biodegradable polymers include synthetic polymers such as polymers of lactic acid and glycolic acid, poly anhydrides, poly(ortho)esters, polyurethanes, poly(butic acid), poly(valeric acid), poly (caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide) and poly(lactide-co- caprolactone), polycaprolactone, and natural polymers such as polysaccharides (e.g., starch, alginate, dextran, agarose, cellulose, etc.), chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), proteins such as gelatin, collagen, keratin, fibrinogen, albumin, albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. According to some embodiments, the biodegradable polymers may be degraded either by enzymatic hydrolysis or exposure to water, by surface or bulk erosion. The hydrogel matrix may contain one polymer, or more than one polymer. When more than one polymer is present, the continuous matrix may contain a mixture of blend of the polymers, or a co-polymer containing the polymers. In some embodiments, biodegradable matrix material may be used to release the associated immunomodulatory compound as the matrix material degrades in situ via any of a variety of degradation pathways, e.g., enzymatic degradation, hydrolysis, pH and / or temperature induced degradation.

[0068] Specific examples of materials (e.g., hydrogels and / or polymers) that may mixed with and / or used to encapsulate an immunomodulatory compound to provide a desired controlled release of the compounds may include, but are not limited to, fibrin polymer, alginate, collagen gel, poly(2-hydroxyethyl methacrylate (pHEMA), poly(2-hydroxypropyl acrylate) (pHPA), poly(lactic-co-glycolic acid) (PLGA), agarose, chitosan, carboxymethylcellulose, poly(vinyl alcohol) (PVA), Eudragit, poly (methyl methacrylate) (PMMA), polylactic acid (PLA), polycaprolactone (PCL), polyacrylonitrile (PAN), blend or copolymer of PAN / PVC,polyurethanes, collagen, laminin, polyethylene glycol (PEG), hydroxyapatite, hydoxypropyl cellulose, Pluronics (e.g., F127), microsphere slurry, carbon nanotubes, and / or any other appropriate material described elsewhere herein.

[0069] The matrix may be present in any of a variety of appropriate shape and / or forms described elsewhere herein. In one set of embodiments, the matrix may be in the form of particles, such as microparticles and / or nanoparticles. For example, the matrix may be in the form of hydrogel particles. Additionally, it should be understood that hydrogel particles may include both a polymeric particle that is swollen with a sufficiently compatible fluid and a polymeric particle in a dehydrated state. In one set of embodiments, the polymeric particle is a PEG and / or PEGA particle. In some cases, one or more immunomodulatory compounds described herein may be contained or encapsulated by the particle, or in some cases, may be chemically conjugated to the particle.

[0070] In some embodiments, the hydrogel is an injectable and / or flowable gel. That is, the injectable and / or flowable gel may be deformed and subject to flow upon application of a force (e.g., a shear force). Such a gel can be advantageously used with a syringe for delivery and localized application. For example, in one set of embodiments, the injectable gel comprises a protein gel such as fibrin gel.

[0071] Any of a variety of methods may be employed to form the immunomodulatory material and / or matrix described herein. For example, in one set of embodiments, protein gel, such as a fibrin gel formed from fibrinogen and thrombin, may be employed as the matrix. In some embodiments, the fibrin gel precursor mixture may comprise a liquid carrier (e.g., a diluent). For example, fibrinogen may be diluted in a liquid carrier (e.g., PBS) prior to being mixed with thrombin. In one embodiment, prior to being mixed with thrombin, fibrinogen may make up at least 50% (e.g., at least 60%, at least 70%, at least 80%) and / or up to 90% (e.g., up to 95%, up to 99%, or up to 100%) of the total volume of a mixture containing fibrinogen and the liquid carrier. In one embodiment, fibrinogen may make up at least 50% (e.g., at least 60%, at least 70%, at least 80%) and / or up to 90% (e.g., up to 95%, up to 99%, or up to 100%) of the total volume of mixture containing fibrinogen and thrombin. In one embodiment, fibrinogen may make up between 50-99%, 50-95%, 60-99%, 60-95%, 70-99%, 70-95%, 80-99%, or 80- 95% of the total volume of mixture containing fibrinogen and thrombin. One or more immunomodulatory compounds described herein may be present within matrix mixture in an amount or concentration described elsewhere herein. The mixture may be gelled to form the gel at any of a variety of temperatures, such as at about 37 °C.

[0072] In some embodiments, a composition is described herein which may be used without a macroencapsulation device where the composition is directly implanted in a targettissue. The composition, in accordance with certain embodiments, comprises a population of cells and at least one immunomodulatory compound. The population of cells may include any of a variety of appropriate populations of cells described elsewhere herein either individually or in combination with one another including, for example, NKX6.1 -positive and / or ISLl-positive cells. Similarly, the immunomodulatory compound may include any one or more of the variety of appropriate immunomodulatory compounds described elsewhere herein, such as a toll-like receptor 4 (TLR4) inhibitor (e.g., TAK242 and / or tannic acid), a nuclear factor K-light-chain- enhancer of activated B cells (NF-KB) inhibitor (e.g., TAK242 and / or tannic acid), a colonystimulating factor 1 receptor (CSF1R) inhibitor (e.g., pexidartinib), and / or a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor (e.g., MCC950).

[0073] The composition, according to some embodiments, may further comprise a matrix described elsewhere herein, such as a hydrogel. In some embodiments, the population of cells may be contained in the matrix, such as being encapsulated or dispersed in the matrix. In some embodiments, the immunomodulatory compound may be associated with the matrix in any of a variety of appropriate manners described elsewhere herein. For example, in some embodiments, the immunomodulatory compound may be contained in (e.g., disperse in, encapsulated by, and / or impregnated in the pores of) the matrix. Alternatively or additionally, the immunomodulatory compound may be attached to a portion of the matrix, such as via chemical conjugation or physical association. The matrix may comprise any of a variety of suitable compositions described elsewhere herein.

[0074] In some embodiments, sustained exposure or release of the immunomodulatory material or compound(s) may be achieved using the devices and methods described herein. For example, the immunomodulatory material or compound(s) may be exposed or released to the tissues at the site of implantation over a prolonged period of time, such as at least 1 day, at least 2 days, at least 4 days, at least 7 days, at least 10 days, at least 14 days, or more, and / or up to 21 days, up to 28 days, or more. For example, the immunomodulatory material or compound(s) may be exposed or released to the tissues at the site of implantation over a period of time of at least 1 day. In some embodiments, the immunomodulatory material or compound(s) may be exposed or released to the tissues at the site of implantation over a period of at least 2 days. In some embodiments, the immunomodulatory material or compound(s) may be exposed or released to the tissues at the site of implantation over a period of at least 4 days. In some embodiments, the immunomodulatory material or compound(s) may be exposed or released to the tissues at the site of implantation over a period of at least 7 days. In some embodiments, the immunomodulatory material or compound(s) may be exposed or released to the tissues at the site of implantation over a period of at least 10 days. In some embodiments, the immunomodulatorymaterial or compound(s) may be exposed or released to the tissues at the site of implantation over a period of at least 14 days or more. In some embodiments, the immunomodulatory material or compound(s) may be exposed or released to the tissues at the site of implantation over a period of up to 21 days. In some embodiments, the immunomodulatory material or compound(s) may be exposed or released to the tissues at the site of implantation over a period of up to 28 days. Combinations of the above-referenced ranges are possible (e.g., at least 1 day and up to 28 days, or at least 1 day and up to 2 weeks). Other ranges are also possible.

[0075] The inventors have discovered that by using an immunomodulatory material and / or a macroencapsulation devices as disclosed herein, a foreign body response can be favorably modulated during delivery and / or implantation of the macroencapsulation device to a desired location in a subject. For example, by employing the immunomodulatory material described herein, the macrophages may be polarized towards the M2 macrophage (relative to the Ml macrophage), such that unfavorable foreign body response may be at least partially attenuated and angiogenesis and vascularization may be enhanced. The immunomodulatory material and / or macroencapsulation devices described herein may be associated with a number of additional advantages, such as sustained release of an immunomodulatory compound over a prolonged period of time, little or no cytotoxicity, little to no disruption of vessel network formation, enhanced angiogenesis and vascularization, enhanced chemical stability associated with the immunomodulatory compound, effective delivery of a therapeutic compositions produced by a population of cells contained within the macroencapsulation device, and overall reduced foreign body response compared to a device that does not contain the immunomodulatory material described herein.

[0076] As noted above, the use of a macroencapsulation device comprising the immunomodulatory compound or material described herein may be associated with enhanced reduction in unfavorable foreign body response, e.g., a pro-inflammatory response. For example, a macroencapsulation device comprising one or more of the immunomodulatory material or compound described herein may lead to a reduced foreign body response during implantation compared to a conventional macroencapsulation device that does not contain the immunomodulatory material or compound. In some cases, a macroencapsulation device described herein may lead to a decrease in pro-inflammatory response compared to a macroencapsulation device without the immunomodulatory material or compound under similar conditions by a factor of at least 1.1, 1.3, 1.5, 2, 4, 6, 10, 15, 20, or other appropriate factor. In some embodiments, a macroencapsulation device described herein may exhibit a decrease in pro- inflammatory response compared to a macroencapsulation device without the immunomodulatory material or compound under similar conditions by a factor less than or equalto or up to 100, 50, 40, 30, 20, 15, 10, or other appropriate factor. For example, in some embodiments, a macroencapsulation device described herein may exhibit a decrease in pro- inflammatory response compared to a macroencapsulation device without the immunomodulatory material or compound under similar conditions by a factor of up to 30. In some embodiments, a macroencapsulation device described herein may exhibit a decrease in pro- inflammatory response compared to a macroencapsulation device without the immunomodulatory material or compound under similar conditions by a factor of up to 50. Combinations of the above-referenced ranges are possible (e.g., a decrease by a factor that is between or equal to 1.1 and 11, 1.1 and 25, 1.1 and 30, 1.1 and 50, or other appropriate combination). Other ranges are also possible.

[0077] According to some embodiments, foreign body response may be characterized by a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) relative to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated by macrophages upon exposing the macroencapsulation device to the macrophages. The macrophages may include a monocyte, a M0 macrophage, and / or a Ml macrophage. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device comprising the immunomodulatory compound(s) and / or material(s) described herein is at least 1.05 times, 1.1 times, at least 1.5 times, least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 8 times, at least 10 times, at least 15 times, or at least 20 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device comprising the immunomodulatory compound(s) and / or material(s) described herein is at least 1.1 times the ratio of the total amount of antiinflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) to the total amount of pro- inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device comprising the immunomodulatory compound(s) and / or material(s) described herein is at least 1.5 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of amacroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of antiinflammatory cytokines (e.g., IL- 10) to the total amount of pro-inflammatory cytokines (e.g., IL- 1P) generated per macrophage in the presence of a macroencapsulation device comprising the immunomodulatory compound(s) and / or material(s) described herein is at least 2 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device comprising the immunomodulatory compound(s) and / or material(s) described herein is at least 3 times the ratio of the total amount of antiinflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) to the total amount of pro- inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device comprising the immunomodulatory compound(s) and / or material(s) described herein is at least 4 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of antiinflammatory cytokines (e.g., IL- 10) to the total amount of pro-inflammatory cytokines (e.g., IL- 1P) generated per macrophage in the presence of a macroencapsulation device comprising the immunomodulatory compound(s) and / or material(s) described herein is at least 5 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing the immunomodulatory compound(s) and / or material(s) described herein is up to 10 times, up to 20 times, up to 25 times, up to 30 times, up to 50 times, up to 75 times, or up to 100 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / ormaterial(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL-10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing the immunomodulatory compound(s) and / or material(s) described herein is up to 10 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro- inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL-10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing the immunomodulatory compound(s) and / or material(s) described herein is up to 20 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing the immunomodulatory compound(s) and / or material(s) described herein is up to 25 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL-10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing the immunomodulatory compound(s) and / or material(s) described herein is up to 30 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro- inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL-10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing the immunomodulatory compound(s) and / or material(s) described herein is up to 50 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) to thetotal amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing the immunomodulatory compound(s) and / or material(s) described herein is up to 75 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro-inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. In some embodiments, a ratio of the total amount of anti-inflammatory cytokines (e.g., IL-10) to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing the immunomodulatory compound(s) and / or material(s) described herein is up to 100 times the ratio of the total amount of anti-inflammatory cytokines to the total amount of pro- inflammatory cytokines generated per macrophage in the presence of a macroencapsulation device without the immunomodulatory compound(s) and / or material(s), under otherwise identical conditions. Combinations of the above-referenced ranges are possible (e.g., at least 1.05 times and up to 100 times, at least 1.1 times and up to 30 times, at least 1.1 times and up to 40 times, at least 2 times and up to 25 times, or at least 6 times and up to 20 times). Other ranges are also possible.

[0078] The ratio of the total amount of anti-inflammatory cytokines (e.g., IL- 10) relative to the total amount of pro-inflammatory cytokines (e.g., IL-ip) generated by macrophages can be measured using the following method. Macrophages (e.g., monocyte, M0 macrophage, or Ml macrophages) can be treated with an immunomodulatory compound or material described herein, for a period of 6 days and compared to an otherwise identical control sample without the immunomodulatory compound. To determine IL-ip generated per cell and IL- 10 generated per cell for each of the treated sample and the control, the amount of IL-ip and IL- 10 generated by the macrophages in the treated sample and the control may be measured, for example, using ELISA and normalized respectively by the measured cell viability (e.g., number of alive cells) in the corresponding treated and control sample. Cell viability of M0 macrophages can be measured, for example, by using CellTiterGlo Luminescent Cell Viability Assay kit. A ratio of the amount of IL-ip to the amount of IL- 10 per macrophage can be then calculated for each of the treated sample and the control by dividing the amount IL-ip generated per cell by the amount of IL- 10 generated per cell for the respective sample.

[0079] In some embodiments, the use of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be associated with reduced generation of pro-inflammatory cytokines (e.g., IL-ip) compared to a macroencapsulation device without the immunomodulatory compound and / or material. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of amacroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 10%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. For example, in some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 10% less than the amount of pro- inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro -inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 20% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 30% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 50% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 60% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 70% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / ormaterial described herein. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 80% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 90% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be at least 95% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, up to 95%, or up to 99% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro -inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be up to 50% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro -inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be up to 60% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro -inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be up to 70% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence ofmacroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro -inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be up to 80% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro -inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be up to 90% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro -inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be up to 95% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. In some embodiments, the amount of pro -inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be up to 99% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. Combinations of the above-referenced ranges are possible (e.g., at least 10% and up to 99%, at least 20% and up to 95%, at least 30% and up to 80%, at least 50% and up to 99%, or at least 60% and up to 95%). Other ranges are also possible. For example, in some embodiments, the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of a macroencapsulation device containing an immunomodulatory compound and / or material described herein may be between 10-99%, 10-95%, 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-30%, 10-20%, 20-99%, 20-95%, 20-90%, 20-80%, 20-70%, 20-60%, 20-50%, 20- 30%, 30-90%, 30-95%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 50-99%, 50-95%, 50-90%, 50-80%, 50-70%, 50-60%, 60-99%, 60-95%, 60-90%, 60-80%, 60-70%, 70-99%, 70-95%, 70- 90%, 70-80%, 80-99%, 80-95%, or 90-99% less than the amount of pro-inflammatory cytokines (e.g., IL-ip) generated per macrophage in the presence of macroencapsulation device without the immunomodulatory compound and / or material described herein. The amount of pro- inflammatory cytokines generated per macrophage cell (e.g., IL-ip per cell) may be determined using a method described elsewhere herein.

[0080] The macroencapsulation devices disclosed herein may use any appropriate type of membranes and may have any appropriate type of construction for containing a population of cells for delivering a desired therapeutic compound to a subject. In addition to retaining a population of cells within an interior of a device, in some embodiments, the membranes of a device may be configured to protect the one or more populations of cells disposed in an interior of the device from an immune attack while permitting the passage of a desired biological product, such as insulin, produced by the cells as well as waste and nutrients used and produced by the cells across the semipermeable portions of the membranes. In some embodiments, the membranes are configured to protect the cells from an immune attack in the absence of an immune suppression therapy.

[0081] The membranes of a macroencapsulation device may be formed from any appropriate biocompatible material. The biocompatible material may be substantially inert towards cells housed within the macroencapsulation device and the surrounding tissue. The biocompatible material may comprise a synthetic polymer or a naturally occurring polymer. In some embodiments, the polymer may also be a linear polymer, a cross linked polymer, a network polymer, an addition polymer, a condensation polymer, an elastomer, a fibrous polymer, a thermoplastic polymer, a non-degradable polymer, combinations of the foregoing, and / or any other appropriate type of polymer as the disclosure is not limited in this fashion. Appropriate types of polymers may comprise polyvinylchloride (PVC), polyethylene (PE), polypropylene (PP), poly methylmetacry late (PMMA), polystyrene (PS), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polyurethane (PU), polyamide (nylon), polyethylenterephthalate (PET), polyethersulfone (PES), polyetherimide (PEI), polyvinylidene difluoride (PVDF), Polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), poly-L- lactide (PLLA), any combination of the foregoing, and / or any other appropriate polymeric material. The synthesis methods used for forming one or more of the porous membranes from the above noted polymeric materials may include, but are not limited to, expansion, solventcasting, immersion precipitation and phase separation, electrospinning, methods that yield isoreticular networks, methods that yield trabecular networks, or any other appropriate method of forming a porous polymer membrane.

[0082] Sintering of a membrane may be used to alter the porosity and flux properties of a membrane. For example, the sintering may increase the porosity of the membrane while maintaining its pore structure. The sintering may also improve the mechanical stability and diffusive flux of the membrane. Thus, sintering may be used to alter the porosity and / or mechanical properties of the membranes, which in turn can be used to tune the porosity and the flux properties of the macroencapsulation device. Accordingly, in some embodiments, anydesired combination of sintered and / or unsintered membranes may be used. For instance, two exterior membranes of a device may be bonded together where either a sintered and unsintered membrane are bonded together, two sintered membranes are bonded together, or two unsintered membranes are bonded together. Further, any number of intermediate membranes positioned between these exterior membranes may be used where these intermediate membranes may be sintered or unsintered.

[0083] The membranes of a macroencapsulation device as described herein may be made from porous membrane materials that are configured to allow for transport through the membranes of materials, such as a therapeutic or biological product, with a molecular weight less than about 3000 kDa, 2000 kDa, 1000 kDa, 500 kDa, 400 kDa, 300 kDa, 200 kDa, 100 kDa, 50 kDa, 40 kDa, 30 kDa, 20 kDa, 10 kDa, 6 kDa, 5 kDa, 4 kDa, 3 kDa, 2 kDa, 1 kDa, and / or any other appropriate range of molecular weights depending on the desired application.Combinations of the above-referenced ranges are possible (e.g., at least 1 kDa and less than about equal to 3000 kDa). Other ranges are also possible. The membranes of a macroencapsulation device as described herein may be made from porous membrane materials that are configured to allow for transport through the membranes of materials, such as a biological product, only within the molecular weight range of 1-3000 kDa, 1-2000 kDa, 1-1000 kDa, 1-500 kDa, 1-400 kDa, 1-300 kDa, 1-200 kDa, 1-100 kDa, 1-50 kDa, 1-40 kDa, 1-30 kDa, 1-20 kDa, 1-10 kDa, 1-6 kDa, 1-5 kDa, 1-4 kDa, 1-3 kDa, or 1-2 kDa. For example, the one or more membranes of a macroencapsulation device may be configured to permit the flow of insulin through the membranes which has a molecular weight of about 5.8 kDa. In some embodiments, the one or more membranes of a macroencapsulation device may be configured to permit the flow of materials, such as a biological product, only within the range of 1-10 kDa. In some embodiments, the one or more membranes of a macroencapsulation device may be configured to permit the flow of materials, such as a biological product, only within the range of 1-6 kDa. In some embodiments, the one or more membranes of a macroencapsulation device may be configured to permit the flow of materials, such as a biological product, only within the range of 1-5 kDa. In some embodiments, the one or more membranes of a macroencapsulation device may be configured to permit the flow of materials, such as a biological product, only within the range of 1-4 kDa. In some embodiments, the one or more membranes of a macroencapsulation device may be configured to permit the flow of materials, such as a biological product, only within the range of 1-3 kDa. In some embodiments, the one or more membranes of a macroencapsulation device may be configured to permit the flow of materials, such as a biological product, only within the range of 1-2 kDa. For example, the one or more membranes of a macroencapsulation device may be configured to permit the flow of insulinthrough the membranes which has a molecular weight of about 5.8 kDa. Additionally, the pores of the membranes may be sized to allow for transport of one or more immunomodulatory compounds through the membrane of materials.

[0084] To provide the desired selectivity, the porous membranes used with the macroencapsulation devices disclosed herein may have an open porous structure with average pore sizes that are greater than or equal to about 1 nm, 5 nm, 10 nm, 15 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60nm, 70 nm, 80 nm, 90 nm, 100 nm, 200 nm, 300 nm, and / or any other appropriate size range. Correspondingly, the average pore size of the various membranes described herein may have an average pore size that is less than or equal to 2500 nm, 2000 nm, 1700 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, and / or any other appropriate size range. Combinations of the foregoing are contemplated including, for example, an average pore size that is between or equal to 1 nm and 20 nm, 1 nm and 2500 nm, 50 nm and 1200 nm, and / or any other appropriate combination. In some embodiments, the average pore size of the various membranes described herein is between 25 nm and 1500 nm. In some embodiments, the average pore size of the various membranes described herein is between 50 nm and 1200 nm. In some embodiments, the average pore size of the various membranes described herein is between 50 nm and 1000 nm. In some embodiments, the average pore size has an upper size limit of 1500 nm. In some embodiments, the average pore size has an upper size limit of 1200 nm. In some embodiments, the average pore size has a lower size limit of 25 nm. In some embodiments, the average pore size has a lower size limit of about 50 nm. While specific average pore sizes are described above, it should be understood that any appropriate average pore size may be used for the various membranes described herein including average pore sizes both greater than and less than those noted above.

[0085] To provide sufficient strength and / or rigidity for a macroencapsulation device, the various membranes and frames may be made from materials that are sufficiently stiff. The desired stiffness may be provided via an appropriate combination of a materials Young’s modulus, thickness, and overall construction which may be balanced with a desired permeability of the device. Appropriate Young’s moduli for the various membranes and frames described herein may be at least 105Pa, 106Pa, 107Pa, 108Pa, 109Pa, 1010Pa, and / or any other appropriate moduli both greater than and less than these ranges. Of course ranges between the foregoing Young’s moduli are contemplated including, for example, a Young’s modulus between or equal to about 106Pa and 1010Pa.

[0086] In some embodiments, it may be desirable for one or more of the membranes included within a macroencapsulation device to be hydrophilic to facilitate loading of cells intothe macroencapsulation device and / or to facilitate the flow of one or more fluids, biological compounds, therapeutics, cell nutrients, cell waste, and / or other materials through the membranes of a device. Additionally, a hydrophilic outer membrane may also reduce the occurrence of fibrosis when the device is positioned in vivo. Accordingly, the membranes of a macroencapsulation device may either be made from a hydrophilic material and / or treated with a hydrophilic coating. Appropriate hydrophilic materials may include, but are not limited to an appropriate hydrophilic polymer, polyethylene glycol, polyvinyl alcohol, polydopanine, any combination thereof, and / or any other appropriate hydrophilic material capable of forming a coating on the membranes or that the membranes may be made from.

[0087] The membranes described in the various embodiments of macroencapsulation devices described herein may be bonded to one another using any appropriate bonding method as the disclosure is not limited in this fashion. For example, adjacent membranes may be bonded to one another using an adhesive, an epoxy, a weld or other fusion based technique (e.g. ultrasonic bonding, laser bonding, physical bonding, thermal bonding, etc.), mechanical clamping using a frame or fixture, and / or any other appropriate bonding method. In one specific embodiment, adjacent membranes may be bonded using a heated tool that is used to press or strike two or more membranes against each other for a set fusion time with a predetermined pressure and / or force. In view of the above, it should be understood that the current disclosure is not limited to the use of any particular method for bonding the membranes together.

[0088] In certain embodiments, it may be desirable to limit a maximum thickness of a macroencapsulation device in a direction perpendicular to a plane in which a maximum transverse dimension of the device lies. Accordingly, one or more interior portions of first and second membranes disposed within a frame may be bonded together to limit the extent to which the membranes may be displaced relative to one another. These bonded portions of the membranes may be dispersed uniformly within the interior portion of the membranes located within the frame. These bonded portions may have any appropriate shape including, for example, dots, lines, curves, or any other appropriate shape. While the bonded interior portions may have any appropriate size for a desired application, in one embodiment using bonded dots, the diameter of the bonded dots may be greater than or equal to about 0.5 mm, 0.75 mm, 1 mm, 1.25 mm, 1.5mm, and / or any other appropriate diameter. Correspondingly, the diameter of the dots may be less than or equal to about 3 mm, 2.75 mm, 2.5 mm, 2.25 mm, 2.0 mm, and / or any other appropriate diameter. Combinations of the above noted ranges are contemplated including, for example, a diameter that is between or equal to 0.5 mm and 3 mm. While specific shapes and size ranges are provided above, it should be understood that other shapes and sizes both smallerand greater than those noted above are contemplated as the disclosure is not limited in this fashion.

[0089] In some embodiments, it may be desirable to improve the vascularization of a macroencapsulation device. Accordingly, in certain embodiments, one or more through holes may be formed in the one or more bonded portions located within an interior portion of the membranes disposed radially inwards from a frame of the device. These through holes may permit vasculature to growth through the through holes in addition to growing around the upper and lower surfaces of the device. The one or more through holes may be formed in the bonded portions of the membranes using laser ablation, mechanical puncture, cutting, or any other appropriate method of forming a through hole in the one or more bonded portions of the membranes.

[0090] In some embodiments, the internal volume formed between the first membrane layer and the second membrane layer comprises a plurality of channels. As elaborated on below, in some embodiments, one or more portions of adjacent membranes may be bonded together such that the interior volume within the device is subdivided into a plurality of interconnected channels, which in some embodiments may be shaped like a lumen though any appropriate shape or configuration of the channels may also be used. The channels may have an inner maximum transverse dimension, such as an inner diameter, that is greater than or equal to 40 pm, 50 pm, 100 pm, 200 pm, 300 pm, 400 pm, and / or any other appropriate dimension. Correspondingly, the channels may have an inner maximum transverse dimension that is less than or equal to 800 pm, 700 pm, 600 pm, 500 pm, 400 pm, and / or any other appropriate dimension. Combinations of the foregoing are contemplated including, for example, an inner maximum transverse dimension of the plurality of channels that is between or equal to 40 pm and 800 pm, 40 pm and 100 pm, 100 pm and 200 pm, 200 pm and 400 pm, 400 pm and 500 pm, 500 pm and 600 pm, 600 pm and 800 pm, etc. Further, a density of the interconnected channels forming the various compartments of a device may have a density per unity area within a transverse plane of the device that is be greater than or equal to about 10 channels / cm2, 15 channels / cm2, 20 channels / cm2, 25 channels / cm2, 30 channels / cm2, 35 channels / cm2, 40 channels / cm2, 45 channels / cm2, 50 channels / cm2, 60 channels / cm2, 70 channels / cm2, 80 channels / cm2, 90 channels / cm2, 100 channels / cm2, 110 channels / cm2, 120 channels / cm2, 130 channels / cm2, 140 channels / cm2, 150 channels / cm2, 175 channels / cm2, or 200 channels / cm2. Ranges extending between any of the above noted density of channels are also contemplated including, for example, a density of channels that is between or equal to about 10 channels / cm2and 200 channels / cm2, 10 channels / cm2and 50 channels / cm2, 50 channels / cm2and 100 channels / cm2,100 channels / cm2and 150 channels / cm2, or 150 channels / cm2and 200 channels / cm2. Though densities both greater than and less than the ranges described above are also contemplated.

[0091] A macroencapsulation device as described herein may have any appropriate combination of internal volumes, external dimensions, and / or other appropriate physical parameter. For example, an internal volume encompassed by the outer membranes of a macroencapsulation device may be between or equal to 40 pL and 250 pL, 40 pL and 100 pL, or 100 pL and 250 pL. A width, or maximum transverse dimension, of the macroencapsulation device may also be between about 20 mm and 80 mm. Additionally, to provide a desired diffusion of oxygen into the interior of a macroencapsulation device to support cells contained therein, a maximum oxygen diffusion distance from an exterior of the device to an interior portion of the device including a population of cells may be less than 50 pm, 100 pm, 150 pm, 200 pm, 250 pm, 300 pm, 350 pm, 400 pm, 450 pm, or 500 pm. Correspondingly, a maximum thickness, or dimension perpendicular to a maximum transverse dimension, of the overall device and / or an internal volume located within the device may be less than 50 pm, 100 pm, 150 pm, 200 pm, 250 pm, 300 pm, 350 pm, 400 pm, 450 pm, or 500 pm.

[0092] Further, in some embodiments, an outer surface area to volume ratio of the device may be greater than or equal to about 20 cm'1, 40 cm'1, 50 cm'1, 60 cm'1, 80 cm'1, 100 cm'1, 120 cm'1, 150 cm'1, 200 cm'1, 300 cm'1, 400 cm'1, 500 cm'1, 600 cm'1, 700 cm'1, 800 cm'1, 900 cm'1, or 1000 cm'1. In some embodiments, an outer surface area to volume ratio of the device may be between 25 cm'1and 1250 cm'1. In some embodiments, an outer surface area to volume ratio of the device may be between 50 cm'1and 1000 cm'1. In some embodiments, an outer surface area to volume ratio of the device may be between 100 cm'1and 500 cm'1. Ranges extending between any of the forgoing values for the various dimensions and parameters as well as ranges both greater than and less those noted above are also contemplated.

[0093] While specific dimensions, parameters, and relationships related to the macroencapsulation device and the materials it is made from are described above, it should be understood that dimensions, parameters, and relationships both greater than and less than those noted above are contemplated as the disclosure is not limited in this fashion. Accordingly, any appropriate combination of size, construction, material properties, and / or relative performance parameters may be used for a device depending on the desired application.

[0094] In some embodiments, a macroencapsulation device may include at least one population of cells disposed within an internal volume of the device. For example, the population of cells may be disposed within an internal volume formed between two or more opposing exterior membrane layers of the device where an exterior edge of the internal volume may be defined by one or more bonds extended around a perimeter of the membranes or otherappropriate portion of the membranes. In such an embodiment, at least the exterior membranes of the device may be configured to block passage of the one or more populations of cells out of the device. Accordingly, the one or more populations of cells may be retained within the interior volume of the device. Of course, while the use of two exterior membrane layers forming a single internal volume is noted, the use of multiple intermediate membranes positioned between the exterior membranes of a device and / or multiple unconnected interior volumes within a device are also contemplated.

[0095] As noted above, in some embodiments, the methods and systems disclosed herein may be used to diffuse a therapeutic composition across at least one membrane layer of a macroencapsulation device that at least partially encapsulates a population of cells. For example, upon implantation of the macroencapsulation device containing the population cells to a site of implantation, a therapeutic composition (e.g., a biological product) may be produced by the encapsulated population of cells. Accordingly, the therapeutic composition may diffuse across the first membrane layer and / or the second membrane layer. The membrane layers, as described in more detail below, may be configured to prevent the population of cells from passing through the membrane layer(s) while permitting diffusion of the therapeutic composition across the membrane layer(s). The population of cells may be any of a variety of cells described elsewhere herein, such as insulin producing cells. The therapeutic agent may be any of a variety of therapeutic agents described herein, such as insulin. The therapeutic composition may diffuse across at any of a variety of appropriate diffusion rates, depending on the molecular weight of the therapeutic composition and / or membrane properties (e.g., pore size, thickness, etc.). In some embodiments, sustained release of the therapeutic composition can be achieved using the devices and methods described herein. For example, the therapeutic composition may be released to the tissues at the site of implantation over a prolonged period of time, such as at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, or more, and / or up to 52 weeks, up to 40 weeks, up to 30 weeks, up to 20 weeks, or any other appropriate time period. Combinations of the above-referenced ranges are possible (e.g., at least 1 week and up to 52 weeks). In some embodiments, the therapeutic composition may be released to the tissues at the site of implantation over at least 2 weeks. In some embodiments, the therapeutic composition may be released to the tissues at the site of implantation over at least 4 weeks. In some embodiments, the therapeutic composition may be released to the tissues at the site of implantation over at least 6 weeks. In some embodiments, the therapeutic composition may be released to the tissues at the site of implantation for greater than 52 weeks. Other ranges are also possible.

[0096] In some embodiments, the cell population contained within an interior volume of a macroencapsulation device may be an insulin secreting cell population. In some embodiments, the cell population comprises at least one cell derived from a stem cell derived cell. In some embodiments, at least one cell is a genetically modified cell. In some cases, at least one cell is genetically engineered to reduce an immune response in a subject upon implantation of the device, as compared to comparable cells that are not genetically engineered. In some embodiments, the cell population is a stem cell derived cell that is capable of glucose-stimulated insulin secretion (GSIS). For example, an appropriate population of cells may comprise pancreatic progenitor cells, endocrine cells, beta cells, alpha cells, delta cells, a matrix including one or more of the foregoing, or any combination thereof. Further, a matrix may comprise isolated islet cells, isolated cells from pancreas, isolated cells from a tissue, stem cells, stem cell- derived cells, induced pluripotent cells, differentiated cells, transformed cells, or expression systems, which can synthesize one or more biological products. Optionally, in some embodiments, the matrix may comprise a second type of cells that support the first type of cells that synthesize one or more biological products. In some embodiments, the cells may be encapsulated before being placed within the matrix. In such an embodiment, the cells may be encapsulated in a microcapsule or may be conformally coated. However, naked, i.e. uncoated, cells may also be used. Of course, other types of cells may be used with the disclosed immunomodulatory compounds and macroencapsulation devices disclosed herein as the disclosure is not limited to any particular cell type.

[0097] In some embodiments, the disclosure provides for a composition comprising a population of cells and any one or more of the immunomodulatory compounds disclosed herein. In some embodiments, at least 30% of the cells in the cell population are NKX6.1-positive, ISL1 positive. In some embodiments, at least 20% of the cells in the cell population are NKX6.1- negative, ISL1 positive. In some embodiments, less than 25% of the cells in the cell population are NKX6.1-positive, ISL1 negative. In some embodiments, less than 10% of the cells in the population are NKX6.1 -negative, ISL1 negative. In some embodiments, 20-50%, 20-45%, 20- 40%, 20-35%, 20-30%, 20-25%, 25-50%, 25-45%, 25-40%, 25-35%, 25-30%, 30-50%, 30-45%, 30-40%, 30-35%, 35-50%, 35-45%, 35-40%, 40-50%, 40-45% or 45-50% of the cells in the population are NKX6.1-positive, ISL1 positive. In some embodiments, 15-50%, 15-40%, 15- 30%, 15-25%, 20-50%, 20-45%, 20-40%, 20-35%, 20-30%, 20-25%, 25-50%, 25-45%, 25-40%, 25-35%, 25-30%, 30-50%, 30-45%, 30-40%, 30-35%, 35-50%, 35-45%, 35-40%, 40-50%, 40- 45% or 45-50% of the cells in the population are NKX6.1 -negative, ISLl-positive. In some embodiments, 1-25%, 1-15%, 1-8%, 2-25%, 2-15%, 2-8%, 3-25%, 3-15%, 3-8%, 6-25%, 6-15%, 6-10%, 9-25%, 9-15%, 15-25%, or 20-30% of the cells in the population are NKX6.1-positive,ISLl-negative. In some embodiments, 1-10%, 1-8%, 1-5%, 1-3%, 3-10%, 3-8%, 5-10%, 5-8%, 10-15%, or 0.5-1% of the cells in the population are NKX6.1 -negative, ISLl-negative. In some embodiments, 20-50%, 20-45%, 20-40%, 20-35%, 20-30%, 20-25%, 25-50%, 25-45%, 25-40%, 25-35%, 25-30%, 30-50%, 30-45%, 30-40%, 30-35%, 35-50%, 35-45%, 35-40%, 40-50%, 40- 45% or 45-50% of the cells in the population express insulin. In some embodiments, 15-50%, 15-40%, 15-30%, 15-25%, 20-50%, 20-45%, 20-40%, 20-35%, 20-30%, 20-25%, 25-50%, 25- 45%, 25-40%, 25-35%, 25-30%, 30-50%, 30-45%, 30-40%, 30-35%, 35-50%, 35-45%, 35-40%, 40-50%, 40-45% or 45-50% of the cells in the population express glucagon.

[0001] In some embodiments, the disclosure provides for a composition comprising a population of stem cell-derived P cell and any one or more of the immunomodulatory compounds disclosed herein. The terms “stem cell-derived P cell,” “SC-P cell,” “functional P cell,” “functional pancreatic P cell,” “mature SC-P cell,” and their grammatical equivalents can refer to cells (e.g., non-native pancreatic P cells) that display at least one marker indicative of a pancreatic P cell (e.g., PDX-1 or NKX6.1) and expresses insulin. In some embodiments, the SC- P cells display a glucose stimulated insulin secretion (GSIS) response characteristic of an endogenous mature P cell. In some embodiments, the terms “SC-P cell” and “non-native P cell” as used herein are interchangeable. In some embodiments, the “SC-P cell” comprises a mature pancreatic cell. It is to be understood that the SC-P cells need not be derived (e.g., directly) from stem cells. Examples of detailed protocols of generating endocrine cells from stem cells to provide at least one SC-islet cell (e.g., SC-beta cell) are described in U.S. Patent Application Publication Nos. US20150240212, US20150218522, US20210198632, and US 20220090020, PCT Publications WO2022 / 147056 and W02022192300, and US Patent No. 11,466,256, each of which is herein incorporated by reference in its entirety. Additional methods of making SC-P cells include, for example, US Patent No. 10,030,229; US Patent No. 10,443,042; US Patent No. 11,466,256, published applications US 20200332262 US20150240212, US20150218522, US20210198632, and US 20220090020; and PCT Publications WO2022 / 147056 and WO2022192300, each of which is incorporated by reference in its entirety.

[0002] In some embodiments, the cells express one or more P cell markers. The term “P cell marker” refers to, without limitation, proteins, peptides, nucleic acids, polymorphism of proteins and nucleic acids, splice variants, fragments of proteins or nucleic acids, elements, and other analytes which are specifically expressed or present in pancreatic P cells. Exemplary P cell markers may include, but are not limited to, pancreatic and duodenal homeobox 1 (PDX1) polypeptide, insulin, c-peptide, amylin, E-cadherin, Hnf3p, PC 1 / 3, B2, Nkx2.2, GLUT2, PC2, ZnT-8, ISL1, Pax6, Pax4, NeuroD, 1 Inf lb, Hnf-6, Hnf-3beta, and MafA, and those described in Zhang et al., Diabetes. 50(10):2231-6 (2001). In some embodiment, the P cell marker is anuclear P-cell marker. In some embodiments, the P cell marker is PDX1 or PH3. In some embodiments, the population of cells comprises non-native cells expressing C-peptide and ISL1

[0003] In some embodiments, the SC-P cells exhibit a response to multiple glucose challenges (e.g., at least one, at least two, or at least three or more sequential glucose challenges). In some embodiments, the response resembles the response of endogenous islets (e.g., human islets) to multiple glucose challenges. In some embodiments, the morphology of the SC-P cell resembles the morphology of an endogenous P cell. In some embodiments, the SC-P cell exhibits an in vitro GSIS response that resembles the GSIS response of an endogenous P cell. In some embodiments, the SC-P cell exhibits an in vivo GSIS response that resembles the GSIS response of an endogenous P cell. In some embodiments, the SC-P cell exhibits both an in vitro and in vivo GSIS response that resembles the GSIS response of an endogenous P cell. In some embodiments, the GSIS response of composition comprising a population of stem cell-derived P cell and any one or more of the immunomodulatory compounds disclosed herein can be observed within two weeks of transplantation of the SC-P cell into a host (e.g., a human or animal). In some embodiments, the SC-P cells package insulin into secretory granules. In some embodiments, the SC-P cells exhibit encapsulated crystalline insulin granules. In some embodiments, the SC-P cells exhibit cytokine-induced apoptosis in response to cytokines. In some embodiments, insulin secretion from the SC-P cells is enhanced in response to known antidiabetic drugs (e.g., secretagogues). In some embodiments, the SC-P cells are monohormonal. In some embodiments, the SC-P cells do not abnormally co-express other hormones, such as glucagon, somatostatin or pancreatic polypeptide. In some embodiments, the SC-P cells exhibit a low rate of replication. In some embodiments, the SC-P cells increase intracellular Ca2+ in response to glucose. In some embodiments, the SC-P cells express lower levels of MAFA than P cells from the pancreas of a healthy control adult subject. In some embodiments, the SC-P cells express higher levels of MAFB than P cells from the pancreas of a healthy control adult subject. In some embodiments, the SC-P cells express higher levels of SIX2, HOPX, IAPP and / or UCN3 than P cells from the pancreas of a healthy control adult subject. In some embodiments, the SC-P cells do not express MAFA. In some embodiments, the SC-P cells express MAFB. In some embodiments, any of the cell markers disclosed herein (e.g., MAFA, MAFB, SIX2, HOPX, IAPP and / or UCN3) are detected by flow cytometry.

[0098] In some embodiments, any of the cells disclosed herein comprise a genomic disruption in at least one gene sequence, wherein said disruption reduces or eliminates expression of a protein encoded by said gene sequence. In some embodiments, said at least one gene sequence is the ABO sequence, such that the disruption results in the cell being blood type O. In some embodiments, said at least one gene sequence encodes an MHC-Class I gene. Insome embodiments, said MHC-Class I gene encodes beta-2 microglobulin (B2M), HLA-A, HLA-B, or HLA-C. In some embodiments, said at least one gene sequence encodes CIITA. In some embodiments, the cells comprise a genomic disruption in the genes encoding HLA-A and HLA-B, but do not comprise a genomic disruption in the gene encoding HLA-C. In some embodiments, the cells comprise a genomic disruption in the gene encoding CXCL10. In some embodiments, the cells comprise a genomic disruption in the gene encoding renalase. In some embodiments, said cells comprise a genomic disruption in a natural killer cell activating ligand gene. In some embodiments, said natural killer cell activating ligand gene encodes intercellular adhesion molecule 1 (ICAM1), CD58, CD 155, carcinoembryonic antigen- related cell adhesion molecule 1 (CEACAM1), cell adhesion molecule 1 (CADM1), MHC-Class I polypeptide-related sequence A (MICA), or MHC-Class I polypeptide-related sequence B (MICB). In some embodiments, the cells have reduced expression of one or more of beta-2 microglobulin, CIITA, HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, and HLADR, relative to cells that are not genetically modified. In some embodiments, the cells have increased expression of CD47, PDL1, HLA-G, CD46, CD55, CD59, CTLA, PDL2, HLA-C, HLA-E, HLA-G, Cl-inhibitor, IL- 35, DUX4, IDO1, IL10, CCL21, CCL22, CD16, CD52, H2-M3, CD200, FASLG, MFGE8, and / or SERPINB9 relative to cells that are not genetically modified. In particular embodiments, the cells disclosed herein (e.g., the NKX6.1-positive, ISLl-positive cells) have increased expression of PDL1 as compared to endogenous pancreatic islet cells from a healthy control subject. In particular embodiments, the pancreatic islet cells disclosed herein (e.g., the SC-beta cells) have increased expression of CD47 as compared to endogenous pancreatic islet cells from a healthy control subject. In some embodiments, the genomic disruption is induced by use of a gene editing system, e.g., CRISPR Cas technology. In some embodiments, any of the isolated cells (e.g., a NKX6.1-positive, ISLl-positive cell) described herein comprises a disruption (e.g., deletion, insertion, translocation, inversion, or substitution of one or more nucleotides) in any one or more of the genes encoding: B2M, CIITA, CXCL10, renalase, HLA-A, HLA-B, HLA-C, RFX-ANK, NFY-A, NLRC5, RFX5, RFX-AP, HLA-G, HLA-E, NFY-B, PD-L1, NFY-C, IRF1, TAPI, GITR, 4-1BB, CD28, B7-1, CD47, B7-2, 0X40, CD27, HVEM, SLAM, CD226, ICOS, LAG3, TIGIT, TIM3, CD160, BTLA, CD244, LFA-1, ST2, HLA-F, CD30, B7-H3, VISTA, TLT, PD-L2, CD58, CD2, HELIOS, IDO1, TRAC, TRB, NFY-A, CCR5, F3, CD142, MICA, MICB, LRP1, HMGB1, ABO, RHD, FUT1, KDM5D, PDGFRa, OLIG2, and / or GFAP. In some embodiments, disruption of a gene results in an at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% decrease in expression of the gene as compared to the expression of the gene in the same type of cell without the disruption. In some embodiments, the gene is disrupted using CRISPR / Cas, piggybac transposon, TALEN, and / or zinc finger technology. In someembodiment, the gene is disrupted heterozygously in the cell. In other embodiments, the gene is disrupted homozygously in the cell.

[0099] In some embodiments, a cell (e.g., an isolated stem cell or a NKX6.1-positive,ISLl-positive cell) described herein is negative for A antigen and negative for B antigen. In some embodiments, the cell described herein is negative for A antigen. In some embodiments, the cell described herein is negative for B antigen. In some embodiments, a cell (e.g., a NKX6.1-positive, ISLl-positive cell) described herein is negative for Rh antigen. In some embodiments, a cell (e.g., an isolated stem cell or a NKX6.1-positive, ISLl-positive cell) described herein is negative for A antigen, negative for B antigen, and negative for Rh antigen. An “A antigen,” as used herein, refers to a histo-blood group antigen produced by 3a-N- acetylgalactosaminyltransferase and expressed as a cell-surface antigen. A “B antigen,” as used herein, refers to a histo-blood group antigen produced by 3a-galactosaminyltransferase and expressed as a cell-surface antigen. In some embodiments, the cell comprises a disruption in the ABO gene. In some embodiments, the cell comprises a disruption in the ABO gene such that the cell has reduced or absent levels of A and B antigens. In some embodiments, the cell comprises a disruption in the FUT1 gene. In some embodiments, the cell comprises a disruption in the FUT1 gene such that Galactoside 2-alpha-L-fucosyltransferase 1 expression is reduced or absent. An “Rh antigen,” as used herein, refers to a highly immunogenic antigen encoded by two highly polymorphic genes, RHD and RHCE. Rh antigen proteins are transmembrane proteins. In some embodiments, the cell comprises a disruption in the RHAG gene. In some embodiments, the cell comprises a disruption in the RHAG gene such that the cell has reduced or absent levels of Rh- associated glycoprotein. In some embodiments, the cell has a reduced or eliminated Rh protein antigen expression selected from the group consisting of Rh C antigen, Rh E antigen, Kell K antigen (KEL), Duffy (FY) Fya antigen, Duffy Fy3 antigen, Kidd (JK) Jkb antigen, MNS antigen U, and MNS antigen S.

[0100] In some embodiments, any of the cells disclosed herein (e.g., a NKX6.1- positive, ISLl-positive cell) comprises a “safety switch.” In some embodiments, the safety switches are nucleic acid constructs encoding a switch protein that inducibly causes cell death or stops cell proliferation. In some embodiments, the safety switch is inserted at a defined, specific target locus (e.g., a safe harbor locus) in the genome of an engineered cell, usually at both alleles of the target locus. In some embodiments, the target locus is a safe harbor locus, such as ActB or CLYBL. In some embodiments, the target locus is a gene targeted for disruption (e.g., B2M or CIITA). In some embodiments, the switch protein is activated by contacting with an effective dose of a clinically acceptable orthologous small molecule. In some embodiments, when activated, the safety switch causes the cell to stop proliferation, in some embodiments byactivating apoptosis of the cell. In some embodiments, the switch protein comprises herpes- simplex-thymidine-kinase. In some embodiments the switch protein comprises a human caspase protein, e.g. caspase 1, caspase 2, caspase 3, caspase 4, caspase 5, caspase 6, caspase 7, caspase8, caspase 9, caspase 10, caspase 14, etc. In certain embodiments the protein is human caspase9. In some embodiments, the caspase protein is fused to a sequence that provides for chemically induced dimerization (CID), in which dimerization occurs only in the presence of the orthologous activating agent. One or more CID domains may be fused to the caspase protein, e.g. two different CID domains may be fused to the caspase protein. In some embodiments the CID domain is a dimerization domain of FKBP or FRB (FKBP-rapamycin-binding) domain of mTOR, which are activated with rapamycin analogs. In some embodiments, the safety switch is any of the safety switches described in WO2021173449 and Jones et al., 2014, Frontiers in Pharmacology, 5(254): 1-8, each of which is incorporated herein in its entirety.

[0101] In some embodiments, the population further comprises a medium. In some embodiments, the medium comprises a sugar. In some embodiments, the sugar is sucrose or glucose. In some embodiments, the medium comprises the sugar at a concentration of between about 0.05% and about 1.5%. In some embodiments, the medium is a CMRL medium; or wherein the medium is HypoThermosol® FRS Preservation Media.

[0102] Depending on the particular embodiment, a therapeutically effective density of cells may be loaded into one or more compartments of a macroencapsulation device. Appropriate cell densities disposed within a compartment may be greater than or equal to about 1,000 cells / pL, 10,000 cells / pL, 50,000 cells / pL, 100,000 cells / pL, 500,000 cells / pL, 750,000 cells / pL, 1,000,000 cells / pL, and / or any other appropriate cell density. Appropriate cell densities disposed within the compartment may also be less than or equal to about 1,000,000 cells / pL, 500,000 cells / pL, 100,000 cells / pL, 50,000 cells / pL, 10,000 cells / pL, and / or any other appropriate cell density. Combinations of the foregoing are contemplated including cell densities between about 1000 cells / pL and 1,000,000 cells / pL. In some embodiments, cell densities disposed within the compartment is between 100,000 cells / pL and 1,000,000 cells / pL. In some embodiments, cell densities disposed within the compartment is between 75,000 cells / pL and 500,000 cells / pL. In some embodiments, cell densities disposed within the compartment is between 500,000 cells / pL and 1,000,000 cells / pL. In some embodiments, cell densities disposed within the compartment is between 750,000 cells / pL and 1,000,000 cells / pL. In some embodiments, cell densities disposed within the compartment is between 750,000 cells / pL and 1,250,000 cells / pL. Of course, cell densities both greater than and less than those noted above may also be used depending on the desired application and cell types being used.

[0103] The macroencapsulation devices described herein may be implanted in a subject in vivo at various sites. In one example, a device may be implanted in a subject by properitoneal or retrorectus implantation. In other examples, the device can be placed by intra-omental implantation. In another example, the device can be placed by subcutaneous implantation. In another example, the device can be placed by suprahepatic implantation. In some instances, the macroencapsulation devices described herein may be fixed in vivo at an implantation site using any appropriate fixation method including, for example, the application of a tissue adhesive. Appropriate tissue adhesives may include, but are not limited to, fibrin, cyanoacrylate, polyethylene glycol, albumin-based adhesive, polymer-based adhesive, and / or any other appropriate adhesive. In another example, the device may be fixed using platelet-rich plasma and / or any other appropriate fixation method as the disclosure is not limited in this fashion.

[0104] Turning to the figures, specific non-limiting embodiments are described in further detail. It should be understood that the various systems, components, features, and methods described relative to these embodiments may be used either individually and / or in any desired combination as the disclosure is not limited to only the specific embodiments described herein.

[0105] FIGS. 1A-1B depict one embodiment of a macroencapsulation device after the membranes have been mounted to a corresponding frame and prior to being filled with a desired material such as a population of cells. Specifically, as illustrated in the figures, the macroencapsulation device may include a first membrane 102, a second membrane 104, and a frame 220 that extends along at least a portion of the perimeter of the first and second membranes. The first and second membranes may either corresponding to adjacent layers of a single membrane that has been folded onto itself and / or the first and second membranes may be separate membranes as the disclosure is not limited in this fashion. The device is illustrated in an unfilled relaxed state where the extra surface area of the first and second membranes relative to the transverse cross-sectional area of the frame within which the membranes are mounted causes the bonded membranes to hang below the frame due to the resulting slack in the membranes. Due to the bonded portions 122 located within an interior region of the device, through holes 132, and other appropriate features having already been formed on the membranes, the macroencapsulation device may now be easily filled with a desired material, such as a population of cells, with minimal additional processing and handling. The interior volume may be filled using a port, an opening in the perimeter bond and / or any other appropriate method. In either case, after filling a macroencapsulation device with a desired material, the internal volume contained between the first and second membranes 102 and 104 may expand which may take up the slack in the membranes as the membranes are placed under tension in the filled configuration due to the internal volume between the membranes expanding. This may result in the first andsecond membranes being deformed such that the membranes generally extend in a direction that is approximately parallel to a plane of the frame 220, see FIG. 1C. Correspondingly, the first and second membranes may now extend outwards from opposing surfaces of the frame by approximately equal distance due to this increase in the internal volume of the now filled device. In instances where portions 132 of the membranes have been bonded together at a location located radially inwards from the frame, the expanded structure may again form a plurality of interconnected channels 126.

[0106] A macroencapsulation device may be filled using any appropriate filling method. For example, a population of cells, or other desired material, may be flowed into an interior volume of the macroencapsulation device formed between the outer membranes of the device. This may be accomplished through the use of a sealable or removable port extending into the interior volume and / or there may be an opening in the perimeter bond and / or frame of the macroencapsulation device that may be subsequently sealed. While any appropriate inlet to the interior volume may be used to flow material into the interior volume of the device, the flow of this material may be controlled in a number of different ways to provide the desired filling of the interior volume. For example, in one embodiment, a pressure applied to an interior volume of the macroencapsulation device may correspond to a desired amount of tension present in the membranes of the device in the filled configuration. Accordingly, filling of the device may continue until a predetermined pressure and / or membrane tension threshold has been reached. However, any appropriate method for controlling the amount of material flowed into the interior volume may also be used as the disclosure is not limited in this fashion. This may include, for example, control based on an absolute volume of material flowed into the interior volume, time duration for a given flow rate, and / or any other appropriate control method.

[0107] FIG. 2 illustrates a diagram of a macroencapsulation device that has been filled with a population of cells. Similar to the above described embodiments, the device may include a first membrane 102 and a second membrane 104 bonded along their perimeters to form an internal volume 250 between the membranes. The depicted device also includes bonded portions 124 with through holes 132 located within a central portion of the membranes disposed within a frame, not depicted. As shown, the internal volume 250 comprises a plurality of interconnected channels.

[0108] While specific embodiments of a macroencapsulation device have been illustrated in the figures, it should be understood that the various immunomodulatory compounds and materials disclosed herein may be used with any appropriate type of macroencapsulation device as the disclosure is not so limited.

[0109] FIG. 3 shows a flow diagram of a method for delivering a therapeutic composition produced by a population of cells. Upon implantation of the macroencapsulation device containing a population of cells to the implantation site, a therapeutic composition (e.g., a biological product) may be produced by the encapsulated population of cells. As illustrated by step 410, the therapeutic composition may diffuse across the first membrane layer and / or the second membrane layer to the surrounding tissues. The therapeutic composition may diffuse across at any of a variety of appropriate diffusion rates, depending on the molecular weight of the therapeutic composition and / or membrane properties (e.g., pore size, thickness, etc.). Prior to, during, or after the diffusion of the therapeutic composition across the at least one membranes, the immunomodulatory compound may be released to the tissues surrounding the macroencapsulation device, as illustrated by step 420. In embodiments in which the immunomodulatory material is disposed on the surface(s) and / or within the pores of one or more membrane layers, the immunomodulatory compound may be released from the surface(s) and / or the pores of the of the one or more membrane layers. Alternatively or additionally, in cases in which the immunomodulatory material or compound is immobilized to the one or more membrane layers via one or more linker molecules, the immunomodulatory compound may be released from the one or more membrane layers upon degradation of the one or more linker molecules. Alternatively or additionally, in cases where the immunomodulatory material or compound is directly applied to tissues at an area of implantation surrounding the one or more membrane layers, the immunomodulatory material or compound may be released upon deposition to the tissues. Next, as illustrated by step 430, upon release of the immunomodulatory material or compound to the tissues, the material or compounds may be exposed the surrounding tissues and induce a favorable foreign body response, such as a decrease in pro-inflammatory cytokines and / or an increase in the amount of anti-inflammatory cytokines relative to pro-inflammatory cytokines generated by the macrophages.

[0110] FIG. 4 shows a cross-sectional schematic of a macroencapsulation device including an internal volume and an immunomodulatory material associated with the one or more membrane layers according to some embodiments. In the depicted embodiment, device 300 comprises a first outer membrane 102, a second outer membrane 104, and an internal volume corresponding to an internal compartment 250 formed where the first outer membrane and the second membrane are bonded to one another around the periphery of the internal compartment. As shown in FIG. 4, one or more immunomodulatory compound 145 may be disposed in the device in any of a variety of appropriate fashions. For instance, the immunomodulatory compound may be disposed on a surface (e.g., an external surface) of the one or more membrane layers 102 / 104 as a surface coating 170 or 180. In some instances, theimmunomodulatory compound may be contained with a matrix 160 (e.g., a hydrogel matrix) and deposited onto membrane layer as surface coating 180. Alternatively, the immunomodulatory compound may be deposited onto membrane layer alone (without the matrix) as surface coating 170. In some cases, the immunomodulatory material or compound may be immobilized to the one or more membrane layers 102 and / or 104 and retained on or in a portion of the device via a linker molecule 150. Alternatively or additionally, the immunomodulatory material or compound included in the composition may be impregnated in the pores of the membranes (not depicted).

[0111] In another embodiment, an immunomodulatory material or compound may be disposed in the internal volume 250 of the macroencapsulation device. For example, the immunomodulatory material or compound may be disposed in the internal volume 250 by itself or along with a matrix 160 (e.g., polymer or hydrogel). In some cases, the immunomodulatory material or compound may be physically mixed with matrix 160. In some such cases, the immunomodulatory material or compound may be released via diffusion out of matrix 160. In other cases, the immunomodulatory material or compound may be immobilized to matrix 160. As mentioned previously, in some embodiments, matrix 160 may be a biodegradable material that may be used to release the immunomodulatory material or compound as the material degrades. It should be noted that different types of materials may be selected to tune the rate of degradation and modulate the rate of immunomodulatory material or compound release.

[0112] Alternatively or additionally, the immunomodulatory material may be disposed adjacent the one or more membrane layers, such as disposed external and adjacent to the first membrane layer 102 and / or the second membrane layer 104. For example, the immunomodulatory material 190 containing the compound (in matrix 160) may be applied to tissue surrounding the macroencapsulation device such that the immunomodulatory material and / or compound is disposed around at least a portion of macroencapsulation device.

[0113] Although not shown in FIG. 4, internal volume 250 may be configured to house a population of cells along with the noted one or more immunomodulatory material or compounds. Alternatively, the one or more immunomodulatory materials or compounds 145 may be immobilized to an interior surface, an exterior surface, and / or within the pores of the membrane layers enclosing the internal volume 140 that houses the population of cells.

[0114] It should be noted that although FIG. 4 shows a macroencapsulation device including a single internal volume with one or more immunomodulatory materials or compounds disposed in and / or immobilized to a portion of a macroencapsulation device, the disclosed methods, materials, and / or compounds may be used with any appropriate type of macroencapsulation device including any number of internal volumes, arrangement of one ormore semipermeable membranes, or other appropriate construction. Accordingly, it should be noted that any of the aforementioned embodiments relating to the one or more immunomodulatory materials or compounds shown in FIG. 4 and described elsewhere herein are also applicable to any of the other devices and methods disclosed herein as the disclosure is not limited to use with any particular construction of macroencapsulation device.

[0115] Example 1

[0116] Macrophages play a key role in the foreign body response (FBR). The classically activated macrophages (Ml) are pro-inflammatory while the alternatively activated macrophages (M2) are anti-inflammatory. This example illustrates that polarization of macrophages towards the M2 macrophage could attenuate the FBR and promote angiogenesis and vascularization. In this example, a panel of immunomodulatory compounds were tested to determine their effect on macrophage polarization, angiogenesis, and vascularization.

[0117] Naive macrophages (M0) were differentiated by treating human monocytes (THP- 1, ATCC® TIB202™) with phorbol 12-myristate 13-acetate (PMA, 200 nM) for 3 days. The effect of a panel of compounds on the macrophage polarization was tested by culturing the M0 macrophages with the compounds for 6 days. The secretion of interleukin (IL)-ip (pro- inflammatory cytokine) and IL- 10 (anti-inflammatory cytokine) was measured respectively using the enzyme-linked immunosorbent assay (ELISA).

[0118] Pro-inflammatory macrophages (Ml) were differentiated by treating M0 macrophages with 100 ng / mL lipopolysaccharide (LPS) and 100 ng / mL interferon-y (IFN-y) for 3 days. The effect of a panel of compounds on the macrophage polarization was tested by culturing the M0 with the compounds for 6 days. The secretion of IL-ip (pro-inflammatory cytokine) and IL- 10 (anti-inflammatory cytokine) was measured respectively using the enzyme- linked immunosorbent assay (ELISA).

[0119] M0 macrophages were treated with various compounds for 6 days. These compounds covered a wide range of inhibitors for diverse cell signaling pathways. As shown in FIG. 5, the panel of compounds tested included those belonging natural product (e.g., tannic acid, pentacyclic triterpene lupeol), CSF1R inhibitor (e.g., pexidartinib, edicotinib, GW2580, BLZ945), CCR2 inhibitor (e.g., PF-04136309), NF-kB inhibitor (e.g., sitagliptin), JAK inhibitor (e.g., ruxolitinib, baricitinib, tofacitinib), PDE4 inhibitor (e.g., roflumilast, apremilast), ROCK inhibitor (e.g., fasudil), NLRP3 inhibitor (e.g., glyburide, forskolin), a metabolite (e.g,. succinic acid, intaconate). As shown in FIG. 5, the concentration of all tested compounds was 1.0 pM except pexidartinib (0.25, 0.5 and 1.0 p M). For each treatment condition and the no drug control, cell viability of M0 was measured by using CellTiterGlo Luminescent Cell Viability Assay kit to show the cytotoxicity of the compounds. The amount of IL-ip and IL-10 for eachcompound treatment and the no drug control was normalized by the corresponding cell viability measured for the corresponding treatment condition or control. A ratio of normalized IL- 10 amount to normalized IL-ip amount was then calculated for each compound treatment and the no drug control (FIG. 5). The fold change in the ratio relative to the no drug control was calculated by dividing the ratio for each compound treatment with that of the no drug control.

[0120] As shown in FIG. 5, various compound exhibited higher ratios of IL-10 to IL-ip relative to the no drug control. In particular, a fold change in ratio of at least 4 was observed for tannic acid and pexidartinib. Tannic acid and pexidartinib decreased the IL-ip secretion and increased IL- 10 secretion, indicating the effect on the Ml macrophage downregulation and antiinflammatory macrophage (M2) upregulation. While tannic acid is a polyphenolic compound with redox scavenging and anti-inflammatory effects, and pexidartinib (PLX-3391) is the inhibitor of colony stimulating factor 1 receptor (CSF1R).

[0121] Moreover, the cytotoxicity of tested compounds on the macrophages was evaluated. The fold change in cell viability relative to the no drug control was calculated by dividing the cell viability of each compound treatment with that of no drug control. Pexidartinib and ruxolitinib at concentration of 1.0 pM exhibited cytotoxicity. However, the lower concentrations of pexidartinib (0.25 and 0.5 pM) maintained the cell viability at the same level of no drug control. All other compounds were not cytotoxic to the macrophages. In addition, tannic acid and pexidartinib showed high ratio of IL- 10 to IL-ip. All these data suggest that tannic acid (1 pM) and pexidartinib (0.25 and 0.5 pM) may be capable of inhibiting pro- inflammatory response of M0 macrophages.

[0122] As shown in FIGS. 6-7, M0 macrophages were treated with different compounds of various concentrations. These compounds included pexidartinib, tannic acid, gallic acid, rhein, curcumin, TAK242, and verteporfin. As shown in FIG. 6, pexidartinib (0.125 and 0.25 pM), tannic acid (0.25, 0.5 and 1.0 pM) and TAK242 (2.0 and 4.0 pM) decreased pro- inflammatory IL-ip production per cell, and the effect was dose dependent. On the other hand, rhein (4.0 pM) and curcumin (1.0 pM) increased IL-ip level. TAK242 is a toll-like receptor 4 (TLR4) and nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor. Furthermore, as shown in FIG. 7, MCC950 (0.25 to 8 pM) decreased IL-ip level but the effect was not dose dependent, which suggests a concentration of 0.25 pM may already have reached the threshold of effect level. MCC950 is a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor. As shown in FIGS. 5-7, pexidartinib (0.125 and 0.25 pM), tannic acid (0.25, 0.5 and 1.0 pM), TAK242 (2.0 and 4.0 pM) and MCC950 (0.25 to 8.0 pM) inhibited the secretion of IL-ip per cell, which may indicate a decrease in pro-inflammatory response of macrophages. Molecular structure of the above-referenced compounds are providedin FIGS. 8A-8D. As shown in FIGS. 8A-8D, both tannic acid and TAK242 are toll-like receptor 4 (TLR4) and nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitors, MCC950 is a NLRP3 inflammasome inhibitor, and pexidartinib is a CSF1R inhibitor.

[0123] Example 2

[0124] In this example, studies were performed to determine the effective in vivo dosage for a panel of immunomodulatory compounds capable of reducing pro-inflammatory macrophage response. First, the dose range that is able to inhibit pro-inflammatory macrophages was identified. Second, the identified dose range was assessed to exclude any dose that was (i) cytotoxic to islets (therapeutic cell product) and endothelial cells, as well as (ii) preventing endothelial network formation in vitro (which simulated the angiogenesis and vascularization in vivo). Finally, the selected dose range was tested for drug loading and delivery.

[0125] Dosage dependence of various compounds on inhibition of pro -inflammatory response

[0126] FIG. 9A-9B are graphs showing the fold change in IL-ip secreted by the M0 macrophage (FIG. 9A) or the Ml macrophage (FIG. 9B) at each compound condition with respect to a control (control of DMSO without any compound). As shown in FIGs. 9A-9B, the dose ranges of tannic acid, pexidartinib, TAK242 and MCC950 that are capable of inhibiting pro-inflammatory response of M0 and Ml macrophages were identified. For M0 macrophages, tannic acid was effective at 0.25, 0.5 and 1.0 pM, pexidartinib was effective at 0.0625, 0.125 and 0.25 pM, TAK242 was effective at 2.0 and 4.0 pM, and MCC950 was effective at 0.25, 0.5, 1.0, 2.0, 4.0 and 8.0 pM (FIG. 9A). For Ml macrophages, tannic Acid was effective at 1.0 pM, pexidartinib was effective at 0.0625, 0.125 and 0.25 pM, TAK242 was effective at 4.0 pM, and MCC950 was effective at 0.25, 0.5, 1.0, 2.0, 4.0 and 8.0 pM.

[0127] As shown in FIG. 10, rat islets were purchased from Joslin Diabetes Center and seeded into ultra-low 96-well plates (0.16 mL, 200 islets / mL, 32 islets to each well). The fold change in cell viability relative to the no drug control was calculated by dividing the cell viability of each compound treatment with that of the DMSO control (without any of the compound). Rat islets were treated with immunomodulatory compounds (pexidartinib, tannic Acid, TAK242 and MCC950) for 4 days. After treatment, the cytotoxicity of the compounds was evaluated with CellTiter-Glo® 3D Cell Viability Assay kit. The result showed that tannic acid (1.0 pM), pexidartinib (0.25 pM) and MCC950 (8.0 pM) undesirably decreased the viability of rat islets.

[0128] Cytotoxicity of various compounds on endothelial cells

[0129] As shown in FIG. 11, the cytotoxicity of the compounds on endothelial cells was evaluated on a monolayer of cultured human umbilical vein endothelial cells (HUVECs).HUVECs were treated with different compounds of various concentrations for 6 days. The cell number was measured by using the CyQUANT® Cell Proliferation Assay kit. Compared to the normal media control (no compounds treatment), a decrease in cell numbers could suggest the cytotoxicity of the compounds. As shown, tannic acid and pexidartinib did not exhibit cytotoxicity at the selected doses. MCC950 was observed to correlate with an increase in cell numbers. However, TAK242 at higher doses (4.0 and 8.0 pM) exhibited cytotoxicity to HUVECs.

[0130] Effect of various compounds on endothelial network formation

[0131] Furthermore, as shown in FIGS. 12A-12Q, the effect of the compounds on the endothelial network formation was assessed by culturing HUVECs in a collagen gel. HUVECs expressing green fluorescent protein (GFP) were embedded in collagen gel and then the compounds (e.g., MCC950 at 0.25 pM - 4.0 pM, TAK242 at 1.0 pM -8.0 pM, pexidartinib at 0.0625 pM-0.25 pM, tannic acid at 0.25 pM - 4.0 pM) were added in the EGM-2 media separately to investigate whether they would affect the endothelial network formation in the collogen gel. After 6 days of treatment, the endothelial network was imaged under the fluorescent microscope. Compared to the network in EGM-2 media control (FIG. 12A) and DMSO drug vehicle control (FIG. 12B), tannic acid (FIGs. 12C-12E), pexidartinib (FIGs. 12F- 12H) and MCC950 (FIGs. 12M-12Q) at the selected concentrations showed comparable levels of endothelial network formation. However, TAK242 at 8.0 pM appeared to inhibit endothelial network formation (FIGs. 12I-12E).

[0132] Another tubular endothelial network formation assay was performed using GDC- 2394 at various concentrations. For this assay, HUVECs were cultured on Matrigel and exposed to GDC-2394 for a period of 24 hours. The data show that tubular formation was present at various GDC-2394 concentrations tested (O.lpM, 0.5pM, and 2.5pM) (FIGS. 12R-12T).

[0133] In summary, dose range where compounds appeared both active (effective) and non-cytotoxic were identified. For tannic acid, the dose range was from 0.25 pM to 0.5 pM. For pexidartinib, the dose range was from 0.125 pM to 0.25 pM. For TAK242, the dose range was from 2.0 pM to 4.0 pM. For MCC950, the dose range was from 0.25 pM to 4.0 pM. For GDC- 2394, the dose range was from 0.1 pM to 2.5 pM. Once loaded into a delivery vehicle, the release of the compound could be controlled to persist for approximately 10 days to inhibit pro- inflammatory response from macrophages.

[0134] Example 3

[0135] This example illustrates various encapsulation schemes for various immunomodulatory compounds. Specifically, fibrin glue (FG) was used as the encapsulant for encapsulating immunomodulatory (IMM) compounds (e.g., tannic acid, MCC950, pexidartinibRECTIFIED SHEET (RULE 91) ISA / EPand TAK242). The fibrin glue encapsulated immunomodulatory compounds can be implanted as an injectable hydrogel form or can be lyophilized to produce sponges (FIGS. 13A-13B) for the ease of storage and transportation. FIGS. 13A-13B illustrate lyophilized fibrin glue encapsulated with immunomodulatory compounds before (FIG. 13 A) and after swelling with PBS (FIG. 13B).

[0136] To encapsulate IMM compounds into fibrin glue, fibrinogen and thrombin were collected separately using a double chamber syringe provided by the manufacturer (Baxter Healthcare Corp). 4 pL of IMM compounds in dimethyl sulfoxide (DMSO) at different concentrations was mixed with 21 pL of thrombin, and then 25 pL of fibrinogen was added to this mixture. The mixture was subsequently incubated at 37 °C for 30 minutes to form the IMM- encapsulated fibrin glue.

[0137] Fibrin glue containing different fibrinogen concentrations (10%, 25%, 50% and 100%) were used to successfully form hydrogel within 30 minutes at 37 °C. As shown, fibrin glue constructs with lower fibrinogen concentrations (50%) (as shown in FIG. 14A) had larger pore sizes than higher fibrinogen (100%) (as shown in FIG. 14B).

[0138] To study the release of IMM compounds from fibrin glue, the IMM-encapsulated FG constructs were placed in 1.2 mL of cell culture medium containing 10% fetal bovine serum (FBS) and incubated at 37 °C. At predetermined time points, the medium was collected for HPLC analysis and 1.2 mL of the fresh medium was replaced. The amount of IMM compounds released in the medium was separated using a reversed-phase C18 column (Atlantis Silica T3) and detected using a PDA detector in the HPLC system.

[0139] Effect of concentration of fibrinogen in FG on release of TA

[0140] Fibrin glue (FG) constructs containing different fibrinogen concentrations (50% and 100%) and loaded with different doses of tannic acid (TA) (e.g., containing 2, 20 and 200 pg of TA, respectively) were fabricated to investigate the effect of fibrinogen concentrations on the release profile of tannic acid from fibrin glue. The fibrin glue (FG) construct with 100% fibrinogen (FIG. 15 A) provided more prolonged release of tannic acid (TA) compared to 50% fibrinogen (FIG. 15B). This could be explained by the smaller pore sizes of 100% FG compared to the 50% FG, which could reduce the diffusion of immunomodulatory (IMM) molecules out of the FG construct. A tannic acid (TA) dose of 200 pg in 50 pL of 100% FG provided a sustained release for up to 21 days. Based on the above result, 100% fibrinogen was selected as the concentration for encapsulation of other IMM compounds.

[0141] Effect of IMM dosage on release from FGfor various IMMs

[0142] Different immunomodulatory (IMM) compounds (MCC950, pexidartinib and TAK242) at different doses were loaded into 50 pL of fibrin glue (FG) and their releases in the medium at 37 °C were analyzed using HPLC (FIG. 16A-16C). Higher doses of IMMcompounds could be loaded to FG for prolonged release above the minimum effective concentrations (MEC) as represented by the dotted lines. As shown in FIG. 16A, with the dose of 200 nmol, MCC950 was released from FG at above the MEC for 8 days. As shown in FIG. 16C, with a dose of 40 nmol, pexidartinib had a sustained release from FG for more than 10 days. Without wishing to be bound by any particular theory, the longer period of sustained release exhibited by pexidartinib compared to MCC950 could be explained by its higher degree of hydrophobicity. As shown in FIG. 10B, even though high doses (e.g., 600 nmol) of TAK242 were loaded into FG, it was only able to maintain above the MEC for up to 2 days. Interestingly, TAK242 released in the medium was increased above the MEC on day 8, which could be possibly due to the degradation of FG starting from this time point. As indicated by FIG. 16D, TAK242 was less stable and depleted faster in cell culture medium at 37°C, while MCC950 and Pexidartinib were stable.

[0143] Effect ofIMM released from FG on macrophages

[0144] To investigate the effects of immunomodulatory (IMM) compounds released from fibrin glue (FG) on macrophages, an in vitro experiment was designed in which macrophages were in an indirect or direct contact with FG. For the indirect contact, M0 macrophages were seeded onto a cell culture insert of 0.4 pm pore size, while the IMM-encapsulated FG was placed at the bottom of the well (FIG. 17A). For the direct contact, the IMM-encapsulated FG was first placed onto the cell culture insert, and M0 macrophages were then seeded on top of the construct (FIG. 17B). Media was collected at day 4 and day 7 for cytokine analysis (e.g., IL-ip, (TNF)-a, interferon (IFN)-y). Results are shown in FIG. 18.

[0145] As shown in FIG. 18, the IMM compounds were release from the fibrin gel and the effect of released compounds on M0 macrophages was evaluated. The fold change was calculated by dividing each compound treatment with the no drug control. For IL-ip, pexidartinib did not reduce the cytokine level at the tested low and high doses, MCC950 of low and high doses decreased the cytokine secretion, and TAK242 of high dose showed inhibitory effect (FIG. 18). For tumor necrosis factor (TNF)-a, Pexidartinib in direct contact group showed the inhibitory effect. MCC950 and TAK242 showed similar effect as on IL-ip. The effect of the compounds on Interferon (IFN)-y was similar to the effect on TNF-a. Taken together, direct contact group appeared to be in general more effective than indirect contact group. MCC950 and TAK 242 of the high doses were the most effective, and the effect was able to be sustained for 7 days.

[0146] Cytotoxicity ofIMM compounds on SC-islets

[0147] To evaluate the cytotoxicity effect of IMM compounds on human stem cell derived islets (SC-islets), higher doses of the above-referenced compounds were loaded into fibrin glue (FG).

[0148] As shown in FIG. 19A, the effect of released compounds on cell viability of SC- islets was evaluated. Only the indirect group was assessed since there would be no direct contact between the SC-islets and fibrin glue in vivo. The fold change of dead cells was calculated by dividing each compound treatment with the no drug control. As shown, MCC950 at 12 nmol dose increased cell viability of SC-islets whereas TAK242 at 600 nmol dose decreased cell viability of SC-islets. Therefore, MCC950 appears to be effective at reducing pro -inflammatory cytokines and enhancing SC-islets viability. Consistent with SC-islets, the viability of pig islets cultured with MCC950-encapsulated FG was also significantly increased compared to the controls without MCC950 (FIG. 19B).

[0149] FIG. 19C shows the percent viability of SC-islets following exposure to MD2-IN- 1 or GDC-2394 at various concentrations. The data show the percent viability of SC-islets was similar to the no drug control group across various concentrations assessed of the test compounds.

[0150] In summary, it was discovered that a variety of immunomodulatory compounds (e.g., tannic acid, pexidartinib, TAK-242, MCC950) demonstrated enhanced capability at reducing macrophage inflammatory response while also providing a low (if any) observed cytotoxicity, sustained release capabilities, maintenance of vascularization, and / or other applicable benefits. For example, a variety of immunomodulatory compounds (e.g., tannic acid, pexidartinib, MCC950) exhibited capability at preventing disruption of vessel network formation over non-cytotoxic dose ranges and allowed for sustained release over prolonged period of time. In particular, TAK242 was observed to be effective at reducing proinflammatory cytokines, while not causing any observed toxicity to islets, and MCC950 appeared to be effective at reducing proinflammatory cytokines and enhancing islet viability while being non-cytotoxic to islet over a broad dose range. The immunomodulatory compounds (e.g., pexidartinib, MCC950) also demonstrated drug stability over time in aqueous media at 37 °C.

[0151] Example 4

[0152] This example illustrates the release of an immunomodulatory compound (e.g., tannic acid (TA)) from a sintered membrane versus an unsintered membrane. For example, tannic acid at various concentrations (10 pg / mL, 100 pg / mL, 1 mg / mL, 10 mg / mL) was separately used to soak a sintered membrane (FIG. 20A) and an unsintered membrane (FIG. 20B) and the accumulative release of tannic acid from the respective membranes was monitored over a period of 22 days. As shown, the accumulative release (or release rate) of tannic acidfrom the sintered membrane was about half the accumulative release (or release rate) of tannic acid from the unsintered membrane over the same period of time.

[0153] While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present invention.

Claims

CLAIMS1. A macroencapsulation device comprising: a first membrane layer; a second membrane layer disposed on the first membrane layer, wherein the first membrane layer and the second membrane layer are bonded together to form a seal extending at least partially around an internal volume disposed between the first membrane layer and the second membrane layer, wherein the first membrane layer and / or the second membrane layer includes pores; and at least one immunomodulatory compound associated with the first membrane layer and / or the second membrane layer, wherein the at least one immunomodulatory compound includes at least one selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor.

2. The macroencapsulation device of claim 1, wherein the at least one immunomodulatory compound is included in a matrix.

3. The macroencapsulation device of any preceding claim, wherein the at least one immunomodulatory compound is disposed on the first membrane layer and / or the second membrane layer.

4. The macroencapsulation device of any preceding claim, wherein the at least one immunomodulatory compound is disposed on a frame of the macroencapsulation device.

5. The macroencapsulation device of any preceding claim, wherein the at least one immunomodulatory compound is disposed in the pores of the first membrane layer and / or the second membrane layer.

6. The macroencapsulation device of any preceding claim, wherein the at least one immunomodulatory compound is immobilized to the first membrane layer and / or the second membrane layer via a linker.

7. The macroencapsulation device of any preceding claim, wherein when implanted the macroencapsulation device exhibits a reduction in pro-inflammatory response compared to a macroencapsulation device without the at least one immunomodulatory compound under otherwise substantially identical conditions.

8. The macroencapsulation device of any preceding claim, wherein the first membrane layer and the second membrane layer are bonded along a perimeter of the first and second membranes to form the internal volume there between.

9. The macroencapsulation device of any preceding claim wherein the first membrane layer and / or the second membrane layer is semipermeable.

10. The macroencapsulation device of any preceding claim, further comprising a frame that extends along at least a portion of the perimeter of the first and second membrane layers.

11. The macroencapsulation device of any preceding claim, wherein the first and second membrane layers are configured to block passage of a population of cells out of the device.

12. The macroencapsulation device of claim 11, further comprising the population of cells disposed in the internal volume.

13. The macroencapsulation device of any one of claims 11-12, wherein the population of cells comprises at least one selected from the group of pancreatic progenitor cells, endocrine cells, alpha cells, delta cells, and beta cells.

14. The microencapsulation device of any one of claims 11-12, wherein the population of cells comprises NKX6.1 -positive, ISLl-positive cells.

15. A method for delivering a therapeutic composition produced by a population of cells, the method comprising: diffusing the therapeutic composition across at least one membrane layer that at least partially encapsulates the population of cells; and exposing tissues surrounding the at least one membrane layer to at least one immunomodulatory compound selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor.

16. The method of claim 15, wherein the at least one immunomodulatory compound is included in a matrix.

17. The method of claim 16, wherein the matrix comprises a hydrogel.

18. The method of any one of claims 15-17, wherein exposing tissues surrounding the at least one membrane layer to the at least one immunomodulatory compound comprises releasing the at least one immunomodulatory compound from the at least one membrane layer.

19. The method of any one of claims 15-18, wherein exposing tissues surrounding the at least one membrane layer to the at least one immunomodulatory compound comprises applying the at least one immunomodulatory compound to the tissues surrounding the at least one membrane layer.

20. The method of any one of claims 15-19, wherein the therapeutic composition is released across the at least one membrane layer to tissues within a subject over a period of at least 2 weeks.

21. The method of any one of claims 15-20, wherein the at least one immunomodulatory compound is exposed to the tissues over a period of at least 1 day and up to 2 weeks.

22. The method of any one of claims 15-21, wherein the therapeutic composition comprises a therapeutic agent selected from the group of insulin and glucogan.

23. The method of any one of claims 15-22, wherein the population of cells comprises at least one selected from the group of pancreatic progenitor cells, endocrine cells, alpha cells, delta cells, and beta cells.

24. The method of any one of claims 15-22, wherein the population of cells comprises NKX6.1-positive, ISLl-positive cells.

25. The method of any one of claims 15-24, further comprising increasing an amount of antiinflammatory cytokines generated relative to pro-inflammatory cytokines upon exposure of the tissue to the immunomodulatory compound.

26. An immunomodulatory material comprising: a matrix; and at least one immunomodulatory compound selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor included in the matrix.

27. The immunomodulatory material of claim 26, wherein the matrix comprises a hydrogel.

28. The immunomodulatory material of any one of claims 26-27, wherein the immunomodulatory material comprises a plurality of microparticles and / or nanoparticles.

29. The immunomodulatory material of any one of claims 26-28, wherein the matrix comprises a protein gel.

30. The immunomodulatory material of any one of claims 26-29, wherein the matrix is selected from the group of fibrin glue, alginate, collagen gel, polyethylene glycol (PEG), polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL), Matrigel, poly-L-lactide (PLLA), and / or poly glycolic acid (PGA).

31. The immunomodulatory material of any one of claims 26-30, wherein the matrix comprises fibrin glue comprising fibrinogen at a concentration of between 10 wt% and 100 wt%.

32. The immunomodulatory material of any one of claims 26-31, wherein the immunomodulatory material comprises a population of cells.

33. The immunomodulatory material of claim 32, wherein the population of cells comprises at least one cell selected from the group of pancreatic progenitor cells, endocrine cells, alpha cells, delta cells, and beta cells.

34. The immunomodulatory material of any one of claims 32-33, wherein the population of cells comprises NKX6.1 -positive, ISLl-positive cells.

35. A composition, comprising: a population of cells; and at least one immunomodulatory compound selected from the group of a toll-like receptor 4 (TLR4) inhibitor, a nuclear factor K-light-chain-enhancer of activated B cells (NF-KB) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, and a NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor.

36. The composition of claim 35, wherein the composition includes a matrix.

37. The composition of any one of claims 35-36, wherein the population of cells is contained in a matrix.

38. The composition of claim 36 or 37, wherein the matrix comprises a hydrogel.

39. The composition of any one of claims 35-38, wherein the immunomodulatory compound is contained in a matrix.

40. The composition of any one of claims 36-39, wherein the matrix comprises a protein gel.

41. The composition of any one of claims 36-40, wherein the matrix is selected from the group of fibrin glue, alginate, collagen gel, polyethylene glycol (PEG), polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL), Matrigel, poly-L-lactide (PLLA), and / or poly glycolic acid (PGA).

42. The composition of any one of claims 36-41, wherein the matrix comprises fibrin glue comprising fibrinogen at a concentration of between 10 wt% and 100 wt%.

43. The composition of any one of claims 35-42, wherein the population of cells comprises at least one cell selected from the group of pancreatic progenitor cells, endocrine cells, alpha cells, delta cells, and beta cells.

44. The composition of any one of claims 35-43, wherein the population of cells comprises NKX6.1-positive, ISLl-positive cells.

45. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound comprises the TLR4 inhibitor.

46. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound comprises the NF- KB inhibitor.

47. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound comprises the CSF1R inhibitor.

48. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound comprises the NLRP3 inflammasome inhibitor.

49. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the CSF1R inhibitor comprises pexidartinib.

50. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the TLR4 comprises at least one of TAK242 and tannic acid, or derivatives or analogs thereof.

51. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the NF-kB inhibitor comprises at least one of TAK242 and tannic acid, or derivatives or analogs thereof.

52. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the NLRP3 inflammasome inhibitor comprises MCC950, or derivatives or analogs thereof.

53. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the TLR4 and / or NF-kB inhibitor comprises a polyphenol, or derivatives or analogs thereof.

54. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound is present at a concentration of greater than or equal to 0.005 mmol / L and less than or equal to 12 mmol / L.

55. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound includes MCC950 at a concentration of greater than or equal to 0.04 mmol / L and less than or equal to 4 mmol / L.

56. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound includes pexidartinib at a concentration of greater than or equal to 0.01 mmol / L and less than or equal to 0.8 mmol / L.

57. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound includes TAK242 at a concentration of greater than or equal to 0.3 mmol / L and less than or equal to 12 mmol / L.

58. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound includes tannic acid at a concentration of greater than or equal to 0.02 mmol / L and less than or equal to 2 mmol / L.

59. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound is present in a therapeutic dose of greater than or equal to 0.1 pM and less than or equal to 4 pM.

60. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound comprises MCC950 in a therapeutic dose of between or equal to 0.25 pM and less than or equal to 4 pM.

61. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound comprises pexidartinib in a therapeutic dose of between or equal to 0.125 pM and less than or equal to 0.25 pM.

62. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound comprises TAK242 in a therapeutic dose of between or equal to 2 pM and less than or equal to 4 pM.

63. The macroencapsulation device, method, composition, or immunomodulatory material of any preceding claim, wherein the at least one immunomodulatory compound comprises tannic acid in a therapeutic dose of between or equal to 0.25 pM and less than or equal to 0.5 pM.

64. A method of treating a type 1 diabetes patient comprising administering to the patient in need thereof a composition of any one of claims 35-63.

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