Covalently bonded photocrosslinked polysaccharides and methods of use thereof

Abstract

Covalently bonded photocrosslinked polysaccharides and methods of use thereof are provided. Described herein are polysaccharide polymers that can be covalently crosslinked to other moieties, such as other polysaccharide polymers, as well as related compositions, hydrogel capsules containing same, and uses thereof.

Description

[Technical Field]

[0001] CLAIM OF PRIORITY This application claims priority to U.S. Application No. 63 / 357,874, filed July 1, 2022, and U.S. Application No. 63 / 452,125, filed March 14, 2023. The disclosure of each of the foregoing applications is incorporated herein by reference in its entirety. [Background technology]

[0002] The function of implanted devices is highly dependent on the recipient's biological immune response pathways (Anderson et al., Semin. Immunol. 20:86-100 (2008), Langer, Adv. Mater. 21:3235-3236 (2009)). Modulation of the immune response can have beneficial effects on the fidelity and function of these devices. Therefore, there is a need in the art for novel compounds, compositions, and devices that achieve this goal. Summary of the Invention

[0003] Described herein are polysaccharide polymers that can be covalently crosslinked to other moieties, such as other polysaccharide polymers, as well as related compositions, hydrogel capsules containing the same, and their uses. In one embodiment, the polysaccharide polymer comprises a photoactive crosslinking moiety, such as a compound of formula (IV) or a pharmaceutically acceptable salt thereof. In one embodiment, the polysaccharide polymer comprises both a photoactive crosslinking moiety (e.g., a compound of formula (IV)) and a compound of formula (I) (e.g., a non-fibrous compound), or a pharmaceutically acceptable salt thereof. These polysaccharide polymers can be incorporated into hydrogel capsules that can encapsulate cells. Inclusion of a photoactive crosslinking agent within the polysaccharide polymer, and thus hydrogel capsules incorporating the polysaccharide polymer, can allow for tailoring of certain properties of the hydrogel capsule, including capsule diameter, stability, and integrity.

[0004] The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the detailed description, drawings, examples, and claims. [Brief explanation of the drawings]

[0005] [Figure 1] 1 shows a representative LC-UV chromatogram used to characterize components in a photoactive crosslinker reaction. [Figure 2] Figures A-C show representative images of two-compartment alginate hydrogel capsules. Figure A shows an image of an alginate hydrogel capsule in which both the inner and outer compartments contain a blend of VLVG / SLG100 alginate. Figure B shows an image of an alginate hydrogel capsule in which both the inner and outer compartments contain a blend of modified and unmodified alginate (VLVG / SLG100), with the inner compartment containing dextrin beads that mimic mammalian cells. Figure C shows an image of a hydrogel capsule in which both the inner and outer compartments contain a blend of methacrylamide-modified VLVG / SLG100 (70 / 30), with the inner compartment containing dextrin beads that mimic mammalian cells. [Figure 3] A-C show representative images of the alginate hydrogel capsules of Figures 2A-2C after storage in buffer for 1 month. [Figure 4A] Representative images are shown comparing the size and stability of dual cross-linked alginate hydrogel capsules prepared with different concentrations of photoactive cross-linker, 7% photoactive cross-linker. [Figure 4B] Representative images are shown comparing the size and stability of dual cross-linked alginate hydrogel capsules prepared with different concentrations of photoactive cross-linker, 5% photoactive cross-linker. [Figure 4C] Representative images are shown comparing the size and stability of dual cross-linked alginate hydrogel capsules prepared with different concentrations of photoactive cross-linker, 3% photoactive cross-linker. [Figure 4D]Representative images are shown comparing the size and stability of dual cross-linked alginate hydrogel capsules prepared with different concentrations of photoactive cross-linker, 1.5% photoactive cross-linker. [Figure 4E] 1 is a chart showing the corresponding breaking strength of alginate hydrogel capsules described in A-D. [Figure 5] The average fracture strength of exemplary hydrogel capsules containing covalently crosslinked polymers containing Compound 101 (2) is compared to an ionically crosslinked alginate hydrogel (2), as described in Example 7. [Figure 6] The average fracture strength of exemplary hydrogel capsules containing a covalently crosslinked polymer containing Compound 111 (2) is compared to an ionically crosslinked alginate hydrogel (2), as described in Example 7. [Figure 7A] 1 shows an exemplary microscope image of Hydrogel Capsule 1 described in Table 10. [Figure 7B] 1 shows an exemplary microscope image of Hydrogel Capsule 2 described in Table 10. [Figure 8A] 1 shows an exemplary microscopic image of a dual cross-linked alginate hydrogel capsule containing an exemplary mammalian cell. [Figure 8B] 1 shows an exemplary microscopic image of a dual cross-linked alginate hydrogel capsule containing an exemplary mammalian cell. [Figure 9] FIG. 1 is a bar plot comparing the fold change in macrophage adhesion in various modified alginate hydrogel capsules described herein: (1) empty spheres, (2)-(5) dual cross-linked polymer hydrogel capsules containing exemplary mammalian cells. [Figure 10] Percent viability (A) and total cell count (B) of exemplary mammalian cells encapsulated in dual cross-linked alginate hydrogels are shown, with (1) and (3) performed at room temperature and (2) and (4) performed at 4°C. [Figure 11]1 shows the effect of UV exposure time (A) and UV intensity (B) on the fracture strength of exemplary modified alginate hydrogel capsules. [Figure 12] 1 shows the effect of UV exposure time (A) and UV intensity (B) on the viability of mammalian cells encapsulated in exemplary modified alginate hydrogel capsules. [Figure 13] 1 is a plot showing the effect of UV exposure on the release rate of encapsulated dextran polymer from exemplary modified alginate polymers described herein. [Figure 14] 1 is a plot comparing the viability over time of mammalian cells encapsulated in different exemplary covalently cross-linked modified alginate capsules described herein: (1) ionically cross-linked alginate hydrogel capsules, (2) ionically cross-linked alginate hydrogel capsules containing RGD peptide, (3) and (5) double-cross-linked alginate hydrogel capsules, and (4) double-cross-linked alginate hydrogel capsules containing RGD peptide. [Figure 15] 1 shows the effect of different concentrations of modified alginate polymers on the cytotoxicity of ARPE-19 cells. [Figure 16] Figures A-C show the effect of in vivo residence time on compound retention (A), structural integrity (B), and mechanical strength (C) of exemplary modified alginate hydrogel capsules described herein, where light gray represents doubly cross-linked alginate hydrogel capsules and dark gray represents ionically cross-linked alginate hydrogel capsules. [Figure 17] 1 shows the effect of in vivo residence time on the viability of exemplary mammalian cells encapsulated in modified alginate hydrogel capsules described herein, where light gray represents doubly cross-linked hydrogel capsules and dark gray represents ionically cross-linked alginate hydrogel capsules. [Figure 18]Figures A-B show the effect of different molar percentages of (i) the compound of formula (I) and (ii) the compound of formula (IV) on the diameter (A), initial breaking strength (B), and absolute breaking strength (C) of exemplary modified alginate capsules described herein, where diamonds represent 1X Compound 101, circles represent 2X Compound 101, and squares represent 3X Compound 101. [Figure 19] 1 shows the viability of exemplary mammalian cells in the dual cross-linked alginate hydrogel capsules of Example 4. [Figure 20] 1 is a graph showing the relative PFO response of (1) empty spheres, (2) dual cross-linked alginate hydrogel capsules containing exemplary cells described herein, and (3) polystyrene beads. [Figure 21A] The effect of varying batch size on the size of the two-compartment hydrogel capsules described herein is compared. The hydrogel capsules contain the same composition as described in Example 9 (Hydrogel Capsule #1). [Figure 21B] The effect of varying batch size on the strength of the two-compartment hydrogel capsules described herein is compared. The hydrogel capsules contain the same composition as described in Example 9 (Hydrogel Capsule #1). [Figure 21C] The effect of varying batch size on IgG absorption of the two-compartment hydrogel capsules described herein is compared. The hydrogel capsules contain the same composition as described in Example 9 (Hydrogel Capsule #1). [Figure 22] AB compare the effect of varying the density of the compound of formula (IV) on insulin diffusion (A) and IgG absorption (B) of the two-compartment hydrogel capsules described herein. [Figure 23]Figure 1 shows the effect of varying the density of the compound of Formula (IV) on the strength (A), flexibility (B), and diameter (C) of two-compartment hydrogel capsules described herein, where (1, circle) refers to the control hydrogel capsule, and (2, square), (3, triangle), and (4, diamond) refer to hydrogel capsules with 75%, 62%, and 50% reduction in Compound 205, respectively. The hydrogel capsules contain the same composition as described in Example 9 (Hydrogel Capsule #1). [Figure 24A] Figure 1 shows the effect of varying the density of the compound of Formula (IV) on the strength of two-compartment hydrogel capsules described herein, where (1, circle) refers to control hydrogel capsules, and (2, square) and (3, triangle) refer to hydrogel capsules with a 62% and 50% reduction in Compound 205, respectively. Sample (4) refers to ionically cross-linked spheres in the absence of a covalent cross-linker. Sample (5) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9). Sample (6) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells. [Figure 24B] Figure 1 shows the effect of varying the density of the compound of Formula (IV) on the flexibility of two-compartment hydrogel capsules described herein, where (1, circle) refers to control hydrogel capsules, and (2, square) and (3, triangle) refer to hydrogel capsules with a 62% and 50% reduction in Compound 205, respectively. Sample (4) refers to ionically cross-linked spheres in the absence of a covalent cross-linker. Sample (5) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9). Sample (6) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further comprising exemplary mammalian cells. [Figure 24C]Figure 1 shows the effect of varying the density of the compound of Formula (IV) on the diameter of two-compartment hydrogel capsules described herein, where (1, circle) refers to control hydrogel capsules, and (2, square) and (3, triangle) refer to hydrogel capsules in which Compound 205 was reduced by 62% and 50%, respectively. Sample (4) refers to ionically cross-linked spheres in the absence of a covalent cross-linker. Sample (5) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9). Sample (6) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further comprising exemplary mammalian cells. [Figure 24D] Figure 1 shows the effect of varying the density of the compound of Formula (IV) on IgG absorption in two-compartment hydrogel capsules described herein, where (1, circle) refers to control hydrogel capsules, and (2, square) and (3, triangle) refer to hydrogel capsules in which Compound 205 was reduced by 62% and 50%, respectively. Sample (4) refers to ionically cross-linked spheres in the absence of a covalent cross-linker. Sample (5) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9). Sample (6) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further comprising exemplary mammalian cells. [Figure 25A]The hydrogel capsules tested to demonstrate the effect of varying UV irradiation conditions on the diameter of the two-compartment hydrogel capsules described herein are those described in Example 9 (Hydrogel Capsule #1). Sample (4) refers to ionically cross-linked spheres in the absence of a covalent cross-linker, Sample (5) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), and Sample (6) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells. [Figure 25B] The hydrogel capsules tested to demonstrate the effect of varying UV irradiation conditions on the strength of the two-compartment hydrogel capsules described herein are those described in Example 9 (Hydrogel Capsule #1). Sample (4) refers to ionically cross-linked spheres in the absence of a covalent cross-linker, Sample (5) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), and Sample (6) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells. [Figure 25C] The hydrogel capsules tested to demonstrate the effect of varying UV irradiation conditions on the flexibility of the two-compartment hydrogel capsules described herein are those described in Example 9 (Hydrogel Capsule #1). Sample (4) refers to ionically cross-linked spheres in the absence of a covalent cross-linker, Sample (5) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), and Sample (6) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells. [Figure 25D]The hydrogel capsules tested to demonstrate the effect of varying UV irradiation conditions on IgG absorption of the two-compartment hydrogel capsules described herein are those described in Example 9 (Hydrogel Capsule #1). Sample (4) refers to ionically cross-linked spheres in the absence of a covalent cross-linker, Sample (5) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), and Sample (6) refers to dual-cross-linked spheres in which the inner and outer compartments comprise alginate modified with compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells. [Figure 26] 1 shows the volume expansion ratio of an exemplary two-compartment hydrogel capsule described herein in different media. The hydrogel capsule tested was that described in Example 9 (Hydrogel Capsule #1). [Figure 27A] Figure 1 shows the effect of different alginate types in the inner compartment on the strength of two-compartment hydrogel capsules described herein. The hydrogel capsules tested were those described in Example 9 (Hydrogel Capsule #1), but with different alginates in the inner compartment. Sample (1) refers to ionically cross-linked spheres in which no covalent cross-linking agent is present; Sample (2) refers to dual-cross-linked spheres in which the inner and outer compartments contain alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9); Sample (3) refers to dual-cross-linked spheres in which the inner and outer compartments contain alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells; and Sample (4) refers to an empty well control. [Figure 27B]Figure 1 shows the effect of different alginate types in the inner compartment on the flexibility of two-compartment hydrogel capsules described herein. The hydrogel capsules tested were those described in Example 9 (Hydrogel Capsule #1), but with different alginates in the inner compartment. Sample (1) refers to ionically cross-linked spheres in which no covalent cross-linking agent is present; Sample (2) refers to dual-cross-linked spheres in which the inner and outer compartments contain alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9); Sample (3) refers to dual-cross-linked spheres in which the inner and outer compartments contain alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells; and Sample (4) refers to an empty well control. [Figure 27C] Figure 1 shows the effect of different alginate types in the inner compartment on encapsulated cell viability in two-compartment hydrogel capsules described herein. The hydrogel capsules tested were those described in Example 9 (Hydrogel Capsule #1), but with altered alginate in the inner compartment. Sample (1) refers to ionically cross-linked spheres in which no covalent cross-linking agent is present; Sample (2) refers to dual-cross-linked spheres in which the inner and outer compartments contain alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9); Sample (3) refers to dual-cross-linked spheres in which the inner and outer compartments contain alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells; and Sample (4) refers to an empty well control. [Figure 27D]Figure 1 shows the effect of different alginate types in the inner compartment on IgG absorption in two-compartment hydrogel capsules described herein. The hydrogel capsules tested were those described in Example 9 (Hydrogel Capsule #1), but with altered alginate in the inner compartment. Sample (1) refers to ionically cross-linked spheres in which no covalent cross-linking agent is present; Sample (2) refers to dual-cross-linked spheres in which the inner and outer compartments contain alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9); Sample (3) refers to dual-cross-linked spheres in which the inner and outer compartments contain alginate modified with Compounds 101 and 205 (Hydrogel Capsule #2 in Example 9), further containing exemplary mammalian cells; and Sample (4) refers to an empty well control. [Figure 28] 1 is a line graph showing the release rate of barium from exemplary alginate hydrogel capsules, where Sample (1) refers to ionically cross-linked spheres without covalent cross-linking agent that were washed 15 times with buffer, Sample (2) refers to Hydrogel Capsule #1 of Example 9 that was washed 8 times with buffer, and Sample (3) refers to Hydrogel Capsule #1 of Example 9 that was washed with EDTA. [Figure 29] 1 is a bar graph showing residual barium in an exemplary alginate hydrogel capsule (Hydrogel Capsule #1 of Example 9) after increasing numbers of washes in CMRL or HPLM media. [Figure 30] FIG. 1 is a schematic diagram showing an overview of an indirect curing process. [Figure 31] 1A-C show the effect of indirect covalent crosslinking on the strength (A), diameter (B), and insulin diffusion (C) of exemplary two-compartment hydrogel capsules described herein. [Figure 32] 1A-1C are schematic diagrams showing exemplary architectures of the polymers and associated hydrogel capsules described herein. DETAILED DESCRIPTION OF THE INVENTION

[0006] The present disclosure provides polysaccharide polymers comprising a photoactive cross-linking moiety and a compound of formula (I), as well as related compositions, hydrogel capsules comprising same, and methods of making and using same.

[0007] Abbreviations and Definitions In order that the present disclosure may be more readily understood, certain technical and scientific terms used herein are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0008] As used in this specification, including the appended claims, the singular forms of terms such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0009] "About" or "approximately," when used herein to modify a numerically defined parameter (e.g., a physical description of a hydrogel capsule, e.g., diameter, sphericity, number of cells encapsulated therein, number of capsules in a preparation), means that the stated numerical value is within an acceptable functional range for the defined parameter as determined by one of ordinary skill in the art, which depends in part on how the measurement or determination was made, e.g., the limits of the measurement system (including the acceptable error range for that measurement system). For example, "about" can mean a range of 20% above and below the stated numerical value. As a non-limiting example, a hydrogel capsule defined as having a diameter of about 1.5 millimeters (mm) and encapsulating about 5 million (M) cells may have a diameter of 1.2-1.8 mm and encapsulate 4-6 M cells. As another non-limiting example, a preparation of about 100 devices (e.g., hydrogel capsules) includes a preparation having 80-120 devices. In some embodiments, the term "about" means that the modified parameter may vary by 15%, 10%, or 5% above or below the stated numerical value for that parameter. Alternatively, with respect to certain properties of the devices described herein, such as the integrity of the hydrogel encapsulation of non-fibrous compounds in particular, the term "about" can mean within an order of magnitude above or below the recited value, e.g., within 5-fold, 4-fold, 3-fold, 2-fold, or 1-fold.

[0010] "Obtain" or "obtaining," as used herein, refers to obtaining a possession of a value, e.g., a numerical value, or an image, or a physical entity (e.g., a sample), by "directly obtaining" or "indirectly obtaining" the value or physical entity. "Directly obtaining" means performing a process (e.g., performing an analytical method or protocol) to obtain the value or physical entity. "Indirectly obtaining" refers to receiving a value or physical entity from another party or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a value or physical entity includes performing a process that involves a physical change in a physical substance, or using a machine or device. An example of directly obtaining a value includes obtaining a sample from a human subject. Directly obtaining a value includes performing a process using a machine or device, e.g., obtaining fluorescence microscopy data using a fluorescence microscope.

[0011] "Administer," "administering," or "administration," as used herein, refers to implanting, absorbing, ingesting, injecting, or otherwise introducing into a subject an entity described herein (e.g., a hydrogel capsule, device, or preparation of a hydrogel capsule or device), or providing such an entity to a subject for administration.

[0012] "Non-fibrous," as used herein, refers to a compound or material that mitigates foreign body reaction (FBR). For example, the amount of FBR in a biological tissue induced by implantation of a device (e.g., a hydrogel capsule) containing a non-fibrous compound (e.g., a hydrogel capsule comprising a polymer covalently modified with a compound listed in Table 3) into the tissue is lower than the FBR induced by implantation of a non-fibrous null reference device lacking any non-fibrous compound but of substantially the same composition (e.g., the same cell type(s)) and structure (e.g., diameter, shape, number of compartments). In one embodiment, the degree of FBR is assessed by the immunological response in the tissue containing the implanted device (e.g., hydrogel capsule), which may include, for example, protein adsorption, macrophages, multinucleated foreign body giant cells, fibroblasts, and angiogenesis, using assays known in the art, e.g., as described in WO 2017 / 075630, or as described in Vegas, A., et al. al., Nature Biotechnol (ibid.) (e.g., subcutaneous cathepsin measurement of implanted capsules, Masson's trichrome staining (MT), hematoxylin or eosin staining of tissue sections, quantification of collagen density, cell staining and confocal microscopy of macrophages (CD68, or F4 / 80), myofibroblasts (alpha-muscle actin, SMA), or general cellular deposits, quantification of 79 RNA sequences of known inflammatory factors and immune cell markers, or FACS analysis of macrophages and neutrophil cells in devices (e.g., capsules) recovered after 14 days in the intraperitoneal space of suitable test subjects, e.g., immunocompetent mice). In one embodiment, FBR is assessed by measuring the levels of one or more biomarkers of an immune response, e.g., cathepsin, TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-4, CCL2, or CCL4, in a tissue, including an implant.In some embodiments, the FBR induced by a device of the invention (e.g., a hydrogel capsule comprising a non-fibrous compound disposed on its exterior surface) is at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% lower than the FBR induced by an FBR-null reference device, e.g., a device that is substantially identical to a test or claimed device except for lacking a means for mitigating FBR (e.g., a hydrogel capsule that does not include a non-fibrous compound but is otherwise substantially identical to a claimed capsule). In some embodiments, the FBR (e.g., the level of biomarker(s)) is measured after about 30 minutes, about 1 hour, about 6 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 1 week, about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, or more.

[0013] As used herein, "cell" refers to an engineered or non-engineered cell. In one embodiment, the cell is an immortalized cell or an engineered cell derived from an immortalized cell. In one embodiment, the cell is a viable cell, e.g., viable as measured by any technique described herein or known in the art.

[0014] "Cell-binding peptide (CBP)," as used herein, refers to a linear or cyclic peptide comprising an amino acid sequence derived from the cell-binding domain of a ligand of a cell adhesion molecule (CAM) (e.g., mediating cell-matrix or cell-cell connections). The CBP is less than 50, 40, 30, 25, 20, 15, or 10 amino acids in length. In one embodiment, the CBP is between 3 and 12 amino acids in length, 4 and 10 amino acids in length, or 3, 4, 5, 6, 7, 8, 9, or 10 amino acids in length. The CBP amino acid sequence may be identical to a naturally occurring binding domain sequence or a conservatively substituted variant thereof. In one embodiment, the CAM ligand is a mammalian protein. In one embodiment, the CAM ligand is a human protein selected from the group of proteins listed in Table 1 below. In one embodiment, the CBP comprises a cell-binding sequence listed in Table 1 below, or a conservatively substituted variant thereof. In one embodiment, the CBP comprises at least one of the cell-binding sequences listed in Table 1 below. In one embodiment, the CBP consists essentially of a cell-binding sequence listed in Table 1 below. In one embodiment, the CBP is an RGD peptide, meaning that the peptide comprises the amino acid sequence RGD (SEQ ID NO: 43), optionally comprising one or more additional amino acids located at either or both of the N-terminus and C-terminus. In one embodiment, the CBP is a cyclic peptide comprising RGD (SEQ ID NO: 43), such as one of the cyclic RGD peptides described in Vilaca, H. et al., Tetrahedron 70 (35): 5420-5427 (2014). In one embodiment, the CBP is a linear peptide comprising RGD (SEQ ID NO: 43) and is less than 6 amino acids in length. In an embodiment, the CBP is a linear peptide consisting essentially of RGD (SEQ ID NO: 43) or RGDSP (SEQ ID NO: 59). [Table 1]

[0015] "CBP-polymer," as used herein, refers to a polymer comprising at least one cell-binding peptide molecule covalently attached to the polymer via a linker. In one embodiment, the polymer is not a peptide or polypeptide. In one embodiment, the polymer in the CBP-polymer does not comprise an amino acid. In one embodiment, the polymer in the CBP-polymer is a synthetic or naturally occurring polysaccharide, e.g., an alginate, e.g., sodium alginate. In one embodiment, the linker is an amino acid linker (i.e., consisting essentially of a single amino acid or a peptide of several identical or different amino acids), which is attached to the N-terminus or C-terminus of CBP via a peptide bond. In one embodiment, the C-terminus of the amino acid linker is attached to the N-terminus of CBP, and the N-terminus of the amino acid linker is attached to at least one pendant carboxyl group in the polysaccharide via an amide bond. In one embodiment, the structure of the linker-CBP is G (1-4) -CBP, which means that the linker has 1, 2, 3, or 4 glycine residues. In one embodiment, one or more of the monosaccharide moieties in the CBP-polysaccharide, e.g., CBP-alginate, are not modified with CBP; e.g., the unmodified moieties have a free carboxyl group or lack a modifiable pendant carboxyl group. In one embodiment, the number of polysaccharide moieties having covalently bound CBP is less than any of the following values: 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1%.

[0016] In one embodiment, the density of CBP modification in a CBP polymer is estimated by combustion analysis for percent nitrogen. In one embodiment, the CBP-polymer is an RGD-polymer (e.g., RGD-alginate) that is a linker-RGD molecule (e.g., a peptide consisting essentially of GRGD (SEQ ID NO: 62) or GRGDSP (SEQ ID NO: 60)), and the density of linker-RGD molecule modification (e.g., conjugation density) is about 0.05% nitrogen (N) to 1.00% N, about 0.10% N to 0.75% N, about 0.20% N to about 0.50% N, or about 0.30% N to about 0.40% N, as determined using the assays described herein. In one embodiment, the conjugation density of the linker-RGD modification in an RGD-alginate (e.g., an MMW alginate covalently modified with GRGDSP (SEQ ID NO: 60)) comprises 0.1-1.0, 0.2-0.8, 0.3-0.7, or 0.4-0.6 micromoles of linker-RGD moieties per gram of RGD-polymer in a solution having a viscosity of 80-120 cP, as determined by any assay capable of quantifying the amount of peptide conjugated to the polymer (e.g., the quantitative peptide conjugation assay described herein). Unless otherwise expressly stated or readily apparent from the context, any specifically recited numerical concentration, concentration range, density, or density range of CBP in a CBP-polymer refers to the concentration or density of conjugated CBP molecules, i.e., does not include residual free (e.g., unconjugated) CBP that may be present in the CBP-polymer.

[0017] "Conservatively modified variant" or "conservative substitution," as used herein, refers to a variant of a reference peptide or polypeptide that is identical to the reference molecule except for one or more conservative amino acid substitutions in its amino acid sequence. In one embodiment, a conservatively modified variant consists of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to the reference amino acid sequence. Conservative amino acid substitutions refer to amino acid substitutions with amino acids that have similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone conformation, rigidity, etc.) and have minimal effect on the biological activity of the resulting substituted peptide or polypeptide. Conservative substitution tables for functionally similar amino acids are well known in the art, and exemplary substitutions grouped by functional characteristics are set forth in Table 2 below. [Table 2]

[0018] "Crosslink," and variations thereof, such as "crosslink," or "x-linkage," as used herein, refer to at least one chemical bond (e.g., ionic or covalent bond) between two or more polymers. In some embodiments, when two or more chemical bonds are present, crosslinks refer to a mixture of both covalent and ionic bonds. In some embodiments, when two or more chemical bonds are present, crosslinks refer to different types of covalent bonds (e.g., covalent bonds involving different or orthogonal functional groups). In some embodiments, when two or more chemical bonds are present, crosslinks refer to the same type of covalent bond (e.g., covalent bonds involving the same functional group). In some embodiments, when two or more chemical bonds are present, crosslinks refer to the same type of ionic bond (e.g., ionic bonds involving the same ion, e.g., Ba 2+ This refers to an ionic bond containing

[0019] "Derived from," as used herein with respect to a cell, refers to a cell obtained from a tissue, a cell line, or optionally, a cell that has then been cultured, passaged, differentiated, induced, etc. to produce a derived cell. For example, mesenchymal stem cells are derived from mesenchymal tissue and can then be differentiated into a variety of cell types.

[0020] "Device," as used herein, refers to any implantable object (e.g., particle, hydrogel capsule, implant, medical device) described herein. In some embodiments, the device contains cells (e.g., living cells) that can express a therapeutic agent after implantation of the device and has a configuration that supports cell viability by allowing cellular nutrients to enter the device. In some embodiments, the device allows for the release of metabolic byproducts and / or therapeutic agents produced by the living cells from the device.

[0021] "Differential volume," as used herein, refers to the volume of one compartment in a device described herein, excluding the space occupied by another compartment(s). For example, in a two-compartment device having an inner and outer compartment, the differential volume of the second (e.g., outer) compartment refers to the volume within the second compartment, excluding the space occupied by the first (inner) compartment.

[0022] As used herein, "effective amount" refers to the amount of a device, device composition, or component of a device or device compound, such as a plurality of hydrogel capsules containing cells, e.g., engineered cells, or a drug produced by cells, e.g., engineered RPE cells, sufficient to elicit a biological response, e.g., treat a disease, disorder, or condition. In some embodiments, the term "effective amount" refers to the amount of a component of a device (e.g., the number of cells in the device, the density of non-fibrous compounds disposed on the surface of the device and / or in the barrier compartment, the density of photocrosslinkers in the cell-containing compartment). As will be appreciated by those skilled in the art, an effective amount can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the therapeutic agent, composition, or device, the condition being treated, the mode of administration, and the age and health of the subject. Effective amounts encompass both therapeutic and prophylactic treatments. For example, to reduce FBR, an effective amount of a compound of Formula (I) can reduce fibrosis or halt the growth or spread of fibrous tissue on or near an implanted device.

[0023] An "endogenous nucleic acid," as used herein, is a nucleic acid that is naturally present in a subject cell.

[0024] An "endogenous polypeptide," as used herein, is a polypeptide that is naturally present in a subject cell.

[0025] An "engineered cell," as used herein, is a cell that has a non-naturally occurring modification, typically comprising a nucleic acid sequence (e.g., DNA or RNA) (e.g., an exogenous nucleic acid sequence) or polypeptide that is not present (or present at different levels) in an otherwise similar cell under similar conditions that is not engineered. In one embodiment, the engineered cell comprises an exogenous nucleic acid (e.g., a vector or an altered chromosomal sequence). In one embodiment, the engineered cell comprises an exogenous polypeptide. In one embodiment, the engineered cell comprises an exogenous nucleic acid sequence, e.g., a sequence, e.g., DNA or RNA, that is not present in a similar cell that is not engineered. In one embodiment, the exogenous nucleic acid sequence is chromosomal, e.g., the exogenous nucleic acid sequence is an exogenous sequence placed within an endogenous chromosomal sequence. In one embodiment, the exogenous nucleic acid sequence is chromosomal or extrachromosomal, e.g., a non-integrated vector. In one embodiment, the exogenous nucleic acid sequence comprises an RNA sequence, e.g., mRNA. In one embodiment, the exogenous nucleic acid sequence comprises a chromosomal or extrachromosomal exogenous nucleic acid sequence comprising a sequence expressed as RNA, e.g., mRNA, or regulatory RNA. In one embodiment, the exogenous nucleic acid sequence comprises a chromosomal or extrachromosomal nucleic acid sequence comprising a sequence encoding or expressed as a polypeptide. In one embodiment, the exogenous nucleic acid sequence comprises a first chromosomal or extrachromosomal exogenous nucleic acid sequence that regulates the conformation or expression of a second nucleic acid sequence, and the second amino acid sequence can be exogenous or endogenous. For example, an engineered cell can comprise an exogenous nucleic acid that controls the expression of an endogenous sequence. In one embodiment, an engineered cell comprises a polypeptide present at a level or distribution that differs from that found in a similar, unengineered cell. In one embodiment, an engineered cell comprises a cell engineered to produce an RNA or polypeptide. For example, an engineered cell can comprise an exogenous nucleic acid sequence comprising a chromosomal or extrachromosomal exogenous nucleic acid sequence comprising a sequence expressed as RNA, e.g., mRNA, or regulatory RNA.In one embodiment, the engineered cell comprises an exogenous nucleic acid sequence, including a chromosomal or extrachromosomal nucleic acid sequence, that comprises a sequence that encodes or is expressed as a polypeptide. In one embodiment, the polypeptide is encoded by a codon-optimized sequence to achieve higher expression of the polypeptide than the naturally occurring coding sequence. Codon-optimized sequences can be generated using commercially available algorithms, such as GeneOptimizer (ThermoFisher Scientific), OptimumGene® (GenScript, Piscataway, NJ USA), GeneGPS® (ATUM, Newark, CA USA), or the Java Codon Adaptation Tool (JCat, www.jcat.de, Grote, A. et al., Nucleic Acids Research, Vol. 33, Issue suppl_2, pp. W526-W531 (2005)). In one embodiment, the engineered cells comprise an exogenous nucleic acid sequence that modulates the conformation or expression of an endogenous sequence. In one embodiment, the engineered cells (e.g., RPE cells) are cultured from a population of stably transfected cells or from a monoclonal cell line.

[0026] An "exogenous nucleic acid," as used herein, is a nucleic acid that does not naturally occur in a subject cell.

[0027] An "exogenous polypeptide," as used herein, is a polypeptide that does not naturally occur in a subject cell, e.g., an engineered cell. Reference to an amino acid position of a particular sequence refers to the position of that amino acid in the reference amino acid sequence, e.g., the sequence of the full-length mature (after signal peptide cleavage) wild-type protein (unless otherwise stated), and does not exclude the presence of variations, e.g., deletions, insertions, and / or substitutions, at other positions in the reference amino acid sequence.

[0028] "Factor VII protein," or "FVII protein," as used herein, unless otherwise specified, refers to a polypeptide comprising the amino acid sequence of a naturally occurring Factor VII protein or a variant thereof having FVII biological activity (e.g., promoting blood clotting) as determined by art-recognized assays. Naturally occurring FVII exists as a single-chain zymogen, a zymogen-like two-chain polypeptide, and a fully activated two-chain form (FVIIa). In some embodiments, reference to FVII includes both single-chain and its two-chain forms (including zymogen-like and FVIIa). FVII proteins that can be produced by the devices described herein (e.g., devices containing engineered RPE cells) include wild-type primate (e.g., human), porcine, canine, and murine proteins, as well as variants of such wild-type proteins, including fragments, mutants, and variants having one or more amino acid substitutions and / or deletions.

[0029] "Factor VIII protein," or "FVIII protein," as used herein, unless otherwise specified, refers to a polypeptide comprising the amino acid sequence of a naturally occurring factor VIII polypeptide, or a variant thereof, having FVIII biological activity, e.g., clotting activity, as determined by art-recognized assays. FVIII proteins that can be produced by the devices described herein (e.g., devices containing engineered RPE cells) include wild-type primate (e.g., human), porcine, canine, and murine proteins, as well as variants of such wild-type proteins, including fragments, mutants, and variants having one or more amino acid substitutions and / or deletions, B-domain deleted (BDD) variants, single-chain variants, and fusions of any of the foregoing wild-type or variants with a half-life-extending polypeptide. In one embodiment, the cells contain an exogenous sequence encoding a precursor factor VIII polypeptide (e.g., having a signal sequence) having a complete or partial deletion of the B domain. In one embodiment, the cells are engineered to encode a single-chain factor VIII polypeptide.

[0030] "Factor IX protein" or "FIX protein," as used herein, unless otherwise specified, refers to a polypeptide comprising the amino acid sequence of a naturally occurring factor IX protein or a variant thereof having FIX biological activity, e.g., clotting activity, as determined by art-recognized assays. FIX is produced as an inactive zymogen that is converted to its active form by factor XIa excision of the activation peptide to generate heavy and light chains held together by one or more disulfide bonds. FVIII proteins that can be produced by the devices described herein (e.g., devices containing engineered RPE cells) include wild-type primate (e.g., human), porcine, canine, and murine proteins, as well as variants of such wild-type proteins, including fragments, mutants, and variants having one or more amino acid substitutions and / or deletions, and fusions of any of the foregoing wild-type or variant proteins with a half-life-extending polypeptide. In one embodiment, cells are engineered to encode a full-length wild-type human factor IX polypeptide (e.g., with a signal sequence) or a functional variant thereof. "Interleukin-2 protein," or "IL-2 protein," as used herein, unless otherwise specified, refers to a polypeptide comprising the amino acid sequence of a naturally occurring IL-2 protein, or a variant thereof that exhibits IL-2 biological activity, e.g., activates IL-2 receptor signaling in Treg cells, as determined by art-recognized assays. IL-2 proteins that can be produced by the devices described herein, e.g., devices containing engineered RPE cells, include wild-type primate (e.g., human), porcine, canine, and murine proteins, as well as variants of such wild-type proteins.

[0031] "Pancreatic islet cells," as used herein, include any naturally occurring or synthetically produced or modified cell and refer to any cell intended to partially or wholly recapitulate, mimic, or otherwise express the function of a cell of a pancreatic islet of Langerhans. The term "pancreatic islet cells" includes glucose-responsive insulin-producing cells derived from stem cells, e.g., induced pluripotent stem cell lines.

[0032] The terms "mesenchymal stem functional cells," or "MSFCs," as used herein, refer to cells derived from or having at least one characteristic specific to cells of mesodermal lineage, wherein MSFCs i) are not in a differentiated terminal state, and ii) can terminally differentiate into one or more cell types. MSFCs do not include cells derived from endothelial origin, e.g., intestinal cells, or cells of ectodermal origin, e.g., skin, CNS, or neural cells. In one embodiment, MSFCs are multipotent. In one embodiment, MSFCs are not totipotent. In one embodiment, MSFCs comprise one or more of the following characteristics: a) it includes mesenchymal stem cells (MSCs), or cells derived therefrom, including cells derived from primary cell cultures of MSCs, including cells isolated directly (without long-term culture, e.g., less than 5 or 10 passages or cell divisions from isolation) from naturally occurring MSCs, e.g., from humans or other mammals, including cells derived from transformed, pluripotent, immortalized, or long-term (e.g., more than 5 or 10 passages or cell divisions) MSC cultures; and b) It is a cell obtained from a less differentiated cell, for example, a cell that has been grown, programmed, or reprogrammed (e.g., in vitro) into an MSC, or a naturally occurring MSC, or a cell from a primary or long-term culture of an MSC, excluding any genetic manipulation, or one or more of the cells described in a) above. Examples of less differentiated cells from which MSCs can be derived include IPS cells, embryonic stem cells, or other totipotent or pluripotent cells. See, for example, Chen, YS et al. (2012) Stem Cells Transl Med 1(83-95); Frobel, J et al. (2014) Stem Cell Reports 3(3):414-422; Zou, L et al. (2013) Sci Rep 3:2243.

[0033] "Parathyroid hormone" or "PTH," as used herein, refers to a polypeptide or peptide comprising the amino acid sequence of a naturally occurring parathyroid hormone polypeptide or peptide, or a variant thereof, having PTH biological activity, e.g., as determined by art-recognized assays. PTH polypeptides and peptides that can be expressed by the encapsulation cells described herein include wild-type primate (e.g., human), porcine, canine, and murine proteins, as well as variants of such wild-type proteins. Such PTH polypeptides and peptides include, but are not limited to, preproPTH polypeptide (115 amino acids), proPTH polypeptide (90 amino acids), the mature 84-amino acid peptide (PTH(1-84)), and biologically active variants thereof, e.g., the truncated variant peptide PTH(1-34).

[0034] "Photoactive," as used herein, refers to a compound or moiety that can form a reactive species after activation by light, e.g., light of a particular wavelength. In one embodiment, a photoactive compound is chemically inactive under standard laboratory conditions, but becomes reactive upon activation by light. A "photoactive crosslinker" is a crosslinker compound that is activated for crosslinking upon activation by light.

[0035] A "polymer composition," as used herein, is a composition (e.g., a solution, a mixture) that includes one or more polymers. As a class, "polymers" include homopolymers, heteropolymers, copolymers, block polymers, and block copolymers, and can be both natural and synthetic. Homopolymers contain one type of building block, or monomer, while copolymers contain multiple types of monomers.

[0036] A "polypeptide," as used herein, is a polymer comprising amino acid residues linked via peptide bonds and having at least 2, and in some embodiments at least 10, 50, 75, 100, 150, or 200 amino acid residues. "Prevention," "prevent," and "preventing," as used herein, refer to treatments that involve administering or applying a therapy, e.g., administering a cell-encapsulated device composition (e.g., as described herein), prior to the onset of a disease, disorder, or condition to prevent physical signs of said disease, disorder, or condition. In some embodiments, "prevention," "prevent," and "preventing" require that no sign or symptom of the disease, disorder, or condition has developed or been observed. In some embodiments, treatment includes prevention, while in other embodiments, it does not include prevention.

[0037] A "replacement therapy" or "replacement protein" is a therapeutic protein, or functional fragment thereof, that replaces or enhances the beneficial function of a protein that is reduced, present in insufficient amounts, altered (e.g., mutated), or absent in a subject with a disease or condition associated with the reduced, altered, or absent protein. Examples include a predetermined blood clotting factor in a predetermined blood clotting disorder, or a predetermined lysosomal enzyme in a predetermined lysosomal storage disease. In one embodiment, the replacement therapy or replacement protein provides the function of an endogenous protein. In one embodiment, the replacement therapy or replacement protein has an amino acid sequence identical to a naturally occurring variant of the protein being replaced, e.g., a wild-type allele or a non-disorder-associated allele. In one embodiment, the replacement therapy or replacement protein differs in amino acid sequence from the naturally occurring variant, e.g., the wild-type allele or a non-disorder-associated allele, e.g., the allele possessed by the subject, at no more than about 1, 2, 3, 4, 5, 10, 15, or 20% of the amino acid residues.

[0038] "RPE cells," as used herein, refer to cells having one or more of the following characteristics: a) retinal pigment epithelial cells (RPE) (e.g., cultured using the ARPE-19 cell line (ATCC® CRL-2302™)), or cells derived therefrom, e.g., by stably transfecting cells cultured from the ARPE-19 cell line with an exogenous sequence encoding a therapeutic protein, or by otherwise engineering such cultured ARPE-19 cells to express an exogenous protein or other exogenous substance; cells derived from primary cell cultures of RPE cells; naturally occurring RPE cells, e.g., cells isolated directly (without long-term culture, e.g., less than 5 or 10 passages or cell divisions from isolation) from a human or other mammal; transformed, immortalized, or derived from long-term (e.g., more than 5 or 10 passages or cell divisions) RPE cell cultures; b) undifferentiated cells, e.g., RPE cells or naturally occurring RPE cells except for any genetic manipulation, or RPE cells. or c) cells obtained from cells that have been grown, programmed, or reprogrammed (e.g., in vitro) into cells that are substantially similar to one or more of the following: cells from PE cells, from primary or long-term culture (e.g., the cells may be derived from IPS cells); or cells that have one or more of the following characteristics: i) express one or more of the biomarkers CRALBP, RPE-65, RLBP, BEST1, or αB-crystallin; ii) express one or more of the biomarkers CRALBP, RPE-65, RLBP, BEST1, or αB-crystallin; iii) are found naturally in the retina and form a monolayer over the choroidal blood vessels in Bruch's membrane; iv) are responsible for epithelial transport, light absorption, secretion, and immunoregulation in the retina; or v) have the same or substantially the same genetic content, and optionally the same or substantially the same epigenetic content, as an immortalized RPE cell line (e.g., the ARPE-19 cell line (ATCC® CRL-2302™)), which has been synthetically produced or modified from a naturally occurring cell.In one embodiment, the RPE cells described herein are engineered to have new properties, e.g., the cells are engineered to express a therapeutic agent when encapsulated in a polysaccharide polymer hydrogel, e.g., modified with a photoactive crosslinking agent. In other embodiments, the RPE cells are not genetically modified.

[0039] "Sequence identity" or "percent identity," as used herein to refer to two nucleotide sequences or two amino acid sequences, means that the two sequences are identical within a specified region, or that when two sequences are compared and aligned for maximum correspondence over a comparison window, or designated region, they have identical nucleotides or amino acids at a specified percentage of nucleotide or amino acid positions within a specified region. Sequence identity can be determined using standard techniques known in the art, including, but not limited to, any of the algorithms described in U.S. Patent Application Publication No. 2017 / 02334455. In one embodiment, the specified percentage of identical nucleotide or amino acid positions is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more.

[0040] "Spherical," as used herein, refers to a device (e.g., a hydrogel capsule or other particle) with a curved surface that forms a sphere (e.g., a perfectly round ball), or a sphere-like shape, which may have, for example, waves and undulations on the surface. Spheres and sphere-like objects can be mathematically defined by the rotation of a circle, an ellipse, or a combination thereof, about each of three orthogonal axes a, b, and c. In a sphere, the three axes are of equal length. Typically, a sphere-like shape is an ellipsoid (about its average surface) with semimajor axes within 10%, 5%, or 2.5% of each other. The diameter of a sphere or sphere-like shape is the average diameter, e.g., the average of the semimajor axes.

[0041] "Ellipsoid," as the term is used herein to refer to a device (e.g., a hydrogel capsule, or other particle), means that the device (i) has a perfect, or classical, oblate, or prolate ellipsoid shape, or (ii) has a surface that roughly forms an ellipsoid, e.g., may have waves and undulations, and / or may be ellipsoidal (about its average surface) with semimajor axes within 100% of each other.

[0042] "Subject," as used herein, refers to a human or a non-human animal. In one embodiment, the subject is, for example, a human of any age group (i.e., male or female), a pediatric subject (e.g., infancy, childhood, adolescence), or an adult subject (e.g., young adult, middle-aged adult, or elderly adult). In one embodiment, the subject is a non-human animal, for example, a mammal (e.g., a mouse, a dog, a primate (e.g., a cynomolgus monkey, or a rhesus monkey)). In one embodiment, the subject is a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird, such as a chicken, a duck, a goose, or a turkey). In certain embodiments, the animal is a mammal. The animal can be male or female and at any stage of development. The non-human animal can be a transgenic animal.

[0043] "Total volume," as used herein, refers to the volume within one compartment of a multi-compartment device, including the space occupied by another compartment. For example, the total volume of the second (e.g., outer) compartment of a two-compartment device refers to the volume within the second compartment, including the space occupied by the first compartment.

[0044] "Treatment," "treat," and "treating," as used herein, refer to one or more of reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of one or more symptoms, signs, or underlying causes of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of a symptom of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of a sign of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of an underlying cause of a disease, disorder, or condition. In some embodiments, "treatment," "treat," and "treating" require that a symptom or sign of a disease, disorder, or condition be developed or observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or condition, e.g., in prophylactic treatment. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence. In some embodiments, treatment includes prevention, while in other embodiments it does not.

[0045] "Von Willebrand factor protein" or "VWF protein," as used herein, unless otherwise specified, refers to a polypeptide comprising the amino acid sequence of a naturally occurring VWF polypeptide, or a variant thereof, having VWF biological activity, e.g., FVIII binding activity, as determined by art-recognized assays. VWF proteins that can be produced by the devices described herein (e.g., expressed by engineered cells contained in the device) include wild-type primate (e.g., human), porcine, canine, and murine proteins, as well as variants of such wild-type proteins. Encapsulated cells can be engineered to encode any of the following VWF polypeptides: the 2813-amino acid precursor VWF, VWF lacking the 22-amino acid signal peptide and, optionally, the 741-amino acid prepropeptide, the 2050-amino acid mature VWF protein, and truncated variants thereof.

[0046] "VLVG," or "VLVG alginate," refers to very low viscosity sodium alginate, which may have an average molecular weight of less than about 75 kDa and contain more than 60% guluronic acid units (i.e., have a glucuronate to mannonate ratio of 1.5 or greater).

[0047] "SG100," or "SG100 alginate," refers to sodium alginate having an average molecular weight of about 150-250 kDa and containing more than 60% guluronic acid units (i.e., having a glucuronate to mannonate ratio of 1 or greater).

[0048] Selected Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thEd., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987. て There are.

[0049] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0050] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0051] As used herein, "alkyl" refers to a group of straight or branched chain saturated hydrocarbon groups having 1 to 24 carbon atoms ("C1-C 24In some embodiments, an alkyl group is a group having 1 to 12 carbon atoms ("C1-C 12 alkyl), 1 to 10 carbon atoms (C1 to C 12 In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C-C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C-C alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each example of an alkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl").

[0052] As used herein, "alkenyl" refers to a group of straight or branched chain hydrocarbon groups having 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C 24 In some embodiments, an alkenyl group refers to an alkyl group having 2 to 10 carbon atoms ("C-C"). 10C2-C4 alkenyl groups have 2 to 8 carbon atoms ("C2-C8 alkenyl"), 2 to 6 carbon atoms ("C2-C6 alkenyl"), 2 to 5 carbon atoms ("C2-C5 alkenyl"), 2 to 4 carbon atoms ("C2-C4 alkenyl"), 2 to 3 carbon atoms ("C2-C3 alkenyl"), or 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the C2-C6 alkenyl groups mentioned above. 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Each example of an alkenyl group independently may be optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl").

[0053] As used herein, the term "alkynyl" refers to a radical of a straight or branched chain hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C 24 In some embodiments, an alkynyl group refers to an alkyl group having 2 to 10 carbon atoms ("C-C"). 10C-C alkynyl groups have 2 to 8 carbon atoms ("C-C alkynyl"), 2 to 6 carbon atoms ("C-C alkynyl"), 2 to 5 carbon atoms ("C-C alkynyl"), 2 to 4 carbon atoms ("C-C alkynyl"), 2 to 3 carbon atoms ("C-C alkynyl"), or 2 carbon atoms ("C alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C-C alkynyl groups include ethynyl (C), 1-propynyl (C), 2-propynyl (C), 1-butynyl (C), 2-butynyl (C), and the like. Each instance of an alkynyl group independently may be optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkynyl").

[0054] As used herein, the term "heteroalkyl" refers to an acyclic, stable, straight-chain, or branched-chain, or combination thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) O, N, P, S, and Si can be located at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A "heteroalkyl" may be recited followed by a particular heteroalkyl group, e.g., -CHO, -NR C R D When the term heteroalkyl is used, the term -CH2O or -NR C R D It is understood that the terms "heteroalkyl" and "heteroalkyl-" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" refers to specific heteroalkyl groups, e.g., -CHO, -NR C R D Nothing herein should be construed as excluding, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Each example of a heteroalkyl group independently may be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted heteroalkyl").

[0055] The terms "alkylene," "alkenylene," "alkynylene," or "heteroalkylene," by themselves or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, or heteroalkyl, respectively. An alkylene, alkenylene, alkynylene, or heteroalkylene group may be described, for example, as a C-C-membered alkylene, a C-C-membered alkenylene, a C-C-membered alkynylene, or a C-C-membered heteroalkylene, where the term "membered" refers to a non-hydrogen atom within the moiety. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- can represent both -C(O)2R'- and -R'C(O)2-.

[0056] As used herein, "aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic, or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 Aryl, for example, anthracyl. The aryl group is, for example, C6-C 10The term "membered" refers to a non-hydrogen ring atom within a moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example of an aryl group may independently be optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl").

[0057] As used herein, "heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared by a cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, if valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being at either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing the heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom within the moiety.

[0058] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group independently may be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted with one or more substituents (a "substituted heteroaryl").

[0059] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0060] As used herein, the terms "arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.

[0061] As used herein, "cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C3-C 10 "cycloalkyl" refers to a group of non-aromatic cyclic hydrocarbon groups having no heteroatoms. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C-C cycloalkyl"), 3 to 6 ring carbon atoms ("C-C cycloalkyl"), or 5 to 10 ring carbon atoms ("C-C 10 Cycloalkyl groups may be described, for example, as C4-C7 membered cycloalkyl, where the term "membered" refers to a non-hydrogen ring atom within the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. 10 Cycloalkyl groups include, but are not limited to, the C3 to C8 cycloalkyl groups mentioned above, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or contains fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic cycloalkyl"), and can be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on the cycloalkyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl").

[0062] "Heterocyclyl," as used herein, refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups, with the point of attachment being on either the cycloalkyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms in the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0063] In some embodiments, heterocyclyl groups are 5- to 10-membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5- to 8-membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5- to 6-membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, 5- to 6-membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0064] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl or thiomorpholinyl-1,1-dioxide. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0065] "Amino," as used herein, refers to the group -NR 70 R 71 (In the formula, R 70 , and R 71 are each independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, C4-C 10 Heterocyclyl, C6-C 10 Aryl and C5-C 10 In some embodiments, amino refers to NH2.

[0066] As used herein, "cyano" refers to the group --CN.

[0067] As used herein, "halo," or "halogen," independently or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0068] As used herein, "hydroxy" refers to the group --OH.

[0069] Alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). Typically, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituents can be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein, that result in the formation of a stable compound. The present disclosure contemplates all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0070] Two or more substituents may optionally be linked to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0071] The compounds of formula (I) described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0072] As used herein, a pure enantiomer compound is substantially free of other enantiomers, or stereoisomers, of a compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess over the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains greater than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of an enantiomer. In certain embodiments, weights are based on the total weight of all enantiomers, or stereoisomers, of a compound.

[0073] The compounds of formula (I) described herein may also contain one or more isotopic substitutions. For example, H may be: 1 H, 2 H (D, or deuterium), and 3 H (T, or tritium), and C can be in any isotopic form. 12 C. 13 C, and 14 C can be any isotopic form, including O 16 O, and 18 It can be in any isotopic form, including O and the like.

[0074] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compound of formula (I) used to prepare the device of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compound used in the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids, e.g., alginates, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds used in the devices (e.g., particles, hydrogel capsules) of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those of ordinary skill in the art. Other pharmaceutically acceptable carriers known to those of ordinary skill in the art are suitable for use in the present disclosure.

[0075] "Polysaccharide," as used herein, refers to a polymer of monosaccharide or disaccharide carbohydrates linked together by glycosidic bonds. Polysaccharides may be linear or branched. Exemplary monosaccharides include glucose, galactose, mannose, allose, altrose, talose, idose, gulose, fructose, ribose, arabinose, lyxose, xylose, rhamnose, glucuronic acid, galacturonic acid, mannuronic acid, and guluronic acid. Exemplary polysaccharides include alginate, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, amylose, chitin, chitosan, or derivatives or variants thereof (e.g., those described in Laurienzo (2010), Mar Drugs 9:2435-65).

[0076] The device of the present disclosure may contain a compound of formula (I) in a prodrug form. Prodrugs are compounds that readily undergo chemical changes under physiological conditions to provide compounds useful for preparing devices in the present disclosure. In addition, prodrugs can be converted to useful compounds of formula (I) by chemical or biochemical methods in an ex vivo environment.

[0077] Certain compounds of formula (I) described herein can exist in unsolvated forms and solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. Certain compounds of formula (I) described herein can exist in polycrystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0078] The term "solvate" refers to a form of a compound associated with a solvent, usually by solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates.

[0079] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is within a defined ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0.

[0080] As used herein, the term "tautomer" refers to an interchangeable form of a compound structure, where there is a change in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shift of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0081] [ka] The term "polymer," as used herein, refers to a connection to an entity, e.g., a polymer (e.g., a hydrogel-forming polymer such as alginate), or to the surface of an implantable device, e.g., a particle, a hydrogel capsule.

[0082] [ka] The connection represented by can refer to a direct bond to an entity, e.g., a polymer or implantable element, or can refer to a linkage to an entity via a linking group. A "linking group," as described herein, refers to a moiety for linking a compound of formula (I) to an entity (e.g., a hydrogel capsule or an implantable device described herein) and can include any linking chemistry known in the art. A list of exemplary linking groups can be found in Bioconjugate Techniques (3 rd ed. Greg T. Hermanson, Waltham, MA: Elsevier, Inc, 2013), which is incorporated herein by reference in its entirety. In some embodiments, the linking group is selected from alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)—, —OC(O)—, —N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -N(R C )N(R D )-, -NCN-, -C(=N(R C )(R D ))O-, -S-, -S(O) x -, -OS(O) x -, -N(R C )S(O) x -, -S(O) x N(R C )-, -P(R F ) y -, -Si(OR A )2-, -Si(R G )(OR A )-, -B(OR A )-, or containing metal, R A , R C , R D , R F , R GEach of x, x, and y is independently as described herein. In some embodiments, the linking group comprises an amine, a ketone, an ester, an amide, an alkyl, an alkenyl, an alkynyl, or a thiol. In some embodiments, the linking group is a crosslinker. In some embodiments, the linking group is -C(O)(C1-C6-alkylene)-, where the alkylene is R 1 is replaced by R 1 is as described herein. In some embodiments, the linking group is -C(O)(C1-C6-alkylene)-, where the alkylene is substituted with 1-2 alkyl groups (e.g., 1-2 methyl groups). In some embodiments, the linking group is -C(O)C(CH3)2-. In some embodiments, the linking group is -C(O)(methylene)-, where the alkylene is substituted with 1-2 alkyl groups (e.g., 1-2 methyl groups). In some embodiments, the linking group is -C(O)CH(CH3)-. In some embodiments, the linking group is -C(O)C(CH3)-.

[0083] The terms "covalent bond," "covalent bond," and "covalent bond," as used herein, refer to a type of chemical bond involving the sharing of electrons between two adjacent atoms. Examples of covalent bonds include those formed between carbon and hydrogen (C-H bond), carbon atoms (C-C bond), carbon and oxygen atoms (C-O bond), and carbon and nitrogen (C-N bond). Depending on the identity of the atoms, a covalent bond can be a single bond, a double bond, or a triple bond. That is, a covalent bond can involve the sharing of one, two, or three pairs of electrons.

[0084] The terms "ionic," "ionic bond," and "ionic bond," as used herein, refer to a type of chemical bond involving Coulombic attraction between adjacent atoms of opposite charge (i.e., ions).

[0085] Modified Polymers The polysaccharide polymers described herein are covalently modified with covalently bound photoactive crosslinker moieties. In one embodiment, the polysaccharide polymer can be a linear, branched, or crosslinked polysaccharide polymer, or a polysaccharide polymer of a selected molecular weight range, degree of polymerization, viscosity, or melt flow rate. The branched polysaccharide polymer can include one or more of the following types: star polymer, comb polymer, brush polymer, dendrimerized polymer, graft co(polymer), ladder polymer, and dendrimer. In some embodiments, the branched polysaccharide polymer is a star polymer. In some embodiments, the branched polysaccharide polymer is a comb polymer. In some embodiments, the branched polysaccharide polymer is a brush polymer. In some embodiments, the branched polysaccharide polymer is a dendron polymer. In some embodiments, the branched polysaccharide polymer is a graft (co)polymer. In some embodiments, the branched polysaccharide polymer is a ladder polymer. In some embodiments, the branched polysaccharide polymer is a dendrimer-type polymer. The polysaccharide polymer can be a thermoresponsive polymer, e.g., a gel (e.g., that becomes solid or liquid upon exposure to heat or a predetermined temperature), or a photocrosslinkable polymer. In some embodiments, the polysaccharide polymer is a photocrosslinkable crosslinked polymer. In some embodiments, the polysaccharide polymer can be biodegradable, e.g., contain labile bonds, or can be degraded by enzymes, e.g., lyases. In some embodiments, the polysaccharide polymer is composed of a single type of repeating monomer unit. In other embodiments, the polysaccharide polymer is composed of different types of repeating monomer units (e.g., two types of repeating monomer units, three types of repeating monomer units, e.g., a polymer blend). In some embodiments, the polysaccharide polymer can be composed of mannuronic acid and guluronic acid monomers.

[0086] In some embodiments, the polysaccharide polymer is a naturally occurring or synthetic polymer. In some embodiments, the polysaccharide polymer is a naturally occurring or synthetic polysaccharide. In one embodiment, the polysaccharide polymer is cellulose, e.g., carboxymethylcellulose. In one embodiment, the polysaccharide polymer is polylactide, polyglycoside, or polycaprolactone. In one embodiment, the polysaccharide polymer is hyaluronate, e.g., sodium hyaluronate. In one embodiment, the polymer is collagen, elastin, or gelatin. In one embodiment, the polysaccharide polymer is chitin.

[0087] In some embodiments, the polysaccharide polymer is a hydrogel-forming polymer. Hydrogel-forming polymers contain a hydrophilic structure and are therefore capable of retaining large amounts of water within a three-dimensional network. Hydrogel-forming polymers can include polymers that form homopolymer hydrogel capsules, copolymer hydrogel capsules, or multipolymer interpenetrating polymer hydrogel capsules, and can be amorphous, semi-crystalline, or crystalline in nature, for example, as described in Ahmed (2015) J Adv Res 6:105-121. Exemplary hydrogel-forming polymers include proteins (e.g., collagen), gelatin, polysaccharides (starch, alginate, hyaluronate, agarose), and synthetic polysaccharides.

[0088] Exemplary polysaccharides include alginate, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, amylose, chitin, chitosan, or derivatives or variants thereof (e.g., those described in Laurienzo (2010), Mar Drugs 9:2435-65). Polysaccharide polymers may include heparin, chondroitin sulfate, dermatan, dextran, or carboxymethylcellulose. In some embodiments, the polysaccharide polymer is a cell surface polysaccharide.

[0089] In some embodiments, the polysaccharide polymer is alginate. Alginate is a polysaccharide composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G). In some embodiments, the alginate is a high guluronic acid (G) alginate, comprising greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more guluronic acid (G). In some embodiments, the alginate is a high mannuronic acid (M) alginate, comprising greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more mannuronic acid (M). In some embodiments, the M:G ratio is about 1. In some embodiments, the M:G ratio is less than 1. In some embodiments, the M:G ratio is greater than 1. In some embodiments, the alginate has an approximate molecular weight of <75 kDa, optionally having a G:M ratio of ≧1.5. In some embodiments, the alginate has an approximate molecular weight of 75 kDa to 150 kDa, optionally having a G:M ratio of ≧1.5. In some embodiments, the alginate has an approximate molecular weight of 150 to 250 kDa, optionally having a G:M ratio of ≧1.5.

[0090] Polysaccharide polymers (e.g., any of the polymers described herein, e.g., any of the alginates described herein) comprising a saccharide moiety having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, may be modified at one or more monomer units. In some embodiments, at least 0.5 percent of the saccharide monomers of the polysaccharide polymer have the structure of Formula (I) (e.g., at least 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99 percent, or more of the saccharide monomers have the structure of Formula (I)). In some embodiments, 0.5-50%, 10-90%, 10-50%, or 25-75% of the saccharide monomers of the polysaccharide polymer have the structure of Formula (I). In some embodiments, 1-20% of the saccharide monomers of the polysaccharide polymer have the structure of Formula (I). In some embodiments, 1-10% of the sugar monomers of the polysaccharide polymer have the structure of Formula (I). In some embodiments, 1-50% of the sugar monomers have the structure of Formula (I).

[0091] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having the structure of Formula (I)) comprises an increase in %N (compared to the unmodified polymer) of at least 0.1, 0.2, 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10%N by weight, where %N corresponds to the amount of the compound of Formula (I) in the modified polymer, as determined by elemental analysis.

[0092] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having the structure of Formula (I)) comprises an increase in %N (compared to the unmodified polymer) of 0.1 to 10%N by weight, where %N corresponds to the amount of the compound of Formula (I) in the modified polymer, as determined by elemental analysis.

[0093] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having the structure of Formula (I)) comprises an increase in %N (compared to the unmodified polymer) of 0.1 to 2%N by weight, where %N corresponds to the amount of the compound of Formula (I) in the modified polymer, as determined by elemental analysis.

[0094] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having the structure of Formula (I)) comprises an increase in %N (compared to the unmodified polymer) of 2-4%N by weight, where %N corresponds to the amount of the compound of Formula (I) in the modified polymer, as determined by elemental analysis.

[0095] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having the structure of Formula (I)) comprises an increase in %N (compared to the unmodified polymer) of 4-8%N by weight, where %N corresponds to the amount of the compound of Formula (I) in the modified polymer, as determined by elemental analysis.

[0096] In some embodiments, any of the polysaccharide polymers (e.g., alginates) described herein comprises a sugar monomer having one or more of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or a pharmaceutically acceptable salt thereof. In some embodiments, the polysaccharide polymer comprises a sugar monomer having the structure of formula (II-a). In some embodiments, the polymer is modified with a compound of formula (II-b). In some embodiments, the polysaccharide polymer comprises a sugar monomer having the structure of formula (II-c). In some embodiments, the polysaccharide polymer comprises a sugar monomer having the structure of formula (II-d). In some embodiments, the polysaccharide polymer comprises a sugar monomer having the structure of formula (II-e). In some embodiments, the polysaccharide polymer comprises a sugar monomer having the structure of formula (II-f).

[0097] In some embodiments, the polysaccharide polymer (e.g., alginate) is modified with a compound shown in Table 3. In some embodiments, the polymer (e.g., alginate) modified with a compound of Formula (I) is not a modified polymer described in any one of WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 187225, WO2016 / 019391, WO2017 / 075630, WO2017 / 075631, WO2018 / 067615, WO2019 / 169333, and US2016-0030359.

[0098] Non-fibrous compounds In some embodiments, the polysaccharide polymers described herein contain at least one non-fibrous compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: A is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-, -C(O)O-, -C(O)-, -OC(O)-, -N(R C )-, -N(RC) C (O)-, -C(O)N(R C )-, -N(R C )C(O)(C1~ C6 -alkylene)-, -N(R C )C(O)(C1-C6-alkenylene)-, -N(R C )N(R D )-, -NCN-, -C(=N(R C )(R D ))O-, -S-, -S(O) x- , -OS(O) x -, -N(R C )S(O) x -, -S(O) x N(R C )-, -P(R F ) y -, -Si(OR A )2-, -Si(R G)(OR A )-, -B(OR A )-, or a metal, each of which is optionally linked to a linking group (e.g., a linking group described herein) and includes one or more R 1 and L 1 , and L 3 is independently a bond, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is selected from one or more R 2 and L 2 is a bond; M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from one or more R 3 and P is absent, cycloalkyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more R 4 and Z is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, -OR A , -C(O)R A , -C(O)OR A , -C(O)N(R C )(R D ), -N(R C )C(O)R A , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R 5 and each R A , R B , R C , R D , R E , R F , and R G are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, azido, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of one or more R 6and R C , and R D together with the nitrogen atom to which it is attached, form one or more R 6 and each R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , S(O) x R E1 , -OS(O) x R E1 , -N(R C1 )S(O) x R E1 , -S(O) x N(R C1 )(R D1 ), -P(R F1 ) y , cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclocyclyl, aryl, and heteroaryl may be selected from the group consisting of one or more R 7 and each R A1 , R B1 , R C1 , R D1 , R E1 , and R F1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocycloalkyl; x is 1 or 2; and y is 2, 3, or 4.

[0099] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, wherein A is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—, —C(O)O—, —C(O)—, —OC(O)—, —N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -N(R C )N(R D )-, N(R C )C(O)(C1-C6-alkylene)-, -N(R C )C(O)(C1-C6-alkenylene)-, -NCN-, -C(=N(R C )(R D ))O-, -S-, -S(O) x -, -OS(O) x -, -N(R C )S(O) x -, -S(O) x N(R C )-, -P(R F )y-, Si(OR A )2, -Si(R G )(OR A ), -B(OR A ), or a metal, each of which is optionally bonded to a linking group (e.g., a linking group described herein), and one or more R 1 and L 1 , and L 3is independently a bond, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is selected from one or more R 2 and L 2 is a bond; M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from one or more R 3 and P is optionally substituted by one or more R 4 and Z is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 5 and each R A , R B , R C , R D , R E , R F , and R G are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, azido, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from the group consisting of one or more R 6 and R C , and R D together with the nitrogen atom to which it is attached, form one or more R 6 and each R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1)C(O)R B1 , -C(O)N(R C1 ), SR E1 , S(O)xR E1 , -OS(O) x R E1 , -N(R C1 )S(O) x R E1 , -S(O) x N(R C1 )(R D1 ), -P(R F1 ) y , cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from the group consisting of one or more R 7 and each R A1 , R B1 , R C1 , R D1 , R E1 , and R F1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocycloalkyl; x is 1 or 2; and y is 2, 3, or 4.

[0100] In some embodiments, for Formulas (I) and (Ia), A is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—, —C(O)O—, —C(O)—, —OC(O)—, —N(R C )C(O)-, -N(R C )C(O)(C1-C6-alkylene)-, -N(R C)C(O)(C1-C6-alkenylene)-, or -N(R C In some embodiments, A is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O—, —C(O)O—, —C(O)—, —OC(O)—, or —N(R C In some embodiments, A is alkyl, alkenyl, alkynyl, heteroalkyl, —O—, —C(O)O—, —C(O)—, —OC(O)—, or —N(R C In some embodiments, A is alkyl, —O—, —C(O)O—, —C(O)—, —OC(O), or —N(R C In some embodiments, A is —N(R C )C(O)-, -N(R C )C(O)(C1-C6-alkylene)-, or -N(R C )C(O)(C1-C6-alkenylene)-. In some embodiments, A is -N(R C In some embodiments, A is —N(R C )- and R C , and R D are independently hydrogen or alkyl. In some embodiments, A is -NH-. In some embodiments, A is -N(R C )C(O)(C1-C6-alkylene)-, where alkylene is R 1 In some embodiments, A is substituted by -N(R C )C(O)(C1-C6-alkylene)-, and R 1 is alkyl (e.g., methyl). In some embodiments, A is —NHC(O)C(CH)—. In some embodiments, A is —N(R C )C(O)(methylene)-, and R 1 is alkyl (e.g., methyl). In some embodiments, A is -NHC(O)CH(CH3)-. In some embodiments, A is -NHC(O)C(CH3)-.

[0101] In some embodiments, for Formulas (I) and (Ia), L 1 is a bond, alkyl, or heteroalkyl. In some embodiments, L 1 is a bond, or alkyl. In some embodiments, L 1 is a bond. In some embodiments, L 1 is alkyl. In some embodiments, L 1 is C1-C6 alkyl. In some embodiments, L 1 is -CH2-, -CH(CH3)-, -CH2CH2CH2, or -CH2CH2-. In some embodiments, L 1 is -CH2-, or -CH2CH2-.

[0102] In some embodiments, for Formulas (I) and (Ia), L 3 is a bond, alkyl, or heteroalkyl. In some embodiments, L 3 is a bond. In some embodiments, L 3 is alkyl. In some embodiments, L 3 is C1~C 12 In some embodiments, L 3 is C1-C6 alkyl. In some embodiments, L 3 is -CH-. In some embodiments, L 3 is heteroalkyl. In some embodiments, L 3 is one or more R 2 C1-C optionally substituted with (e.g., oxo) 12 In some embodiments, L is heteroalkyl. 3 is one or more R 2 (e.g., oxo). In some embodiments, L 3 is —C(O)OCH—, —CH(OCHCH)—, —CH(OCHCH)—, CHCHO—, or —CHO—. In some embodiments, L 3is -CH2O-.

[0103] In some embodiments, for Formulas (I) and (Ia), M is absent, alkyl, heteroalkyl, aryl, or heteroaryl. In some embodiments, M is heteroalkyl, aryl, or heteroaryl. In some embodiments, M is absent. In some embodiments, M is alkyl (e.g., C1-C6 alkyl). In some embodiments, M is -CH2-. In some embodiments, M is heteroalkyl (e.g., C1-C6 heteroalkyl). In some embodiments, M is (-OCH2CH2-)z, where z is an integer selected from 1 to 10. In some embodiments, z is an integer selected from 1 to 5. In some embodiments, M is -OCH2CH2-, (-OCH2CH2-)2, (-OCH2CH2-)3, (-OCH2CH2-)4, or (-OCH2CH2-)5. In some embodiments, M is —OCH 2 CH 2 —, (—OCH 2 CH 2 —) 2 , (—OCH 2 CH 2 —) 3 , or (—OCH 2 CH 2 —) 4 . In some embodiments, M is (—OCH 2 CH 2 —) 3 .

[0104] In some embodiments, for Formulas (I) and (Ia), M is absent, alkyl, heteroalkyl, aryl, or heteroaryl. In some embodiments, M is heteroalkyl, aryl, or heteroaryl. In some embodiments, M is absent. In some embodiments, M is alkyl (e.g., C1-C6 alkyl). In some embodiments, M is -CH2-. In some embodiments, M is heteroalkyl (e.g., C1-C6 heteroalkyl). In some embodiments, M is (-OCH2CH2-)z, where z is an integer selected from 1 to 10. In some embodiments, z is an integer selected from 1 to 5. In some embodiments, M is -OCH2CH2-, (-OCH2CH2-)2, (-OCH2CH2-)3, (-OCH2CH2-)4, or (-OCH2CH2-)5. In some embodiments, M is -OCH2CH2-, (-OCH2CH2-)2, (-OCH2CH2-)3, or (-OCH2CH2-)4. In some embodiments, M is (-OCH2CH2-)3. In some embodiments, M is aryl. In some embodiments, M is phenyl. In some embodiments, M is unsubstituted phenyl. In some embodiments, M is [ka] In some embodiments, M is R 7 (For example, one R 7 In some embodiments, M is phenyl substituted with [ka] In some embodiments, R 7 is CF3.

[0105] In some embodiments, for Formulas (I) and (Ia), P is absent, heterocyclyl, or heteroaryl. In some embodiments, P is absent. In some embodiments, for Formulas (I) and (Ia), P is tricyclic, bicyclic, or monocyclic heteroaryl. In some embodiments, P is monocyclic heteroaryl. In some embodiments, P is nitrogen-containing heteroaryl. In some embodiments, P is monocyclic, nitrogen-containing heteroaryl. In some embodiments, P is 5-membered heteroaryl. In some embodiments, P is 5-membered nitrogen-containing heteroaryl. In some embodiments, P is tetrazolyl, imidazolyl, pyrazolyl, or triazolyl, pyrrolyl, oxazolyl, or thiazolyl. In some embodiments, P is tetrazolyl, imidazolyl, pyrazolyl, or triazolyl, or pyrrolyl. In some embodiments, P is imidazolyl. In some embodiments, P is [ka] In some embodiments, P is triazolyl. In some embodiments, P is 1,2,3-triazolyl. In some embodiments, P is [ka] is.

[0106] In some embodiments, P is heterocyclyl. In some embodiments, P is a 5-membered heterocyclyl or a 6-membered heterocyclyl. In some embodiments, P is imidazolidinonyl. In some embodiments, P is [ka] In some embodiments, P is thiomorpholinyl-1,1-dioxidyl. In some embodiments, P is [ka] is.

[0107] In some embodiments, for Formula (I) or (Ia), Z is alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, Z is heterocyclyl. In some embodiments, Z is monocyclic or bicyclic heterocyclyl. In some embodiments, Z is oxygen-containing heterocyclyl. In some embodiments, Z is a 4-membered heterocyclyl, a 5-membered heterocyclyl, or a 6-membered heterocyclyl. In some embodiments, Z is a 6-membered heterocyclyl. In some embodiments, Z is a 6-membered oxygen-containing heterocyclyl. In some embodiments, Z is tetrahydropyranyl. In some embodiments, Z is [ka] In some embodiments, Z is a 4-membered oxygen-containing heterocyclyl. In some embodiments, Z is [ka] is.

[0108] In some embodiments, Z is a bicyclic oxygen-containing heterocyclyl. In some embodiments, Z is phthalic anhydride. In some embodiments, Z is a sulfur-containing heterocyclyl. In some embodiments, Z is a 6-membered sulfur-containing heterocyclyl. In some embodiments, Z is a 6-membered heterocyclyl containing a nitrogen atom and a sulfur atom. In some embodiments, Z is thiomorpholinyl-1,1-dioxidyl. In some embodiments, Z is [ka] is.

[0109] In some embodiments, Z is a nitrogen-containing heterocyclyl. In some embodiments, Z is a 6-membered nitrogen-containing heterocyclyl. In some embodiments, Z is [ka] is.

[0110] In some embodiments, Z is a bicyclic heterocyclyl. ... 5 In some embodiments, Z is a bicyclic nitrogen-containing heterocyclyl optionally substituted with [ka] In some embodiments, Z is 1-oxa-3,8-diazaspiro[4.5]decan-2-one. In some embodiments, Z is [ka] is.

[0111] In some embodiments, for Formula (I) and (Ia), Z is aryl. In some embodiments, Z is monocyclic aryl. In some embodiments, Z is phenyl. In some embodiments, Z is monosubstituted phenyl (e.g., one R 5 In some embodiments, Z has one R 5 is a nitrogen-containing group. In some embodiments, Z is a monosubstituted phenyl, 5 In some embodiments, Z is a monosubstituted phenyl in which R 5 is an oxygen-containing group. In some embodiments, Z is a monosubstituted phenyl in which one R 5In some embodiments, Z is a monosubstituted heteroalkyl, wherein R is an oxygen-containing heteroalkyl. 5 In some embodiments, Z is a monosubstituted phenyl in which R 5 In some embodiments, Z is a monosubstituted phenyl having one R 5 In some embodiments, Z is a monosubstituted phenyl having one R 5 is in the para position and is a monosubstituted phenyl.

[0112] In some embodiments, for formula (I) and (Ia), Z is alkyl. In some embodiments, Z is C1-C 12 In some embodiments, Z is C1-C 10 In some embodiments, Z is C1-C8 alkyl. In some embodiments, Z is 1-5 R 5 In some embodiments, Z is C1-C8 alkyl substituted with one R 5 In some embodiments, Z is C1-C8 alkyl substituted with one R 5 C1-C8 alkyl substituted by R 5 is alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , or -N(R C1 )(R D1 In some embodiments, Z is selected from the group consisting of one R 5 C1-C8 alkyl substituted by R 5 -OR A1 , or -C(O)OR A1 In some embodiments, Z is one R 5 C1-C8 alkyl substituted by R 5 -OR A1 or —C(O)OH. In some embodiments, Z is —CH 3 .

[0113] In some embodiments, for formula (I) and (Ia), Z is heteroalkyl. In some embodiments, Z is C1-C 12 In some embodiments, Z is a C1-C 10 In some embodiments, Z is a C1-C8 heteroalkyl. In some embodiments, Z is a C1-C6 heteroalkyl. In some embodiments, Z is selected from the group consisting of one or more R 5 In some embodiments, Z is a nitrogen-containing heteroalkyl optionally substituted with 1 to 5 R 5 In some embodiments, Z is N-methyl-2-(methylsulfonyl)ethane-1-aminyl.

[0114] In some embodiments, Z is -OR A , or -C(O)OR A In some embodiments, Z is -OR A (e.g., —OH, or —OCH). In some embodiments, Z is —OCH. In some embodiments, Z is —C(O)OR A (e.g., —C(O)OH).

[0115] In some embodiments, Z is hydrogen.

[0116] In some embodiments, L 2 is a bond, P, and L 3 is independently absent. In some embodiments, L 2 is a bond, P is heteroaryl, and L 3 is a bond and Z is hydrogen. In some embodiments, P is heteroaryl and L 3 is heteroalkyl and Z is alkyl.

[0117] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib): [ka] or a pharmaceutically acceptable salt thereof, wherein ring M 1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from 1 to 5 R 3 and ring Z 1 However, 1 to 5 R 5 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halo, cyano, nitro, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R 2a , and R 2b , or R 2c , and R 2d taken together form an oxo group, and X is absent, N(R 10 )(R 11 ), O, or S, and R C is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 6 R 6 and each R 3 , R 5 , and R 6 are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(RC1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 10 , and R 11 each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, —C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -C(O)N(R C1 ), cycloalkyl, heterocyclyl, or heteroaryl, and each R A1 , R B 1. R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and each m and n is independently 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein. In some embodiments, each R 3 , and R 5 wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally and independently substituted with halogen, oxo, cyano, cycloalkyl, or heterocyclyl.

[0118] In some embodiments, the compound of formula (Ib) is a compound of formula (Ibi): [ka] or a pharmaceutically acceptable salt thereof, wherein ring M 2 but one or more R 3 aryl, or heteroaryl optionally substituted with 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b , or R 2c , and R 2d taken together form an oxo group, X is absent, O, or S, and each R 3 , and R 5 are independently alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 wherein each alkyl and heteroalkyl is optionally substituted with halogen, or two R 5 But together, Ring Z 2 and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0119] In some embodiments, the compound of formula (Ibi) is a compound of formula (Ib-ii): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 2c , and R 2d each is independently hydrogen, alkyl, or heteroalkyl, or R 2c , and R 2d together form an oxo group, and each R 3 , and R 5 are independently alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 wherein each alkyl and heteroalkyl is optionally substituted with halogen; and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; p and q are each independently 0, 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0120] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 2c , and R 2d each is independently hydrogen, alkyl, or heteroalkyl, or R 2c , and R 2d together form an oxo group, and each R 3 , and R 5 are independently alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1, or -C(O)R B1 wherein each alkyl and heteroalkyl is optionally substituted with halogen; and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m is 1, 2, 3, 4, 5, or 6; and each of p and q is independently 0, 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0121] In some embodiments, the compound of Formula (I) is a compound of Formula (Id): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X is absent, O, or S; and R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b , or R 2c , and R 2d taken together form an oxo group, and each R 5 are independently alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 wherein each alkyl and heteroalkyl is optionally substituted with halogen; and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; each of m and n is independently 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0122] In some embodiments, the compound of Formula (I) is a compound of Formula (Ie): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X is absent, O, or S; and R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b , or R 2c , and R 2d taken together form an oxo group, and each R 5 are independently alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; each of m and n is independently 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0123] In some embodiments, the compound of formula (I) is a compound of formula (If): [ka] or a pharmaceutically acceptable salt thereof, wherein M is one or more R 3 and ring P is alkyl optionally substituted with one or more R 4 and L is heteroaryl optionally substituted with 3 but one or more R 2 and Z is alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R 5 optionally substituted with R 2a , and R 2b each is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b together form an oxo group, and each R 2 , R 3 , R 4 , and R 5 are independently alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; and n is independently 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0124] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein M is a bond, alkyl, or aryl, and the alkyl and aryl are selected from the group consisting of one or more R 3 and optionally substituted with L 3but one or more R 2 and Z is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -OR A and alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from the group consisting of one or more R 5 optionally substituted with R A is hydrogen and R 2a , and R 2b each is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b together form an oxo group, and each R 2 , R 3 , and R 5 are independently alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; and n is independently 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein. In some embodiments, the compound of Formula (II) is a compound of Formula (II-a): [ka] or a pharmaceutically acceptable salt thereof, wherein L 3 is alkyl, or heteroalkyl, each of which is selected from one or more R 2 and Z is hydrogen, alkyl, heteroalkyl, or -OR A and alkyl and heteroalkyl are selected from one or more R 5 optionally substituted with R2a , and R 2b each is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b together form an oxo group, and each R 2 , R 3 , and R 5 are independently alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and R A is hydrogen, and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; and n is independently 1, 2, 3, 4, 5, or 6; [ka] refers to the connection to a linking group or polymer described herein.

[0125] In some embodiments, the compound of formula (I) is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein Z 1 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from 1 to 5 R 5 optionally substituted with R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halo, cyano, nitro, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and RC is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and each of the alkyl, alkenyl, alkynyl, or heteroalkyl is selected from 1 to 6 R 6 optionally substituted with R 3 , R 5 , and R 6 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; each m and n is independently 1, 2, 3, 4, 5, or 6; and q is an integer from 0 to 25; [ka] but, It refers to a linking group, or connection to a polymer, as described herein.

[0126] In some embodiments, the compound of formula (III) is a compound of formula (III-a): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from 1 to 5 R 5 optionally substituted with R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, heteroalkyl, halo, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and R 3 , and R 5 each independently represents alkyl, heteroalkyl, halogen, oxo, -ORA1 , -C(O)OR A1 , or -C(O)R B1 and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; o and p are each independently 0, 1, 2, 3, 4, or 5; and q is an integer from 0 to 25; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0127] In some embodiments, the compound of formula (III-a) is a compound of formula (III-b): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from 1 to 5 R 5 optionally substituted with R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, heteroalkyl, halo, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and R 3 , and R 5 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R A1 , and R B1is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; o and p are each independently 0, 1, 2, 3, 4, or 5; and q is an integer from 0 to 25; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0128] In some embodiments, the compound of formula (III-a) is a compound of formula (III-c): [ka] or a pharmaceutically acceptable salt thereof, wherein X is C(R')(R"), N(R'), or S(O) x each of R′ and R″ is independently hydrogen, alkyl, halogen, or cycloalkyl; R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, heteroalkyl, or halo, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and R 3 , and R 5 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, or 5; q is an integer from 0 to 25; and x is 0, 1, or 2; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0129] In some embodiments, the compound of formula (III-c) is a compound of formula (III-d): [ka] or a pharmaceutically acceptable salt thereof, wherein X is C(R')(R"), N(R'), or S(O) x each of R′ and R″ is independently hydrogen, alkyl, halogen, or cycloalkyl; R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, heteroalkyl, or halo, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and R 3 , and R 5 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, or 5; q is an integer from 0 to 25; and x is 0, 1, or 2; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0130] In some embodiments, the compound of Formula (I) is a compound of Formula (III-e): [ka] or a pharmaceutically acceptable salt thereof, wherein Z 1 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from 1 to 5 R 5 optionally substituted with R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halo, cyano, nitro, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R 2a , and R 2b , or R 2c , and R 2d taken together form an oxo group, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and each of the alkyl, alkenyl, alkynyl, or heteroalkyl is selected from 1 to 6 R 6 optionally substituted with R 3 , R 5 , and R 6 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R 12 is independently deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino; and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; q is an integer of 0 to 25; and w is 0 or 1; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0131] In some embodiments, the compound of Formula (I) is a compound of Formula (III-f): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from 1 to 5 R 5 optionally substituted with R 2a , R 2b , R 2c , and R 2d each is independently hydrogen, alkyl, heteroalkyl, halo, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and R C is hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and each of the alkyl, alkenyl, alkynyl, or heteroalkyl is selected from 1 to 6 R 6 optionally substituted with R 3 , R 5 , and R 6 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and each R 12 is independently deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino; and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; o and p are each independently 0, 1, 2, 3, 4, or 5; q is an integer from 0 to 25; and w is 0 or 1; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0132] In some embodiments, the compound of Formula (I) is a compound of Formula (III-g): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from 1 to 5 R 5 optionally substituted with R C is hydrogen, alkyl, -N(R C )C(O)R B , -N(R C )C(O)(C1-C6-alkyl), or -N(R C )C(O)(C1-C6-alkenyl), wherein each of the alkyl and alkenyl is selected from 1 to 6 R 6 optionally substituted with R 2a , R 2b , R 2c , and R 2d are each independently hydrogen or alkyl, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and R 3 , R 5 , and R 6 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and R 12 is hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino, and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; q is an integer from 0 to 25; and x is 0, 1, or 2; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0133] In some embodiments, the compound of Formula (I) is a compound of Formula (III-h): [ka] or a pharmaceutically acceptable salt thereof, wherein R C is hydrogen, alkyl, -N(R C )C(O)R B , -N(R C )C(O)(C1-C6-alkyl), or -N(R C )C(O)(C1-C6-alkenyl), each of the alkyl and alkenyl groups being 1 to 6 R 6 optionally substituted with R 2a , R 2b , R 2c , and R 2d are each independently hydrogen or alkyl, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and R 3 , R 5 , and R 6 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and R 12 is hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino, and each R A1 , and R B1 is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; q is an integer from 0 to 25; x is 0, 1, or 2; and z is 0, 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0134] In some embodiments, the compound of formula (I) is a compound of formula (III-i): [ka] or a pharmaceutically acceptable salt thereof, wherein X is C(R')(R"), N(R'), or S(O) x each of R' and R" is independently hydrogen, alkyl, or halogen; R C is hydrogen, alkyl, -N(R C )C(O)R B , -N(R C )C(O)(C1-C6-alkyl), or -N(R C )C(O)(C1-C6-alkenyl), wherein each of the alkyl and alkenyl is selected from 1 to 6 R 6 optionally substituted with R 2a , R 2b , R 2c , and R 2d are each independently hydrogen or alkyl, or R 2a , and R 2b , or R 2c , and R 2d together form an oxo group, and R 3 , R 5 , and R 6 each independently represents alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 and R 12 is hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino, and each R A1 , and R B1is independently hydrogen, alkyl, or heteroalkyl; m and n are each independently 1, 2, 3, 4, 5, or 6; q is an integer from 0 to 25; x is 0, 1, or 2; and z is 0, 1, 2, 3, 4, 5, or 6; [ka] refers to a linking group, or connection to a polymer, as described herein.

[0135] In some embodiments, the compound is a compound of formula (I). 2 is a bond, P, and L 3 is independently non-existent.

[0136] In some embodiments, the compound is a compound of formula (Ia). In some embodiments of formula (II-a), L 2 is a bond, P is heteroaryl, and L 3 is a bond and Z is hydrogen. In some embodiments, P is heteroaryl and L 3 is heteroalkyl and Z is alkyl. In some embodiments, L 2 is a bond, P, and L 3 is independently absent. In some embodiments, L 2 is a bond, P is heteroaryl, and L 3 is a bond and Z is hydrogen. In some embodiments, P is heteroaryl and L 3 is heteroalkyl and Z is alkyl.

[0137] In some embodiments, the compound is a compound of formula (Ib). In some embodiments, P is absent and L 1 is -NHCH2, and L 2 is a bond, M is aryl (e.g., phenyl), and L 3is —CH 2 O and Z is heterocyclyl (eg, nitrogen-containing heterocyclyl, such as thiomorpholinyl-1,1-dioxide).

[0138] In some embodiments of Formula (Ib), P is absent and L 1 is -NHCH2, and L 2 is a bond, M is absent, and L 3 is a bond and Z is heterocyclyl (eg, an oxygen-containing heterocyclyl such as tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or oxiranyl).

[0139] In some embodiments, the compound is of formula (Ibi). In some embodiments of formula (Ibi), R 2a , and R 2b are each independently hydrogen or CH3, and R 2c , and R 2d are each independently hydrogen, m is 1 or 2, n is 1, X is O, p is 0, and M 2 is one or more R 3 phenyl optionally substituted with R 3 is -CF3 and Z 2 is heterocyclyl (eg, an oxygen-containing heterocyclyl such as tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or oxiranyl).

[0140] In some embodiments, the compound is a compound of formula (Ib-ii). In some embodiments of formula (Ib-ii), R 2a , R 2b , R 2c , and R 2d are independently hydrogen, q is 0, p is 0, m is 1, and Z 2 is heterocyclyl (eg, an oxygen-containing heterocyclyl such as tetrahydropyranyl).

[0141] In some embodiments, the compound is a compound of formula (Ic). In some embodiments of formula (Ic), R 2c , and R 2d are independently hydrogen, m is 1, p is 1, q is 0, and R 5 is -CH3 and Z is heterocyclyl (eg, nitrogen-containing heterocyclyl, such as piperazinyl).

[0142] In some embodiments, the compound is a compound of formula (Id). In some embodiments of formula (Id), R 2a , R 2b , R 2c , and R 2d is independently hydrogen, m is 1, n is 3, X is O, p is 0, and Z is heterocyclyl (e.g., an oxygen-containing heterocyclyl such as tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or oxiranyl).

[0143] In some embodiments, the compound is a compound of formula (If). In some embodiments of formula (If), R 2a , and R 2b is independently hydrogen, n is 1, M is -CH2-, P is a nitrogen-containing heteroaryl (e.g., imidazolyl), and L 3 is —C(O)OCH2— and Z is CH3.

[0144] In some embodiments, the compound is a compound of formula (II-a). In some embodiments of formula (II-a), R 2a , and R 2b are independently hydrogen, n is 1, q is 0, and L 3 is —CH2(OCH2CH2)2 and Z is —OCH3.

[0145] In some embodiments of Formula (II-a), R 2a , and R 2b are independently hydrogen, n is 1, and L3 is a bond or -CH2, and Z is hydrogen or -OH 。

[0146] In some embodiments, the compound is a compound of formula (III). In some embodiments of formula (III), R 2a , R 2b , R 2c , and R 2d are independently hydrogen, m is 1, n is 2, q is 3, p is 0, and R C is hydrogen, and Z 1 is R 5 (e.g., —N(CH3)(CH2CH2)S(O)2CH3).

[0147] In some embodiments, the compound is of formula (III-b). In some embodiments of formula (III-b), R 2a , R 2b , R 2c , and R 2d are independently hydrogen, m is 0, n is 2, q is 3, p is 0, and Z 2 is one R 5 (eg, —NH 2 ) substituted aryl (eg, phenyl).

[0148] In some embodiments, the compound is of formula (III-b). In some embodiments of formula (III-b), R 2a , R 2b , R 2c , and R 2d are independently hydrogen, m is 1, n is 2, q is 3, p is 0, and R C is hydrogen, and Z 2 is heterocyclyl (eg, a nitrogen-containing heterocyclyl, such as a nitrogen-containing spiroheterocyclyl, such as 2-oxa-7-azaspiro[3.5]nonanyl).

[0149] In some embodiments, the compound is of formula (III-d). In some embodiments of formula (III-d), R 2a , R 2b , R 2c , and R 2d is independently hydrogen, m is 1, n is 2, q is 1, 2, 3, or 4, p is 0, and X is S(O). In some embodiments of Formula (III-d), R 2a , and R 2b is independently hydrogen, m is 1, n is 2, q is 1, 2, 3, or 4, p is 0, and X is S(O)2.

[0150] In some embodiments, the compound is a compound of Formula (Ib), (Id), or (Ie). In some embodiments, the compound is a compound of Formula (Ib), (Id), or (II). In some embodiments, the compound is a compound of Formula (Ib), (Id), or (If). In some embodiments, the compound is a compound of Formula (Ib), (Id), or (III).

[0151] In some embodiments, the compound of Formula (I) is not a compound disclosed in WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 019391, WO2017 / 075630, US2012 / 0213708, US2016 / 0030359, or US2016 / 0030360.

[0152] In some embodiments, the compound of Formula (I) comprises a compound shown in Table 3, or a pharmaceutically acceptable salt thereof. In some embodiments, the exterior surface and / or one or more compartments within a device described herein comprises a small molecule compound shown in Table 3, or a pharmaceutically acceptable salt thereof. [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0153] Conjugation of any of the compounds in Table 3 to a polymer (e.g., alginate) can be carried out as described in Example 2 of WO2019 / 195055, or by any other suitable chemistry.

[0154] In some embodiments, the compound is a compound of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (II-a), (III), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), or (III-i)), or a pharmaceutically acceptable salt thereof; [ka] or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the polysaccharide polymers or devices (e.g., hydrogel capsules) described herein are [ka] or a pharmaceutically acceptable salt of either compound.

[0156] In some embodiments, the polysaccharide polymers or devices (e.g., hydrogel capsules) described herein are [ka] or a pharmaceutically acceptable salt of either compound.

[0157] In some embodiments, the polysaccharide polymers or devices (e.g., hydrogel capsules) described herein are [ka] or a pharmaceutically acceptable salt of any of these compounds.

[0158] In some embodiments, a compound of Formula (I) (e.g., compound 101 in Table 3) is covalently attached to alginate (e.g., an alginate having approximately MW<75 kDa, G:M ratio ≧1.5) at a conjugation density of at least 2.0% and less than 9.0%, or between 3.0% and 8.0%, between 4.0 and 7.0, between 5.0 and 7.0, or between 6.0 and 7.0, or about 6.8, as determined by combustion analysis for nitrogen content as described in WO2020 / 069429.

[0159] Photoactive Crosslinkers and Photoinitiators Described herein are polysaccharide polymers covalently attached to photoactive crosslinkers, as well as compositions and methods of use thereof. The photoactive crosslinkers comprise a moiety that is activated upon exposure to light. The light can include light of any wavelength from infrared to X-ray energy. In some embodiments, the light comprises ultraviolet light (e.g., 360 nm to 400 nm, e.g., 370 nm to 390 nm, e.g., 380 nm to 400 nm, e.g., 390 nm to 400 nm). In some embodiments, the light comprises visible light (e.g., 400 nm to 700 nm). Photoactive crosslinkers often comprise at least one unsaturated functional group capable of undergoing free radical polymerization. In some embodiments, the photoactive crosslinker comprises an alkenyl group (e.g., C2 to C6). 12 In some embodiments, the photoactive crosslinker comprises an alkenyl group (e.g., C2-C8 alkenyl). 12alkenyl, C2-C8 alkenyl). Moieties that can be activated upon exposure to radiation include aromatic groups, alkenyl groups, alkynyl groups, and azido groups. Exemplary alkenyl compounds that can act as photoactive crosslinkers include alkenoic acids, such as acrylates, methacrylates, acrylamides, and methacrylamides, as well as their corresponding acid chlorides and anhydrides. In some embodiments, the photoactive crosslinker comprises an acrylate group. In some embodiments, the photoactive crosslinker comprises a methacrylate group. In some embodiments, the photoactive crosslinker comprises an acrylamide group. In some embodiments, the photoactive crosslinker comprises a methacrylamide group. Other exemplary alkenyl compounds include enols (e.g., 2-propen-1-ol), alkenyl halides (e.g., allyl chloride, etc.), organometallic alkenyl compounds (e.g., vinyl magnesium bromide), and aryl compounds (e.g., styrene). Exemplary photoactive crosslinkers include acrylates, methacrylates, ethylene glycol dimethylacrylate, divinylbenzene, 1,3-diisopropylbenzene, and N,N'-methylenebiscrylamide. In one embodiment, the photoactive crosslinker is a bifunctional crosslinker, i.e., has two reactive functional groups. In one embodiment, the photoactive covalent crosslinker has both an alkenyl functional group and an amide functional group. In one embodiment, the photoactive crosslinker has both an alkenyl functional group and a carboxylate functional group. In one embodiment, the photoactive crosslinker has both an alkenyl functional group and an amide functional group.

[0160] In one embodiment, the photoactive crosslinker has the structure of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein X 1 But non-existence, O, NR 33 , or C(R 34a )(R 34b ) and R 30a , R 30b , R31 , R 32 , R 33 , R 34a , and R 34b each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0161] In one embodiment, X 1 is O and R 30a , R 30b , R 31 , and R 32 each is hydrogen; R32 is heteroalkyl (e.g., propylamine, e.g., —CHCHCHNH). In one embodiment, X 1 is O and R 30a , R 30b , R 31 , and R 32 is hydrogen, and R 32is heteroalkyl (e.g., ethylamine, e.g., —CHCHNH). In one embodiment, the photoactive crosslinker of formula (IV) is a methacrylate. In one embodiment, X 1 is non-existent, and R 32 is halo (e.g., chloro), and R 30a , R 30b , and R 31 is hydrogen. In one embodiment, the photoactive crosslinker of formula (IV) is acryloyl chloride.

[0162] In one embodiment, X 1 is NR 33 (e.g., NH), and R 30a , R 30b , R 31 , and R 32 is hydrogen. In one embodiment, the photoactive crosslinker of formula (IV) is acrylamide.

[0163] In one embodiment, the photoactive crosslinker of formula (IV) has the structure of formula (IV-a): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 30a , R 30b , R 31 , R 32 , and R 35 each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, each RA1 , RB1 , RC1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0164] In one embodiment, the photoactive crosslinker of formula (IV) has the structure of formula (IV-b): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 30a , R 30b , R31 , R32 , R 36a , and R 36b each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; R 35 is hydrogen, alkyl, heteroalkyl, halo, cyano, nitro, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and n is 1, 2, 3, 4, 5, or 6.

[0165] In one embodiment, the photoactive crosslinker of formula (IV) has the structure of formula (IV-c): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 30a , R 30b , and R31 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 32 is alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR A1 , -C(O)R B1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1, R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0166] In one embodiment, the photoactive crosslinker of formula (IV) has the structure of formula (IV-d): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, and R 30a , R 30b , R31 , R32 , R 36a , and R 36b each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 32 is alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR A1 , -C(O)R B1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , RC1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and n is 1, 2, 3, 4, 5, or 6.

[0167] In some embodiments, the photoactive crosslinker is a compound in Table 4. [Table 10] [Table 11]

[0168] The photoactive crosslinker can be used alone or, preferably, in the presence of a photoinitiator. As used herein, "photoinitiator" refers to a molecule that can absorb radiation, e.g., light, e.g., photons, and form a reactive species in an excited state. A variety of free radical initiators, as easily identified by one skilled in the art, can be used in the practice of the present invention. In one embodiment, the photoinitiator is an ultraviolet (UV) photoinitiator. Exemplary UV photoinitiators include lithium phenyl-2,4,6-trimethylbenzoylphosphonate (LAP), camphorquinone, benzoin methyl ether, 1-hydroxy-cyclohexyl-phenyl-ketone (i.e., Irgacure 184), 2-hydroxy-2-methyl-1-phenyl-1-propanone (i.e., Darocur 1173), 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methylpropan-1-one (i.e., Irgacure 2959), 2-benzyl-2-(dimethylamino)-1-(4-morpholin-4-ylphenyl)butan-1-one (i.e., Irgacure 369), 2-methyl-1-(4-methylsulfanylphenyl)-2-morpholin-4-ylpropan-1-one (i.e., Irgacure 369), and the like. 907) Diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (e.g., Darocur TPO), benzoin ethyl ether, benzophenone, 9,10-anthraquinone, ethyl-4-N,N-dimethylaminobenzoate, diphenyliodonium chloride, and water-soluble derivatives thereof. In some embodiments, the photoinitiator is LAP. In some embodiments, the photoinitiator is camphorquinone. In some embodiments, the photoinitiator is benzoin methyl ether. In some embodiments, the photoinitiator is Irgacure 2959.

[0169] For visible light polymerization, a dye and cocatalyst system may be used. Exemplary visible light photoinitiators include 2-(2,4,5,7-tetrabromo-3-hydroxy-6-oxoxanthen-9-yl)benzoic acid (i.e., eosin Y), erythrosine, riboflavin, rose bengal, methylene blue, and thionin. In some embodiments, the visible light photoinitiator is eosin Y. In some embodiments, the visible light photoinitiator is erythrosine. In some embodiments, the visible light photoinitiator is riboflavin. In some embodiments, the visible light photoinitiator is rose bengal. In some embodiments, the visible light photoinitiator is methylene blue. In some embodiments, the visible light photoinitiator is thionin. A small amount of comonomer can optionally be added to the crosslinking reaction to increase the polymerization rate. Examples of suitable comonomers include vinylpyrrolidinone, acrylamide, methacrylamide, acrylic acid, methacrylic acid, sodium acrylate, sodium methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate (HEMA), ethylene glycol diacrylate, ethylene glycol dimethacrylate, pentaerythritol trimethacrylate, trimethylpropane triacrylate, trimethylolpropane trimethacrylate, tripropylene glycol diacrylate, tripropylene glycol dimethacrylate, glyceryl acrylate, glyceryl methacrylate, and the like.

[0170] In some embodiments, the photoinitiator is a thermally activated photoinitiator.

[0171] The photoactive crosslinker can be used in the presence of a single photoinitiator or multiple photoinitiators, which can include 2, 3, 4, 5, 6, 7, 8, or more photoinitiators.

[0172] In one embodiment, the covalent cross-linking moieties may be present on the polysaccharide polymer at a density of at least 1%, e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more, as determined, for example, by LC-UV assay. In one embodiment, the covalent cross-linking moieties may be present on the polysaccharide polymer at a density of less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more, as determined, for example, by LC-UV assay. In one embodiment, the covalent cross-linking moieties may be present on the polysaccharide polymer at a density of greater than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more, as determined, for example, by LC-UV assay.

[0173] The modified polysaccharide may include a photoactive crosslinker moiety. The photoactive crosslinker (e.g., a compound of Formula (IV)-(IV-d)) may be covalently attached to a polysaccharide polymer, e.g., an alginate. The modified polysaccharide polymer, e.g., a modified alginate polymer, may be capable of being crosslinked to another polymer. In one embodiment, the polysaccharide polymer is modified with multiple types of photoactive crosslinkers.

[0174] In one embodiment, the polysaccharide polymer is modified with a group capable of undergoing free radical polymerization. In one embodiment, the polysaccharide is modified with a compound of any one of formulas (IV), (IV-a), (IV-b), (IV-c), or (IV-d). In one embodiment, the modified polysaccharide is modified with a compound selected from Table 4. In one embodiment, the polysaccharide is [ka] In one embodiment, the polysaccharide polymer is modified with

[0175] In one embodiment, the modified polysaccharide is a compound of formula (V): [ka] or a pharmaceutically acceptable salt, or tautomer thereof, wherein each of T and U is C(R 40 )(R 41 ), O, or N(R 42 ) and R 38a , R 38b , R 39a , R 39b , R 40 , R 41 , and R 42 each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 32 , R 35 each of R is hydrogen, alkyl, heteroalkyl, halo, cyano, nitro, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl; A1 , R B1 , R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, and the photoactive crosslinker has the structure of formula (IV), (IV-a), (IV-b), (IV-c), and (IV-d).

[0176] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Va): [ka] or a pharmaceutically acceptable salt, or tautomer thereof, wherein each of T and U is C(R 40 )(R 41 ), O, N(R 42 ) and R 30a , R 30b , R 31 , R 32 , R 38a , R 38b , R 39a , R 39b , R 40 , R 41 , and R 42 each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0177] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Vb): [ka] or a pharmaceutically acceptable salt, or tautomer thereof, wherein each of T and U is C(R 40 )(R 41 ), O, N(R 42 ) and R 30a , R 30b , R 31 , R 35 , R 38a , R 38b , R 39a , R 39b , R 40 , R 41 , R 42 , R 43a , and R 43b each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1, R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and n is 1, 2, 3, 4, 5, or 6.

[0178] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Vc): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein U is C(R 40 )(R 41 ), O, N(R 42 ) and R 30a , R 30b , R 31 , R 35 , R 38a , R 38b , R 39a , R 39b , R 40 , R 41 , R 42 , R 43a , R 43b , and R 44 each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SRE1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and n is 1, 2, 3, 4, 5, or 6.

[0179] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Vd): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein U is C(R 40 )(R 41 ), O, N(R 42 ) and R 30a , R 30b , R 31 , R 38a , R 38b , R 39a , R 39b , R 40 , R 41 , R 42 , R 43a , and R 43b each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1)C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and n is 1, 2, 3, 4, 5, or 6.

[0180] In one embodiment, the modified polysaccharide polymer has the structure of formula (VI): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein W, T 1 , T 2 , U 1 , and U 2 each independently represents C(R 40 )(R 41 ), O, N(R 42 ) and R 38a , R 38b , R 38c , R 38d , R 39a , R 39b , R 39a , R 39b、 R 40 , R 41 , and R 42 each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1, -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and RE1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; p is an integer from 1 to 100; the non-fibrous compound has a structure of Formula (I), (Ia), (Ib), (Ibi), (Ib-ii), (Ic), (Id), (Ie), (If), (II), (II-a), (III), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), or (III-i); and the photoactive crosslinker has a structure of Formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), or (IV-e).

[0181] In one embodiment, the modified polysaccharide polymer has the structure of formula (Vi-ai): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein W, T 1 , U 1 , and U 2 each independently represents C(R40 )(R 41 ), O, or N(R 42 ) and R 38a , R 38b , R 38c , R 38d , R 39a , R 39b , R 39c , R 39d , R 40 , R41 , and R 42 each independently is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, each RA1 , R B1 , R C1 , R D1 , and RE1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R7 and each R7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and the variable M 1 , Z 1 , R 2a , R 2b , R 2c , R 2d , X, R C, m, and n are as defined in formula (Ib), p is an integer from 1 to 100, and the photoactive crosslinker has a structure of formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), or (IV-e).

[0182] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Va-ii): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein W, T 1 , U 1 , and U 2 each independently represents C(R 40 )(R 41 ), O, or N(R 42 ) and R 38a , R 38b , R 38c , R 38d , R 39a , R 39b , R 39c , R 39d , R 40 , R 41 , and R 42 each independently is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and the variable Z 1 , R 2a , R 2b , R 2c , R 2d , X, R C , m, n, and q are as defined in formula (III-f), p is an integer from 1 to 100, and the photoactive crosslinker has a structure of formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), or (IV-e).

[0183] In one embodiment, the modified polysaccharide polymer has the structure of formula (Vi-bi): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein W, X 1 , T 2 , U 1 , and U 2 each independently represents C(R 40 )(R 41 ), O, N(R 42 ) and R 30a , R 30b , R 31 , R 32 , R 38a , R 38b , R 38c , R 38d , R 39a , R 39b , R 39c , R 39d , R 40 , R 41 , R 42 , and R 44each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, and the non-fibrous compound has a structure of formula (I), (Ia), (Ib), (Ibi), (Ib-ii), (Ic), (Id), (Ie), (If), (II), (II-a), (III), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), or (III-i).

[0184] In one embodiment, the modified polysaccharide polymer has the structure of formula (Vi-ci): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein X 1 , U 1 , U2, and W each independently represent C(R40 )(R 41 ), O, or N(R 42 ) and R 30a , R 30b , R 31 , R 32 , R 38a , R 38b , R 38c , R 38d , R 39a , R 39b , R 39c , R 39d , R 40 , R 41 , R 42 , and R 44 each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and the variable M 1 , Z 1 , R 2a , R 2b , R 2c , R 2d , X, RC , m, and n are as defined in formula (Ib), and p is an integer of 1 to 100.

[0185] In one embodiment, the modified polysaccharide polymer has the structure of formula (Vi-c-ii): [ka] or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein W, X 1 , Y 1 , and Y2 each independently represents C(R 40 )(R 41 ), O, or N(R 42 ) and R 30a , R 30b , R 31 , R 32 , R 38a , R 38b , R 38c , R 38d , R 39a , R 39b , R 39c , R 39d , R 40 , R 41 , R 42 , and R 44 each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R A1 , R B1 , R C1 , R D1 , and R E1are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; and the variable Z 1 , R 2a , R 2b , R 2c , R 2d , X, R C , m, n, and q are as defined in formula (III-f), and p is an integer of 1 to 100.

[0186] In one embodiment, the modified polysaccharide polymer of formula (VI) is a compound selected from Table 5: [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0187] In one embodiment, the polysaccharide polymer is [ka] is.

[0188] The polysaccharide polymers described herein may be modified with any suitable functional group (e.g., carboxyl or hydroxyl). In one embodiment, the polysaccharide polymer is modified with a single type of functional group. In one embodiment, the polysaccharide polymer is modified with two or more types of functional groups. In one embodiment, the polysaccharide polymer is modified on a carboxyl group. In one embodiment, the polysaccharide polymer is modified on a carboxyl group and a hydroxyl group. In one embodiment, the polysaccharide polymers described herein may be modified on one or more functional groups with a compound of Formula (I) and / or a compound of Formula (IV).

[0189] In one embodiment, the degree of modification (i.e., the percent of functional groups of the polymer modified with the photoactive crosslinker) is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In one embodiment, the degree of modification (i.e., the percent of functional groups of the polymer that are modified with the photoactive crosslinker) is greater than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In one embodiment, the degree of modification (i.e., the percent of functional groups of the polymer that are modified with the photoactive crosslinker) is less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0190] In some embodiments, the polysaccharide polymers described herein retain sufficient unreacted carboxylic acid groups to allow for ionic cross-linking, for example, when the polymers are used to prepare hydrogel capsules with dual cross-linking. In some embodiments, the polysaccharide polymers described herein do not contain more than 10% modification of the carboxylic acid groups. In some embodiments, the polysaccharide polymers described herein do not contain more than 5% modification of the carboxylic acid groups. In some embodiments, the polysaccharide polymers described herein do not contain more than 5%, 6%, 7%, 8%, 9%, or 10% modification of the carboxylic acid groups.

[0191] In one embodiment, the polysaccharide polymers described herein are modified with one, two, three, or more unique compounds. In one embodiment, the polysaccharide polymers described herein are modified with a photoactive crosslinker (e.g., a compound of Formula (IV), a compound of Formula (I), and a cell adhesion molecule (e.g., any of the cell-binding peptides described herein, e.g., RGD, or RGDSP). In one embodiment, the polysaccharide polymers described herein are modified with a photoactive crosslinker. In one embodiment, the polysaccharide polymers described herein are modified with a compound of Formula (I). In one embodiment, the polysaccharide polymers described herein are modified with a cell adhesion molecule. In embodiments, the polysaccharide polymers described herein are modified with both a photoactive crosslinker and a cell adhesion molecule. In a preferred embodiment, the polysaccharide polymers described herein are modified with both a photoactive crosslinker and a compound of Formula (I). In one embodiment, the polysaccharide polymers described herein are modified with both a photoactive crosslinker (e.g., compound 201) and a compound of Formula (I) (e.g., a compound in Table 3).

[0192] In one embodiment, the polysaccharide polymer described herein is [ka] and modified with a compound in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and modified with a compound in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and modified with a compound in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and modified with a compound in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and modified with a compound in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and modified with a compound in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and modified with a compound in Table 3. In one embodiment, the polysaccharide polymers described herein are modified with a compound in Table 3 and are compounds in Table 3.

[0193] In one embodiment, the polysaccharide polymer described herein is [ka] In one embodiment, the polysaccharide polymer described herein is an alginate modified with both of the compounds: [ka] The alginate is modified with both of the compounds.

[0194] In one embodiment, the polysaccharide polymer described herein is modified with both a cell adhesion molecule (e.g., a cell-binding peptide) and a compound of Formula (I). In some embodiments, the polysaccharide polymer modified with a photoactive crosslinker, and optionally one or more crosslinkers, and one or both of a compound of Formula (I) (e.g., of Table 3), and a cell-binding peptide is an alginate, e.g., VLVG alginate, or SLG-100 alginate, e.g., a low-viscosity alginate, e.g., a high G:M ratio alginate. In some embodiments, the polysaccharide polymer described herein is modified with a compound of Formula (I) and a compound of Formula (IV). In one embodiment, the polysaccharide polymer described herein is modified with a compound of Formula (I) and a compound of Formula (IV) and does not comprise heparin. In one embodiment, the polysaccharide polymer described herein is modified with a compound of Formula (I) and a compound of Formula (IV) and does not comprise an anti-CD3 antibody. In one embodiment, the polysaccharide polymer described herein is modified with a compound of Formula (I) and a compound of Formula (IV) and does not comprise an anti-CD28 antibody. In one embodiment, the polysaccharide polymer described herein is modified with a compound of Formula (I) and a compound of Formula (IV) and does not comprise a major histocompatibility peptide. In one embodiment, the polysaccharide polymer described herein is modified with a compound of Formula (I) and a compound of Formula (IV) and does not comprise heparin, an anti-CD3 antibody, an anti-CD28 antibody, or a major histocompatibility peptide.

[0195] Polysaccharides (e.g., alginates) can be modified on the hydroxyl groups to improve one or more physical properties. The polysaccharide polymers of the present invention may or may not be sulfonated (i.e., should not contain sulfate groups).

[0196] Characteristics of hydrogels and hydrogel capsules The present disclosure further features hydrogels and hydrogel capsules comprising the polysaccharide polymers described herein. The hydrogels and hydrogel capsules can be crosslinked (i.e., covalently crosslinked) with photoactive crosslinking groups and / or crosslinked with, for example, divalent cations (e.g., Ba). 2+ ) ionic crosslinking in the presence of a suitable initiator. In one embodiment, the hydrogels or hydrogel capsules described herein are produced by photoactive crosslinking. In one embodiment, the hydrogels or hydrogel capsules described herein are produced by photoactive crosslinking and ionic crosslinking, also referred to herein as "dual crosslinking." Those skilled in the art will recognize that polymerization can be initiated by other methods, including heat, ultrasound, and gamma radiation in the presence of a suitable initiator.

[0197] The polysaccharide polymers described herein containing photoactive crosslinker moieties may be capable of undergoing further polymerization, e.g., reacting with compatible functional groups on the same or a different polymer. In one embodiment, a crosslinked polymer may be formed by reacting a first and second polymer containing a polymer modified to contain thiol groups and a second polymer modified to contain alkene groups. In some embodiments, hydrogel capsules are formed through covalent crosslinking of unsaturated functional groups by a chain growth polymerization process. In one embodiment, hydrogel capsules are formed through covalent crosslinking of unsaturated functional groups on a first polymer with unsaturated functional groups on a second polymer. In one embodiment, hydrogel capsules are formed through covalent crosslinking of unsaturated functional groups on a first polymer with alkenyl functional groups on a second polymer. In some embodiments, hydrogel capsules are formed through covalent crosslinking of unsaturated functional groups by a step-growth polymerization process. In one embodiment, the step-growth polymerization process involves a reaction between one or more unsaturated functional groups (eg, alkenyl groups) of one polysaccharide chain and a thiolated functional group of another polymer chain.

[0198] The hydrogel capsules described herein are formed by crosslinking one or more types of polysaccharide polymers. In one embodiment, the hydrogel capsules contain only polysaccharide polymers. In one embodiment, the hydrogel capsules contain the same type of polysaccharide polymer, e.g., alginate polymer. In one embodiment, the hydrogel capsules are formed by polymerization of two identical polysaccharides. In one embodiment, the hydrogel capsules are formed by polymerization of two different polysaccharides. In one embodiment, the hydrogel capsules contain multiple polymers, e.g., multiple polysaccharide polymers. In one embodiment, the hydrogel capsules contain one polysaccharide polymer and a non-polysaccharide polymer.

[0199] The hydrogel capsules described herein may be homogeneous, i.e., free of non-polysaccharide polymers. In one embodiment, the hydrogel capsules described herein do not contain a polymer selected from polyacrylamide, poly(vinyl alcohol), poly(ethylene oxide), polyethylene glycol (PEG), and polyphosphazene. In one embodiment, the hydrogel capsule does not contain poly(vinyl alcohol). In one embodiment, the hydrogel capsule does not contain poly(ethylene oxide). In one embodiment, the hydrogel capsule does not contain polyethylene glycol (PEG). In one embodiment, the hydrogel capsule does not contain polyphosphazene. In one embodiment, the hydrogel capsule is a two-compartment hydrogel capsule. In a preferred embodiment of the present invention, the hydrogel capsule consists of an inner compartment and an outer compartment. In one embodiment, the two compartments are formed from the same type of modified polysaccharide. In one embodiment, the two compartments are formed from different types of modified polysaccharide. In one embodiment, the inner compartment is formed from a polysaccharide of Formula (Vb) and the outer compartment is formed from a polysaccharide of Formula (Vb). In one embodiment, the inner compartment is formed from a polysaccharide of formula (Vd) and the outer compartment is formed from a polysaccharide of formula (Vd). In one embodiment, the inner compartment is formed from a polysaccharide of formula (Vci) and the outer compartment is formed from a polysaccharide of formula (Vci).

[0200] In some embodiments, the inner compartment is formed from an unmodified polysaccharide and the outer compartment is formed from a polysaccharide modified with a compound of Formula (Vb), (Vd), or (VI-ci). In some embodiments, the outer compartment is formed from an unmodified polysaccharide and the inner compartment is formed from a polysaccharide modified with a compound of Formula (Vb), (Vd), or (VI-ci). In some embodiments, the inner compartment is formed from a polysaccharide modified with a cell-binding agent (e.g., a compound in Table 1) and the outer compartment is formed from a polysaccharide modified with a compound of Formula (Vb), (Vd), or (VI-ci). In some embodiments, the inner compartment is formed from a polysaccharide modified with a compound of Table 1 and the outer compartment is formed from a polysaccharide modified with a compound of Formula (Vb), (Vd), or (VI-ci).

[0201] The present disclosure features a doubly cross-linked polysaccharide polymer for encapsulating mammalian cells. In one embodiment, the doubly cross-linked polysaccharide polymer can further include at least one cell-binding peptide (CBP) (as defined herein). The cells can express a therapeutic agent upon implantation of a device (e.g., a hydrogel capsule) comprising the doubly cross-linked polysaccharide polymer in a subject, e.g., a human or other mammalian subject. The device further includes at least one means for reducing FBR (as defined herein). In one embodiment, the means for reducing FBR includes a non-fibrous compound, as defined herein. In one embodiment, the non-fibrous compound is covalently attached to the doubly cross-linked polysaccharide polymer.

[0202] In some embodiments, the device (e.g., hydrogel capsule) further comprises an unmodified polysaccharide polymer. In some embodiments, the unmodified polysaccharide polymer is unmodified alginate. In some embodiments, the alginate is a high guluronic acid (G) alginate, comprising greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more guluronic acid (G). In some embodiments, the alginate is a high mannuronic acid (M) alginate, comprising greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more mannuronic acid (M). In some embodiments, the M:G ratio is about 1. In some embodiments, the M:G ratio is less than 1. In some embodiments, the M:G ratio is greater than 1. In one embodiment, the unmodified alginate has a molecular weight of 150 kDa to 250 kDa and a G:M ratio of ≧1.5.

[0203] In some embodiments, the device (e.g., hydrogel capsule) comprises a modified polysaccharide polymer that is a non-fibrous polymer, e.g., a non-fibrous alginate, including alginate chemically modified with a compound of Formula (I). The alginate in the non-fibrous polymer can be the same as or different from any unmodified alginate present in the device. In one embodiment, the density (e.g., amount of conjugation) of the compound of Formula (I) in the non-fibrous alginate is between about 4.0% and about 8.0%, between about 5.0% and about 7.0%, or between about 6.0% and about 7.0% nitrogen (e.g., as determined by combustion analysis for nitrogen content). In one embodiment, the amount of Compound 101 results in an increase in %N (when compared to unmodified alginate) of about 0.5%-2%, 2%-4% N, about 4%-6% N, about 6%-8%, or about 8%-10% N), where %N is determined by combustion analysis and corresponds to the amount of Compound 101 in the modified alginate.

[0204] The hydrogel capsules described herein can be porous or non-porous. The pores within polysaccharide hydrogel capsules (e.g., formed from alginate hydrogels) function as a selectively permeable membrane for small proteins and molecules while preventing larger, unwanted molecules, such as immunoglobulins, from accessing the encapsulated cells. In preferred embodiments, the hydrogels and hydrogel capsules described herein are porous. In some embodiments, the average pore diameter is about 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 11 nm, 12 nm, 13 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19 nm, or 20 nm. In some embodiments, the average pore diameter is greater than about 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 11 nm, 12 nm, 13 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19 nm, or 20 nm. In some embodiments, the average pore diameter is less than about 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 11 nm, 12 nm, 13 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19 nm, or 20 nm.

[0205] In some embodiments, the average pore size of the first and second compartments of a particle (e.g., a hydrogel capsule) is substantially the same. In some embodiments, the average pore size of the first and second compartments of a particle differs by about 1.5%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. In some embodiments, the average pore size of a device (e.g., the average pore size of the first compartment and / or the average pore size of the second compartment) depends on numerous factors, such as the material(s) in each compartment, the presence and density of a photoactive crosslinker, and the presence and density of a compound of Formula (I).

[0206] The hydrogel capsules described herein should not have pores of a diameter sufficient to allow the movement of cells (e.g., immune cells, e.g., dendritic cells) through the hydrogel. In some embodiments, the pore diameter is small enough to prevent the movement of antibodies through the hydrogel. In some embodiments, the hydrogel capsules described herein do not have pore sizes greater than 75 μm. In some embodiments, the hydrogel capsules described herein do not have pore sizes greater than 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, or 75 μm.

[0207] The physical properties of the hydrogel capsules described herein (e.g., as described in the Examples) control the release of encapsulated molecules and / or limit the uptake or permeation of undesirable molecules outside the capsule (e.g., as determined by a dextran permeability assay).

[0208] In some embodiments, the average molecular weight permeability is about 1 kDa to about 150 kDa. In some embodiments, the average molecular weight permeability is about 1 kDa, 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, 55 kDa, 60 kDa, 65 kDa, 70 kDa, 75 kDa, 80 kDa, 85 kDa, 90 kDa, 95 kDa, 100 kDa, , 105kDa, 110kDa, 115kDa, 120kDa, 125kDa, 130kDa, 135kDa, 140kDa, 145kDa, 150kDa, 155kDa, 160kDa, 165kDa, 170kDa, 175kDa, 180kDa, 185kDa, 190kDa, 195kDa, or 200kDa. In some embodiments, the average molecular weight permeability is about 1 kDa, 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, 55 kDa, 60 kDa, 65 kDa, 70 kDa, 75 kDa, 80 kDa, 85 kDa, 90 kDa, 95 kDa, 100 kDa , 105kDa, 110kDa, 115kDa, 120kDa, 125kDa, 130kDa, 135kDa, 140kDa, 145kDa, 150kDa, 155kDa, 160kDa, 165kDa, 170kDa, 175kDa, 180kDa, 185kDa, 190kDa, 195kDa, or greater than 200kDa. In some embodiments, the average molecular weight permeability is about 1 kDa, 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, 55 kDa, 60 kDa, 65 kDa, 70 kDa, 75 kDa, 80 kDa, 85 kDa, 90 kDa, 95 kDa, 100 kDa, less than 105kDa, 110kDa, 115kDa, 120kDa, 125kDa, 130kDa, 135kDa, 140kDa, 145kDa, 150kDa, 155kDa, 160kDa, 165kDa, 170kDa, 175kDa, 180kDa, 185kDa, 190kDa, 195kDa, or 200kDa.

[0209] In some embodiments, the hydrogel capsules described herein can be characterized by an absolute breaking strength (e.g., crushing strength) determined by using a texture analyzer. In some embodiments, the absolute breaking strength is between 50 and 800 g. In some embodiments, the hydrogel capsules described herein can be characterized by a weight of about 50 g, 60 g, 70 g, 80 g, 90 g, 100 g, 110 g, 120 g, 130 g, 140 g, 150 g, 160 g, 170 g, 180 g, 190 g, 200 g, 210 g, 220 g, 230 g, 240 g, 250 g, 260 g, 270 g, 280 g, 290 g, 300 g, 310 g, 320 g, 330 g, 340 g, 350 g, 360 g, 370 g, 380 g, 390 g, 400 g, 410 g, 420 g, 430 g, 440 g, 450 g, 460 g, 470 g, 480 g, 490 g, 500 g, 510 g, 520 g, 530 g, 540 g, 550 g, 560 g, 570 g, 580 g, 590 g, 600 g, 610 g, 620 g, 630 g, 640 g, 650 g, 660 g, 670 g, 680 g, 690 g, 700 g, 710 g, 720 g, 730 g, 740 g, 750 g, 760 g, 770 g, 7 In some embodiments, the composition has an absolute strength of 10 g, 420 g, 430 g, 440 g, 450 g, 460 g, 470 g, 480 g, 490 g, 500 g, 510 g, 520 g, 530 g, 540 g, 550 g, 560 g, 570 g, 580 g, 590 g, 600 g, 610 g, 620 g, 630 g, 640 g, 650 g, 660 g, 670 g, 680 g, 690 g, 700 g, 710 g, 720 g, 730 g, 740 g, 750 g, 760 g, 770 g, 780 g, 790 g, or 800 g. The hydrogel capsules may be approximately 50g, 60g, 70g, 80g, 90g, 100g, 110g, 120g, 130g, 140g, 150g, 160g, 170g, 180g, 190g, 200g, 210g, 220g, 230g, 240g, 250g, 260g, 270g, 280g, 290g, 300g, 310g, 320g, 330g, 340g, 350g, 360g, 370g, 380g, 390g, 400g, 410g, 420g, 430g, 440g, 450g, 460g, 470g, 480g, 490g, 500g, 510g, 520g, 530g, 540g, 550g, 560g, 570g, 580g, 590g, 600g, 610g, 620g, 630g, 640g, 650g, 660g, 670g, 680g, 690g, 700g, 710g, 720g, 730g, 740g, 750g, 760g, 770g, 780g, 790g, 800g, 810g, 820g, 830g, 840g, 850g, 860g, 870g, 880g, 890 having an absolute strength of 0g, 440g, 450g, 460g, 470g, 480g, 490g, 500g, 510g, 520g, 530g, 540g, 550g, 560g, 570g, 580g, 590g, 600g, 610g, 620g, 630g, 640g, 650g, 660g, 670g, 680g, 690g, 700g, 710g, 720g, 730g, 740g, 750g, 760g, 770g, 780g, 790g, or greater than 800g.In some embodiments, the hydrogel capsules described herein have a mass of about 50 g, 60 g, 70 g, 80 g, 90 g, 100 g, 110 g, 120 g, 130 g, 140 g, 150 g, 160 g, 170 g, 180 g, 190 g, 200 g, 210 g, 220 g, 230 g, 240 g, 250 g, 260 g, 270 g, 280 g, 290 g, 300 g, 310 g, 320 g, 330 g, 340 g, 350 g, 360 g, 370 g, 380 g, 390 g, 400 g, 410 g, 420 g, 430 g, 440 g, 450 g, 460 g, 470 g, 480 g, 490 g, 500 g, 510 g, 520 g, 530 g, 540 g, 550 g, 560 g, 570 g, 580 g, 590 g, 600 g, 610 g, 620 g, 630 g, 640 g, 650 g, 660 g, 670 g, 680 g, 690 g, 700 g, 710 g, 720 g, 730 g, 740 g, 750 g, 760 g, 770 g, 780 g, 790 g, 800 g, 810 g, 820 g, 830 g, 840 g, 850 g, 860 g, 870 g, 8 having an absolute strength of less than 0g, 420g, 430g, 440g, 450g, 460g, 470g, 480g, 490g, 500g, 510g, 520g, 530g, 540g, 550g, 560g, 570g, 580g, 590g, 600g, 610g, 620g, 630g, 640g, 650g, 660g, 670g, 680g, 690g, 700g, 710g, 720g, 730g, 740g, 750g, 760g, 770g, 780g, 790g, or 800g.

[0210] The present disclosure features particles (e.g., hydrogel capsules) comprising a first compartment, a second compartment, and a photoactive cross-linking moiety described herein (e.g., a compound of Formula (IV, V, or VI), and optionally, a compound of Formula (I), e.g., as described herein). The photoactive cross-linking moiety is covalently bonded to a polysaccharide polymer present in the first and / or second compartments. The particles (e.g., hydrogel capsules) can be spherical or have any other shape. The particles (e.g., hydrogel capsules) can include materials such as metals, metal alloys, ceramics, polymers, fibers, inert materials, and combinations thereof. The particles (e.g., hydrogel capsules) can be made entirely of one type of material or can include multiple other materials within the second (outer) compartment and the first (inner) compartment.

[0211] In some embodiments, the first compartment is modified with a compound of Formula (I). In some embodiments, the second compartment is modified with a compound of Formula (I). In some embodiments, both the first compartment and the second compartment are independently modified with a compound of Formula (I).

[0212] In some embodiments, the particles (e.g., hydrogel capsules) have a largest linear dimension (LLD), e.g., average diameter, or diameter, that is greater than 1 millimeter (mm), preferably about 1.5 mm or greater. In some embodiments, the particles (e.g., hydrogel capsules) can be as large as 10 mm in diameter or diameter. For example, the particles (e.g., hydrogel capsules) described herein may be sized to any of the following: 0.5 mm to 10 mm, 1 mm to 10 mm, 1 mm to 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mm to 6 mm, 1.5 mm to 5 mm, 1.5 mm to 4 mm, 1.5 mm to 3 mm, 1.5 mm to 2 mm, 2 mm to 8 mm, 2 mm to 7 mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 2.5 mm to 8 mm, 2.5 mm to 7 mm, 2.5 mm to 6 mm, 2.5 mm to 5 mm, 2.5 mm to 4 mm, 2.5 mm to 3 mm, In some embodiments, the particles (e.g., hydrogel capsules) have an average diameter, or size, between about 1 mm and about 8 mm. In some embodiments, the particles (e.g., hydrogel capsules) have an average diameter or size between about 1 mm and about 4 mm. In some embodiments, the particles (e.g., hydrogel capsules) have an average diameter or size between about 1 mm and about 2 mm. In some embodiments, the particles (e.g., hydrogel capsules) have an average diameter or size between about 1.5 mm and about 2 mm.

[0213] In some embodiments, the particles (e.g., hydrogel capsules) have a largest linear dimension (LLD), e.g., an average diameter, or diameter, of 1 millimeter (mm) or less. In some embodiments, the particles (e.g., hydrogel capsules) are in the diameter range of 0.3 mm to 1 mm, 0.4 mm to 1 mm, 0.5 mm to 1 mm, 0.6 mm to 1 mm, 0.7 mm to 1 mm, 0.8 mm to 1 mm, or 0.9 mm to 1 mm.

[0214] In one embodiment, the second (outer) compartment completely surrounds the first (inner) compartment, and the inner boundary of the second compartment forms an interface with the outer boundary of the first compartment. In such embodiments, the thickness of the second (outer) compartment refers to the average distance between the outer boundary of the second compartment and the interface between the two compartments. In some embodiments, the thickness of the outer compartment is greater than about 10 nanometers (nm), preferably greater than 100 nm, and can be as large as 1 millimeter (mm). For example, the thickness of the outer compartment in the particles described herein can be 10 nanometers to 1 millimeter, 100 nanometers to 1 millimeter, 500 nanometers to 1 millimeter, 1 micrometer (μm) to 1 millimeter, 1 μm to 1 mm, 1 μm to 500 μm, 1 μm to 250 μm, 1 μm to 1 mm, 5 μm to 500 μm, 5 μm to 250 μm, 10 μm to 1 mm, 10 μm to 500 μm, or 10 μm to 250 μm. In some embodiments, the thickness of the outer compartment is between 100 nanometers and 1 millimeter, between 1 μm and 1 mm, between 1 μm and 500 μm, or between 5 μm and 1 mm.

[0215] In some embodiments, the particles (e.g., hydrogel capsules) contain at least one pore, or opening, for example, to allow free flow of material. In some embodiments, the average pore size of the device is between about 0.1 μm and about 10 μm. For example, the average pore size can be between 0.1 μm and 10 μm, 0.1 μm and 5 μm, 0.1 μm and 2 μm, 0.15 μm and 10 μm, 0.15 μm and 5 μm, 0.15 μm and 2 μm, 0.2 μm and 10 μm, 0.2 μm and 5 μm, 0.25 μm and 10 μm, 0.25 μm and 5 μm, 0.5 μm and 10 μm, 0.75 μm and 10 μm, 1 μm and 10 μm, 1 μm and 5 μm, 1 μm and 2 μm, 2 μm and 10 μm, 2 μm and 5 μm, or 5 μm and 10 μm. In some embodiments, the average pore size of the particles is between about 0.1 μm and 10 μm. In some embodiments, the average pore size of the particles is between about 0.1 μm and 5 μm. In some embodiments, the average pore size of the particle is between about 0.1 μm and 1 μm. In some embodiments, the average pore size of the first compartment and the average pore size of the second compartment of the particle are substantially identical. In some embodiments, the average pore size of the first compartment and the average pore size of the second compartment of the particle differ by about 1.5%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. In some embodiments, the average pore size of the particle (e.g., the average pore size of the first compartment and / or the average pore size of the second compartment) depends on numerous factors, such as the material(s) in each compartment, as well as the presence and density of a compound of Formula (I).

[0216] In some embodiments, the particle (e.g., hydrogel capsule) comprises a polysaccharide, and the polysaccharide is alginate. Alginate is a polysaccharide composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G). In some embodiments, the alginate is a high guluronic acid (G) alginate, comprising about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more guluronic acid (G). In some embodiments, the alginate is a high mannuronic acid (M) alginate, comprising about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more mannuronic acid (M). In some embodiments, the M:G ratio is about 1. In some embodiments, the M:G ratio is greater than 1. In some embodiments, the M:G ratio is less than 1. In alginate-containing particles, the amount of alginate (e.g., weight % of the particle, actual weight of alginate) can be, for example, at least 5%, e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more, w / w, or less than 20%, e.g., 20%, 15%, 10%, 5%, 1%, 0.5%, 0.1%, or less.

[0217] In some embodiments, both the first compartment and the second compartment comprise the same polymer. In some embodiments, the first compartment and the second compartment comprise different polymers. In some embodiments, the first compartment comprises alginate. In some embodiments, the second compartment comprises alginate. In some embodiments, both the first compartment and the second compartment comprise alginate. In some embodiments, the alginate in the first compartment is different from the alginate in the second compartment. In some embodiments, the first compartment comprises alginate and the second compartment comprises a different polymer (e.g., a polysaccharide, e.g., hyaluronate or chitosan). In some embodiments, the second compartment comprises alginate and the first compartment comprises a different polymer (e.g., a polysaccharide, e.g., hyaluronate or chitosan).

[0218] Both the first and second compartments can contain a single component (e.g., a polymer) or two or more components (e.g., a blend of polymers). In some embodiments, the first compartment contains only alginate (e.g., a chemically modified alginate or a blend of unmodified and chemically modified alginate). In some embodiments, the second compartment contains only alginate (e.g., a chemically modified alginate or a blend of unmodified and chemically modified alginate). In some embodiments, both the first and second compartments, independently, contain only alginate (e.g., a chemically modified alginate or a blend of unmodified and chemically modified alginate).

[0219] In some embodiments, the first and second compartments comprise a blend of polymers (i.e., a mixture of polymers). In some embodiments, the first (inner) compartment comprises a blend of polymers. In some embodiments, the second (outer) compartment comprises a blend of polymers. In some embodiments, the first and second compartments comprise the same blend of polymers. In some embodiments, the first and second compartments comprise different blends of polymers. In some embodiments, at least one polymer in the blend comprising the outer compartment is covalently modified with a photoactive crosslinker described herein (e.g., a compound of Formula (IV), (V), or (VI)). In some embodiments, at least one polymer in the blend comprising the second (outer) compartment is covalently modified with a non-fibrous compound described herein (e.g., a compound of Formula (I)). In some embodiments, at least one polymer in the blend comprising the second (outer) compartment is covalently modified with both a photoactive crosslinker and a non-fibrous compound.

[0220] In some embodiments, the first compartment comprises a blend of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more polymers. In some embodiments, the first compartment comprises a blend of 2 polymers. In some embodiments, the first compartment comprises a blend of 3 polymers. In some embodiments, the first compartment comprises a blend of 4 polymers. In some embodiments, the first compartment comprises a blend of 5 polymers. In some embodiments, the first compartment comprises a blend of 6 polymers. In some embodiments, the first (inner) compartment comprises a blend of 7 polymers. In some embodiments, the first (inner) compartment comprises a blend of 8 polymers. In some embodiments, the first (inner) compartment comprises a blend of 9 polymers. In some embodiments, the first (inner) compartment comprises a blend of 10 polymers.

[0221] In some embodiments, the second (outer) compartment comprises a blend of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more polymers. In some embodiments, the second (outer) compartment comprises a blend of two polymers. In some embodiments, the second (outer) compartment comprises a blend of three polymers. In some embodiments, the second (outer) compartment comprises a blend of four polymers. In some embodiments, the second (outer) compartment comprises a blend of five polymers. In some embodiments, the second (outer) compartment comprises a blend of six polymers. In some embodiments, the second (outer) compartment comprises a blend of seven polymers. In some embodiments, the second (outer) compartment comprises a blend of eight polymers. In some embodiments, the second (outer) compartment comprises a blend of nine polymers. In some embodiments, the second (outer) compartment comprises a blend of ten polymers.

[0222] In some embodiments, the first compartment comprises a blend of polymers and the second compartment does not comprise a blend of polymers, hi some embodiments, the first compartment comprises a blend of polymers and the second compartment comprises a blend of polymers.

[0223] In some embodiments, the first compartment does not comprise a blend of polymers and the second compartment comprises a blend of polymers, hi some embodiments, the first compartment comprises a single type of polymer and the second compartment comprises a blend of polymers.

[0224] In some embodiments, the first and second compartments comprise a blend of polymers, where the polymers of the blend are any two miscible polymers.

[0225] In some embodiments, the first and second compartments comprise a blend of polymers, wherein the polymers are selected from the group consisting of alginate, hyaluronate, and chitosan.

[0226] In some embodiments, the first and second compartments comprise a blend of polymers, wherein the polymer is selected from the group consisting of alginate, hyaluronate, and chitosan. In some embodiments, the first compartment comprises a blend of polymers, wherein the polymer is selected from the group consisting of alginate, hyaluronate, and chitosan. In some embodiments, the second compartment comprises a blend of polymers, wherein the polymer is selected from the group consisting of alginate, hyaluronate, and chitosan.

[0227] In some embodiments, the first and second compartments comprise a blend of alginate polymers. In some embodiments, the first compartment comprises a blend of alginate polymers. In some embodiments, the second compartment comprises a blend of alginate polymers.

[0228] In some embodiments, the first and second compartments comprise a blend of alginate polymers, wherein the alginate polymers are selected from high guluronic acid alginate and high mannuronic acid alginate. In some embodiments, the first compartment comprises a blend of alginate polymers, wherein the alginate polymers are selected from high guluronic acid alginate and high mannuronic acid alginate. In some embodiments, the second compartment comprises a blend of alginate polymers, wherein the alginate polymers are selected from high guluronic acid alginate and high mannuronic acid alginate.

[0229] In some embodiments, the first and second compartments comprise a blend of alginate polymers, wherein the alginate polymers are selected from low molecular weight alginates, medium molecular weight alginates, high molecular weight alginates, and ultra-high molecular weight alginates. In some embodiments, the first compartment comprises a blend of alginate polymers, wherein the alginate polymers are selected from low molecular weight alginates, medium molecular weight alginates, high molecular weight alginates, and ultra-high molecular weight alginates. In some embodiments, the second compartment comprises a blend of alginate polymers, wherein the alginate polymers are selected from low molecular weight alginates, medium molecular weight alginates, high molecular weight alginates, and ultra-high molecular weight alginates.

[0230] In some embodiments, the first and second compartments comprise a blend of alginate polymers, wherein the alginate polymers are selected from Kimica Algin IL-2, Kimica Algin IL-6, Kimica Algin I-1, Kimica Algin I-3, Kimica Algin I-5, Kimica Algin I-8, Kimica Algin LZ-2, Kimica Algin ULV-L3, Kimica Algin ULV-L5, Kimica Algin ULV-1G, Kimica Algin ULV-5G, Kimica Algin ULV IL-6G, Pronova UP VLVM, Pronova UP LVM, Pronova UP MVM, Pronova UP VLVG, Pronova UP MVG, Pronova UP LVG, Pronova SLM20, Pronova SLM100, Pronova SLG20, and Pronova SLG100. In some embodiments, the first compartment comprises a blend of alginate polymers, wherein the alginate polymers are selected from Kimica Algin IL-2, Kimica Algin IL-6, Kimica Algin I-1, Kimica Algin I-3, Kimica Algin I-5, Kimica Algin I-8, Kimica Algin LZ-2, Kimica Algin ULV-L3, Kimica Algin ULV-L5, Kimica Algin ULV-1G, Kimica Algin ULV-5G, Kimica Algin ULV IL-6G, Pronova UP VLVM, Pronova UP LVM, Pronova UP MVM, Pronova UP VLVG, Pronova UP MVG, Pronova UP LVG, Pronova SLM20, Pronova SLM100, Pronova SLG20, and Pronova SLG100.In some embodiments, the second compartment comprises a blend of alginate polymers, wherein the alginate polymers are selected from Kimica Algin IL-2, Kimica Algin IL-6, Kimica Algin I-1, Kimica Algin I-3, Kimica Algin I-5, Kimica Algin I-8, Kimica Algin LZ-2, Kimica Algin ULV-L3, Kimica Algin ULV-L5, Kimica Algin ULV-1G, Kimica Algin ULV-5G, Kimica Algin ULV IL-6G, Pronova UP VLVM, Pronova UP LVM, Pronova UP MVM, Pronova UP VLVG, Pronova UP MVG, Pronova UP LVG, Pronova SLM20, Pronova SLM100, Pronova SLG20, and Pronova SLG100.

[0231] In some embodiments, the first and second compartments comprise a blend of two alginate polymers in any ratio. In some embodiments, the ratio of the two alginate polymers in the blend is about 99:1, 95:5, 90:10, 85:15, 80:20, 75:25, 70:30, 65:35, 60:40, 55:45, or 50:50. In some embodiments, the ratio of the two alginate polymers in the blend is about 99:1. In some embodiments, the ratio of the two alginate polymers in the blend is about 95:5. In some embodiments, the ratio of the two alginate polymers in the blend is about 90:10. In some embodiments, the ratio of the two alginate polymers in the blend is about 85:15. In some embodiments, the ratio of the two alginate polymers in the blend is about 80:20. In some embodiments, the ratio of the two alginate polymers in the blend is about 75:25. In some embodiments, the ratio of the two alginate polymers in the blend is about 70:30. In some embodiments, the ratio of the two alginate polymers in the blend is about 65:35. In some embodiments, the ratio of the two alginate polymers in the blend is about 60:40. In some embodiments, the ratio of the two alginate polymers in the blend is about 55:45. In some embodiments, the ratio of the two alginate polymers in the blend is about 50:50.

[0232] In some embodiments, the first and second compartments comprise a blend of two alginate polymers in any ratio. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 99:1, 95:5, 90:10, 85:15, 80:20, 75:25, 70:30, 65:35, 60:40, 55:45, or 50:50. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 99:1. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 95:5. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 90:10. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 85:15. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 80:20. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 75:25. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 70:30. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 65:35. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 60:40. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 55:45. In some embodiments, the ratio of the two alginate polymers in the blend is greater than about 50:50.

[0233] In some embodiments of the invention, the first and second compartments comprise a blend of VLVG alginate and SLG100 alginate. In some embodiments of the invention, the first compartment comprises a blend of VLVG alginate and SLG100 alginate. In some embodiments of the invention, the second compartment comprises a blend of VLVG alginate and SLG100 alginate.

[0234] In some embodiments of the invention, the first and second compartments comprise a blend of VLVG alginate and SLG100 alginate. In some embodiments of the invention, the first compartment comprises a blend of VLVG alginate and SLG100 alginate. In some embodiments of the invention, the second compartment comprises a blend of VLVG alginate and SLG100 alginate.

[0235] In some embodiments, the polymer of one or both of the first and second compartments is (i) a low molecular weight alginate, e.g., having a MW of approximately <75 kDa and a G:M ratio of ≥1.5; (ii) a medium molecular weight alginate, e.g., having a MW of approximately 75-150 kDa and a G:M ratio of ≥1.5; (iii) a high molecular weight alginate, e.g., having a MW of approximately 150 kDa-250 kDa and a G:M ratio of ≥1.5; or (iv) a blend of two or more of these alginates. In one embodiment, the polymer in the first (inner) compartment is an unmodified high molecular weight alginate or an unmodified medium molecular weight alginate, and the polymer in the second (outer) compartment is a blend of chemically modified alginate (e.g., alginate modified with compound 101 shown in Table 3) and unmodified alginate, such as a 70:30 or 60:40 blend of CM-LMW-Alg-101:U-HMW-Alg, which may be prepared as described in the Examples below.

[0236] In some embodiments, the particle (e.g., hydrogel capsule) comprises an alginate, and a compound of Formula (I) is covalently bonded to some or all of the monomers in the alginate. In some embodiments, some or all of the monomers in the alginate are modified with the same compound of Formula (I). In some embodiments, some or all of the monomers in the alginate are modified with different compounds of Formula (I).

[0237] In some embodiments, the polymer of a first compartment of the particle (e.g., a hydrogel capsule) is modified with one compound of Formula (I) and the polymer of a second compartment of the particle (e.g., a hydrogel capsule) is modified with a different compound of Formula (I). In some embodiments, the particle (e.g., a hydrogel capsule) comprises a mixture of a polymer modified with a compound of Formula (I) and an unmodified polymer (e.g., a polymer not modified with a compound of Formula (I)). In some embodiments, the first compartment comprises a mixture (i.e., a blend) of a polymer modified with a compound of Formula (I) and an unmodified polymer (e.g., a polymer not modified with a compound of Formula (I)). In some embodiments, the second compartment comprises a mixture (i.e., a blend) of a polymer modified with a compound of Formula (I) and an unmodified polymer (e.g., a polymer not modified with a compound of Formula (I)).

[0238] The polymer of the particles (e.g., hydrogel capsules) described herein can be modified with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in one or more monomers of the polymer. The modified polymer of the particle (e.g., hydrogel capsule) can be present in the first (internal) compartment of the particle, the second (external) compartment of the particle, or both the first (internal) and second (external) compartments of the particle. In some embodiments, the modified polymer is present only in the second compartment (including the outer surface of the particle). In some embodiments, at least 0.5% of the monomers of the polymer are modified with a compound of Formula (I) (e.g., at least 1%, 2.5%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more of the monomers of the polymer are modified with a compound of Formula (I)). In some embodiments, 0.5% to 50%, 10% to 90%, 10% to 50%, or 25 to 75% of the monomers of the polymer are modified with a compound of Formula (I). In some embodiments, 1% to 20% of the monomers of the polymer are modified with a compound of Formula (I). In some embodiments, 1% to 10% of the monomers of the polymer are modified with a compound of Formula (I).

[0239] In some embodiments, the polymer (e.g., alginate) (when modified with a compound of Formula (I), e.g., compound 101 in Table 3) contains any of the following values: (i) at least 0.1%, 0.2%, 0.5%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% N by weight; (ii) between 0.1% and 10% by weight; (iii) between 0.1% and 2% N by weight; (iv) between 0.1% and 2% N by weight; (v) 2% to 4% N by weight, (v) 4% to 8% N by weight, (vi) 5% to 9% N by weight, (vii) 6% to 9% N by weight, (viii) 6% to 8% N by weight, (ix) 7% to 9% N by weight, (x) 8% to 9% N by weight (in each case, the % N is determined by combustion analysis (e.g., as described in Example 2 herein) and corresponds to the amount of the compound of formula (I) in the modified polymer) (compared to an unmodified polymer, e.g., alginate).

[0240] A particle (e.g., a hydrogel capsule) (e.g., a first compartment or a second compartment therein) can contain a compound of Formula (I) in an amount that imparts a particular characteristic to the particle. For example, the particle surface (e.g., the exterior of the outer compartment) can contain a concentration or density of a compound of Formula (I) such that the particle is non-fibrotic (i.e., mitigates a foreign body reaction) in a subject. In one embodiment, the particle surface comprises an alginate chemically modified with a non-fibrotic effective amount of Compound 101. In one embodiment, an effective amount of Compound 101 results in an increase in %N (relative to unmodified alginate) of about 0.5%-2%, 2%-4%, about 4%-6%, about 6%-8%, or about 8%-10% N, where %N corresponds to the amount of Compound 101 in the modified alginate, as determined by combustion analysis (e.g., as described in Example 2 herein).

[0241] In one embodiment, mechanical testing of hydrogel capsules is performed using a 5 mm probe attached to a 5 kg load cell in a TA.XT plus Texture Analyzer (Stable Micro Systems, Surrey, United Kingdom). Individual capsules are placed on a platform and compressed from above by the probe at a fixed rate of 0.5 mm / s. Contact between the probe and the capsule is detected when a repulsive force of 1 g is measured. The probe continues to move 90% of the distance between the probe's contact height and the platform, compressing the capsule to the point of rupture. The resistance of the probe to compression force is measured and plotted as a function of probe travel (force vs. displacement curve). Typically, capsules fracture slightly before completely rupturing, resulting in a small decrease in the force applied to the probe. An analysis macro can be programmed to detect the first time a 0.25-0.5 g decrease occurs in the force vs. displacement curve. The force applied by the probe when this occurs is referred to as the initial rupture force. In one embodiment, the desired mechanical strength of the particles described herein (eg, two-compartment hydrogel capsules) is an initial breaking force of greater than 1, 1.5, 2, 2.5, or 3 grams, or at least 2 grams.

[0242] In one embodiment, the desired mechanical strength of a particle (e.g., a hydrogel capsule) is its ability to remain intact at a desired time point after implantation in a subject, e.g., both the outer and inner compartments of a hydrogel capsule removed from a subject are visually intact after recovery from an immunocompetent mouse, as observed by light microscopy, e.g., bright field imaging as described in the Examples herein.

[0243] In one embodiment, the particle surface comprises alginate chemically modified with Compound 101 at a concentration, or density, of Compound 101 in the modified alginate that provides the particle with both non-fibrous properties and a desired mechanical strength, e.g., an N% increase (compared to unmodified alginate) of any of the following values: (i) 1% to 3% by weight, (ii) 2% to 4% by weight, (iii) 4% to 8% by weight, (iv) 5% to 9% by weight, (v) 6% to 9% by weight, (vi) 6% to 8% by weight, (vii) 7% to 9% by weight, and (ix) 8% to 9% by weight, where %N corresponds to the amount of Formula (I) compound in the modified alginate, as determined by combustion analysis (e.g., as described in Example 2 herein).

[0244] The particles (e.g., the first and second compartments therein) contain alginate, which can be chemically modified with a compound of Formula (I) using any suitable method known in the art. For example, alginate carboxylic acid moieties can be activated for coupling to one or more amine-functionalized compounds to achieve an alginate modified with a compound of Formula (I). Alginate polymer can be dissolved in water (30 mL / gram polymer) and treated with 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.5 equivalents) and N-methylmorpholine (1 equivalent). To this mixture can be added a solution (0.3 M) of the compound of Formula (I) in a buffer or solvent, such as acetonitrile. The reaction can be heated to 55°C for 16 hours, then cooled to room temperature and concentrated via rotary evaporation. The residue can then be dissolved in a buffer or solvent, such as water. The mixture can then be filtered, for example, through a bed of cyano-modified silica gel (Silicycle), and the filter cake can be washed with water. The resulting solution can then be dialyzed (10,000 MWCO membrane) against buffer or water for 24 hours, for example, with at least one, at least two, at least three, or more changes of buffer or water. The resulting solution can be concentrated, for example, by lyophilization, to provide the desired chemically modified alginate.

[0245] In some embodiments, the particles described herein comprise cells. In some embodiments, the cells are engineered to produce a therapeutic agent (e.g., a protein or polypeptide, e.g., an antibody, protein, enzyme, or growth factor). In some embodiments, the cells are disposed with a first compartment. In some embodiments, the cells are disposed with a second compartment. In some embodiments, the cells are disposed within the first compartment, and the second compartment does not contain cells. The particles (e.g., hydrogel capsules) can comprise active or inactive fragments of proteins or polypeptides, such as glucose oxidase (e.g., for glucose sensors), kinases, phosphatases, oxygenases, hydrogenases, or reductases.

[0246] The particles (e.g., hydrogel capsules) described herein can be configured to release a therapeutic agent, e.g., an exogenous substance, e.g., a therapeutic agent described herein. In some embodiments, the therapeutic agent is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is a biological material. In some embodiments, the therapeutic agent is a nucleic acid (e.g., RNA, or DNA), a protein (e.g., a hormone, enzyme, antibody, antibody fragment, antigen, or epitope), a small molecule, a lipid, a drug, a vaccine, or any derivative thereof.

[0247] Particles (e.g., hydrogel capsules) (e.g., as described herein) can be provided as a preparation or composition for implantation or administration to a subject. In some embodiments, at least 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the particles (e.g., hydrogel capsules) in the preparation or composition have the characteristics described herein, e.g., average pore size.

[0248] In some embodiments, the hydrogel capsule comprises: (i) an inner compartment comprising a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate comprises Compound 101, and the SLG100 alginate is unmodified; and (ii) an outer compartment comprising a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate comprises Compound 101, and the SLG100 alginate is unmodified.

[0249] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate comprises Compound 101 and the SLG100 alginate comprises Compound 205, and (ii) an outer compartment comprising a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate comprises Compound 101 and the SLG100 alginate comprises Compound 205.

[0250] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 200.

[0251] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 201.

[0252] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 202.

[0253] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 203.

[0254] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 204.

[0255] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 205.

[0256] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 214.

[0257] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 215.

[0258] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 216.

[0259] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 217.

[0260] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 218.

[0261] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 101 and Compound 219.

[0262] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 200.

[0263] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 201.

[0264] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 202.

[0265] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 203.

[0266] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 204.

[0267] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 205.

[0268] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 214.

[0269] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 215.

[0270] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 216.

[0271] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 with Compound 101 and Compound 217.

[0272] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 218.

[0273] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 101 and Compound 219.

[0274] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 201.

[0275] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 202.

[0276] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG10020, which comprises Compound 101 and Compound 203.

[0277] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 204.

[0278] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 205.

[0279] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 214.

[0280] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 215.

[0281] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 216.

[0282] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 217.

[0283] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 218.

[0284] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 101 and Compound 219.

[0285] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 114 and Compound 200.

[0286] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 114 and Compound 201.

[0287] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 114 and Compound 202.

[0288] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 114 and Compound 203.

[0289] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 204.

[0290] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 114 and Compound 205.

[0291] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 214.

[0292] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 215.

[0293] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 216.

[0294] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 114 and Compound 217.

[0295] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 218.

[0296] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising LG20, which comprises Compound 114 and Compound 219.

[0297] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 200.

[0298] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 201.

[0299] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 202.

[0300] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 203.

[0301] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 204.

[0302] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 205.

[0303] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 214.

[0304] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 215.

[0305] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing compound 114 and compound 216.

[0306] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 217.

[0307] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 218.

[0308] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified LG20 alginate and (ii) an outer compartment comprising LG20 containing Compound 114 and Compound 219.

[0309] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 114 and Compound 201.

[0310] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 114 and Compound 202.

[0311] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising compound 114 and compound 203.

[0312] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 114 and Compound 204.

[0313] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising compound 114 and compound 205.

[0314] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 114 and Compound 214.

[0315] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 114 and Compound 215.

[0316] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising compound 114 and compound 216.

[0317] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising compound 114 and compound 217.

[0318] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 114 and Compound 218.

[0319] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG100 alginate and (ii) an outer compartment comprising SLG100 comprising Compound 114 and Compound 219.

[0320] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 101 and Compound 205.

[0321] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 101 and Compound 200.

[0322] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 101 and Compound 201.

[0323] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 101 and Compound 202.

[0324] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 101 and Compound 203.

[0325] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 101 and Compound 204.

[0326] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 101 and Compound 206.

[0327] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 114 and Compound 205.

[0328] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 114 and Compound 200.

[0329] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 114 and Compound 201.

[0330] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 114 and Compound 202.

[0331] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 114 and Compound 203.

[0332] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 114 and Compound 204.

[0333] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising unmodified SLG20 alginate and (ii) an outer compartment comprising LG20 alginate modified with Compound 114 and Compound 206.

[0334] Cells and therapeutic agents The hydrogels or hydrogel capsules of the present disclosure can contain a wide variety of different cell types (e.g., human cells), including, but not limited to, adipocytes, epidermal cells, epithelial cells, endothelial cells, fibroblasts, pancreatic islet cells, mesenchymal stem cells, pericytes, subtypes of any of the foregoing, cells derived from any of the foregoing, cells derived from induced pluripotent stem cells, and mixtures of one or more of any of the foregoing. Exemplary cell types include those described in WO2017 / 075631 and WO2019 / 195055. In one embodiment, the hydrogel capsules described herein contain a plurality of cells. In one embodiment, the plurality of cells is in the form of a cell suspension before being encapsulated within the hydrogel capsules described herein. The cells in the suspension can be in the form of single cells (e.g., from a monolayer cell culture) or can be provided in another form, for example, disposed on a microcarrier (e.g., a bead or matrix) or as a three-dimensional aggregate of cells (e.g., a cell cluster or spheroid). The cell suspension may contain multiple cell clusters (e.g., as spheroids) or microcarriers. In some embodiments, the hydrogel capsules do not contain any pancreatic islet cells or any cells capable of producing insulin in response to glucose.

[0335] In some embodiments, the hydrogels or hydrogel capsules of the present disclosure reduce immune cell adhesion compared to an untreated control, e.g., a substantially identical hydrogel capsule lacking the compound of Formula (I). In one embodiment, the hydrogel capsules reduce macrophage adhesion compared to an untreated control. In one embodiment, the reduction in macrophage adhesion is between about 1-10 fold less than the untreated control. In one embodiment, the reduction in macrophage adhesion is between about 1-8 fold less than the untreated control. In one embodiment, the reduction in macrophage adhesion is between about 1-7 fold less than the untreated control. In one embodiment, the reduction in macrophage adhesion is between about 1-6 fold less than the untreated control. In one embodiment, the reduction in macrophage adhesion is between about 1-5 fold less than the untreated control.

[0336] The hydrogels or hydrogel capsules of the present disclosure allow encapsulated cells (e.g., engineered cells) to retain viability (e.g., as determined by a cell viability assay). In some embodiments, the hydrogels or hydrogel capsules allow encapsulated cells to retain viability for at least 7 days, at least 1 month, or at least 1 year.

[0337] The present disclosure features cells that produce or are capable of producing a therapeutic agent for the prevention or treatment of a disease, disorder, or condition described herein. In one embodiment, the cell is a naturally occurring cell, e.g., not engineered. In one embodiment, the cell is an engineered cell. In one embodiment, the cell is engineered to sense a stimulus, such as a chemical signal, and express a therapeutic agent in response to the stimulus. In one embodiment, the cell is differentiated from a stem cell, e.g., an induced pluripotent stem cell, and the differentiated cell can produce the therapeutic agent either continuously or in response to a stimulus. The therapeutic agent can be any biological substance, such as a nucleic acid (e.g., a nucleotide, DNA, or RNA), a polypeptide, a lipid, a sugar (e.g., a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide), or a small molecule (each of which is described in further detail below). Exemplary therapeutic agents include those listed in WO2017 / 075631 and WO2019 / 195055.

[0338] In some embodiments, the cells (e.g., engineered cells) produce nucleic acids. The nucleic acids produced by the cells described herein can vary in size and can contain one or more nucleosides or nucleotides, e.g., 2, 3, 4, 5, 10, 25, 50, or more nucleosides or nucleotides. In some embodiments, the nucleic acids are, e.g., short fragments of RNA or DNA, and can be used, e.g., as reporters or for diagnostic purposes. Exemplary nucleic acids include single nucleosides or nucleotides (e.g., adenosine, thymidine, cytidine, guanosine, uridine monophosphate, inosine monophosphate), RNA (e.g., mRNA, siRNA, miRNA, RNAi), and DNA (e.g., vectors, chromosomal DNA). In some embodiments, the nucleic acids have an average molecular weight (kD) of about 0.25, 0.5, 1, 1.5, 2, 2.5, 5, 10, 25, 50, 100, 150, 200, or more.

[0339] In some embodiments, the therapeutic agent is a peptide or polypeptide (e.g., a protein), such as a hormone, enzyme, cytokine (e.g., a pro-inflammatory cytokine or an anti-inflammatory cytokine), growth factor, clotting factor, or lipoprotein. Peptides or polypeptides (e.g., proteins, such as hormones, growth factors, clotting factors, or coagulation factors, antibody molecules, enzymes, cytokines, cytokine receptors, or chimeric proteins comprising cytokines or cytokine receptors) produced by cells in the implantable component may have a naturally occurring amino acid sequence or may contain a variant of a naturally occurring sequence. Variants may be naturally occurring or non-naturally occurring amino acid substitutions, mutations, deletions, or additions relative to a naturally occurring reference sequence. Naturally occurring amino acid sequences may be polymorphic variants. Naturally occurring amino acid sequences may be human or non-human amino acid sequences. In some embodiments, a naturally occurring amino acid sequence, or a naturally occurring variant thereof, is a human sequence. Furthermore, peptides or polypeptides (e.g., proteins) for use in the present invention may be modified in some way, for example, by chemical or enzymatic modification (e.g., glycosylation, phosphorylation). In some embodiments, the peptide has about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, or 50 amino acids. In some embodiments, the protein has an average molecular weight (kD) of 5, 10, 25, 50, 100, 150, 200, 250, 500, or more.

[0340] In some embodiments, the protein is a hormone. Exemplary hormones include antidiuretic hormone (ADH), oxytocin, growth hormone (GH), prolactin, growth hormone-releasing hormone (GHRH), thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), luteinizing hormone-releasing hormone (LHRH), thyroxine, calcitonin, parathyroid hormone, aldosterone, cortisol, epinephrine, glucagon, insulin, estrogen, progesterone, and testosterone. In some embodiments, the protein is insulin (e.g., insulin A-chain, insulin B-chain, or proinsulin). In some embodiments, the protein is a growth hormone, such as human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, methionine-human growth hormone, des-phenylalanine-human growth hormone, and porcine growth hormone. In some embodiments, the protein is not insulin (eg, insulin A-chain, insulin B-chain, or proinsulin).

[0341] In some embodiments, the protein is a growth factor, such as vascular endothelial growth factor (VEGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF), and insulin-like growth factor-I and -II (IGF-I and IGF-II).

[0342] In some embodiments, the protein is a clotting factor, e.g., a blood clotting factor, hi some embodiments, the protein is a protein involved in coagulation, the process by which blood is converted from a liquid to a solid or gel. Exemplary clotting factors include Factor I (e.g., fibrinogen), Factor II (e.g., prothrombin), Factor III (e.g., tissue factor), Factor V (e.g., proaccelerin, labile factor), Factor VI, Factor VII (e.g., stable factor, proconvertin), Factor VIII (e.g., antihemophilic factor A), Factor VIIIC, Factor IX (e.g., antihemophilic factor B), Factor X (e.g., Stuart-Prower factor), Factor XI (e.g., plasma thromboplastin precursor), Factor XII (e.g., Hageman factor), Factor XIII (e.g., fibrin-stabilizing factor), von Willebrand factor, prekallikrein, heparin cofactor II, high molecular weight kininogen (e.g., Fitzgerald factor), antithrombin III, and fibronectin. In some embodiments, the protein is an anticoagulant, e.g., protein C.

[0343] In some embodiments, the protein is an antibody molecule. As used herein, the term "antibody molecule" refers to a protein, such as, for example, an immunoglobulin chain, or a fragment thereof, comprising at least one immunoglobulin variable domain sequence. The term "antibody molecule" includes, for example, monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region). In one embodiment, an antibody molecule comprises a full-length antibody or a full-length immunoglobulin chain. In one embodiment, an antibody molecule comprises an antigen-binding or functional fragment of a full-length antibody or a full-length immunoglobulin chain. In one embodiment, an antibody molecule is a monospecific antibody molecule that binds to a single epitope, e.g., a monospecific antibody molecule that has multiple immunoglobulin variable domain sequences, each of which binds to the same epitope.

[0344] In one embodiment, the antibody molecule is a multispecific antibody molecule, e.g., comprises a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In one embodiment, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In one embodiment, the multispecific antibody molecule comprises a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule.

[0345] Various types of antibody molecules can be produced by cells within the implantable element (e.g., hydrogel capsule) described herein, including all classes of whole immunoglobulins, fragments thereof, and synthetic proteins comprising at least the antigen-binding variable domain of an antibody. The antibody molecule can be an antibody, such as an IgG antibody, e.g., IgG1, IgG2, IgG3, or IgG4. The antibody molecule can be in the form of an antigen-binding fragment, including a Fab fragment, a F(ab')2 fragment, a single-chain variable region, etc. The antibody can be polyclonal or monoclonal (mAb). Monoclonal antibodies can include "chimeric" antibodies (wherein a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, so long as they specifically bind to the target antigen and / or exhibit the desired biological activity), and fragments of such antibodies. In some embodiments, the antibody molecule is a single domain antibody (e.g., nanobody). The described antibodies can also be modified by recombinant means, for example, by deletion, addition, or substitution of amino acids, to increase the effectiveness of the antibody in mediating the desired function. Exemplary antibodies include anti-beta-galactosidase, anti-collagen, anti-CD14, anti-CD20, anti-CD40, anti-HER2, anti-IL-1, anti-IL-4, anti-IL-6, anti-IL-13, anti-IL-17, anti-IL-18, anti-IL-23, anti-IL-28, anti-IL-29, anti-IL-33, anti-EGFR, anti-VEGF, anti-CDF, anti-flagellin, anti-IFN-α, anti-IFN-β, anti-IFN-γ, anti-mannose receptor, anti-VEGF, anti-TLR1, anti-TLR2, anti-TLR3, anti-TLR4, anti-TLR5, anti-TLR6, anti-TLR9, anti-PDF, anti-PD1, anti-PDL-1, or anti-nerve growth factor antibodies. In some embodiments, the antibody is an anti-nerve growth factor antibody (e.g., furanumab, fasinumab, tanezumab).

[0346] In some embodiments, the protein is a cytokine, or a cytokine receptor, or a chimeric protein comprising a cytokine or its receptor, such as tumor necrosis factor alpha and beta, their receptors, and their derivatives, renin, lipoproteins, colchicine, corticotrophin, vasopressin, somatostatin, lypressin, pancreozymin, leuprolide, alpha-1-antitrypsin, atrial natriuretic factor, pulmonary surfactant, plasminogen other than tissue-type plasminogen activator (t-PA), or the like. gen activators, e.g., urokinase, bombesin, thrombin, enkephalinase, RANTES (expression and secretion of which is normally regulated upon activation of T cells), human macrophage inflammatory protein (MIP-1-alpha), serum albumins, e.g., human serum albumin, Müllerian inhibitory substance, relaxin A-chain, relaxin B-chain, prorelaxin, mouse gonadotropin-related peptide, chorionic gonadotropin, microbial proteins, e.g., beta-lactamase, DNase, inhibin, activin, hormones, or growth factors receptors, integrins, protein A or D, rheumatoid factors, platelet-derived growth factors (PDGF), epidermal growth factors (EGF), transforming growth factors (TGFs), e.g., TGF-α and TGF-β (including TGF-β1, TGF-β2, TGF-β3, TGF-β4, or TGF-β5), insulin-like growth factors-I and -II (IGF-I and IGF-II), des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding proteins, CD proteins, e.g., CD-3, CD-4, CD-8, and CD-19, erythrocyte leukemia (EC 6.0), and leukemia (EC 6.1). thropoietin, osteoinductive factor, antitoxin, interferons such as interferon-alpha (e.g., interferon alpha 2A), beta, gamma, lambda, and consensus interferon, colony stimulating factors (CSF) such as M-CSF, GM-CSF, and G-CSF, interleukins (IL) such as IL-1 to IL-10, superoxide dismutase, T cell receptors, surface membrane proteins, degradation-promoting factors, transport proteins, homing receptors, addressins, conception inhibitors such as prostaglandins, conception enhancers,Included are regulatory proteins, antibodies (including fragments thereof), and chimeric proteins, such as immunoadhesins, precursors, derivatives, prodrugs, and analogs of these compounds, as well as pharmaceutically acceptable salts of these compounds or their precursors, derivatives, prodrugs, and analogs. Suitable proteins or peptides can be native or recombinant, and include, for example, fusion proteins.

[0347] Examples of polypeptides (e.g., proteins) produced by cells in the implantable elements (e.g., hydrogel capsules) described herein also include CCL1, CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL6, CCL7, CCL8, CCL9 (CCL10), CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26 , CCL27, CCL28, CXCL1(KC), CXCL2(SDF1a), CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8(IL8), CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, SF13B, EDA, IL2, IL15, IL4, IL13, IL7, IL9, IL21, IL3, IL5, IL6, IL11, IL27, IL30, IL31, OSM, LIF, CNTF, CTF1, IL12a, IL12b, IL23, IL27, IL35, IL14, IL 16, IL32, IL34, IL10, IL22, IL19, IL20, IL24, IL26, IL29, IFNL1, IFNL2, IFNL3, IL28, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA1 3, IFNA14, IFNA16, IFNA17, IFNA21, IFNB1, IFNK, IFNW1, IFNG, IL1A(IL1F1), IL1B(IL1F2), IL1Ra(IL1F3), IL1F5(IL36RN), IL1F6(IL36A), IL1F7(IL3 7), IL1F8 (IL36B), IL1F9 (IL36G), IL1F10 (IL38), IL33 (IL1F11), IL18 (IL1G), IL17, KITLG, IL25 (IL17E), CSF1 (M-CSF), CSF2 (GM-CSF), CSF3 (G-CSF),SPP1, TGFB1, TGFB2, TGFB3, CCL3L1, CCL3L2, CCL3L3, CCL4L1, CCL4L2, IL17B, IL17C, IL17D, IL17F, AIMP1(SCYE1), MIF, Areg, BC096441, Bmp1, Bmp10, Bmp15, Bmp2, Bmp3, Bmp4, Bmp5, Bmp6, Bmp7, Bmp8a, Bmp8b, C1qtnf4, Ccl21a, Ccl27a, Cd70, Cer1, Cklf, Clcf1, Cmtm2a, Cmtm2b, Cmtm3, Cmtm4, Cmtm5, C mtm6, Cmtm7, Cmtm8, Crlf1, Ctf2, Ebi3, Edn1, Fam3b, Fasl, Fgf2, Flt3l, Gd f10, Gdf11, Gdf15, Gdf2, Gdf3, Gdf5, Gdf6, Gdf7, Gdf9, Gm12597, Gm13271, Gm13275, Gm13276, Gm13280, Gm13283, Gm2564, Gpi1, Grem1, Grem2, Grn, Hmgb1, Ifna11, Ifna12, Ifna9, Ifnab, Ifne, Il17a, Il23a, Il25, Il31, Iltifb , Inhba, Lefty1, Lefty2, Mstn, Nampt, Ndp, Nodal, Pf4, Pglyrp1, Prl7d1, Scg2, Scgb3a1, Slurp1, Spp1, Thpo, Tnfsf10, Tnfsf11, Tnfsf12, Tnfsf13, Tnfsf13b, Tnfsf14, Tnfsf15, Tnfsf18, Tnfsf4, Tnfsf8, Tnfsf9, Tslp, Vegfa, Wnt1, Wnt2, Wnt5a, Wnt7a, Xcl1, epinephrine, melatonin, triiodothyronine, prostaglandins, Leukotrienes, prostacyclin, thromboxane, islet amyloid polypeptide, Müllerian inhibitory factor or hormone, adiponectin, corticotropin, angiotensin, vasopressin, arginine vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, cortistatin, enkephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastric inhibitory polypeptide, gastrin, ghrelin, glucagon, glucagon-like peptide-1, gonadotropin-releasing hormone, hepcidin,These include human chorionic gonadotropin, human placental lactogen, inhibin, somatomedin, leptin, lipotropin, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, pituitary adenylate cyclase-activating peptide, relaxin, renin, secretin, somatostatin, thrombopoietin, thyrotropin, thyrotropin-releasing hormone, vasoactive intestinal peptide, androgens, alpha-glucosidase (also known as acid maltase), glycogen phosphorylase, glycogen debranching enzyme, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, carnitine parmethyltransferase, carnitine, and myoadenylate deaminase.

[0348] In some embodiments, the protein is a replacement therapy or replacement protein. In some embodiments, the replacement therapy or replacement protein is a clotting factor or coagulation factor, such as factor VIII (e.g., comprising a naturally occurring human factor VIII amino acid sequence or a variant thereof) or factor IX (e.g., comprising a naturally occurring human factor IX amino acid sequence or a variant thereof).

[0349] In some embodiments, the encapsulated cells are engineered to express factor VIII, e.g., recombinant factor VIII. In some embodiments, the cells are derived from human tissue and are engineered to express factor VIII, e.g., recombinant factor VIII. In some embodiments, the recombinant factor VIII is recombinant B-domain deleted factor VIII (FVIII-BDD).

[0350] In some embodiments, the encapsulated cells are derived from human tissue and engineered to express factor IX, e.g., recombinant factor IX. In some embodiments, the cells are engineered to express factor IX, e.g., wild-type human factor IX (FIX), or a polymorphic variant thereof. In some embodiments, the cells are engineered to express a gain-of-function (GIF) variant of the wild-type FIX protein (FIX-GIF), where the GIF variant has a higher specific activity than the corresponding wild-type FIX.

[0351] In some embodiments, the replacement therapy or replacement protein is an enzyme, such as alpha-galactosidase, alpha-L-iduronidase (IDUA), or N-sulfoglucosamine sulfohydrolase (SGSH). In some embodiments, the replacement therapy or replacement protein is an enzyme, such as alpha-galactosidase A (e.g., comprising a naturally occurring human alpha-galactosidase A amino acid sequence, or a variant thereof). In some embodiments, the replacement therapy or replacement protein is a cytokine or an antibody.

[0352] In some embodiments, the therapeutic agent is a sugar, such as a monosaccharide, disaccharide, oligosaccharide, or polysaccharide. In some embodiments, the sugar comprises a triose, tetrose, pentose, hexose, or heptose moiety. In some embodiments, the sugar comprises a linear monosaccharide or a cyclic monosaccharide. In some embodiments, the sugar comprises a glucose, galactose, fructose, rhamnose, mannose, arabinose, glucosamine, galactosamine, sialic acid, mannosamine, glucuronic acid, galacturonic acid, mannuronic acid, or guluronic acid moiety. In some embodiments, the sugar is attached to a protein (e.g., an N-linked glycan or an O-linked glycan). Exemplary sugars include glucose, galactose, fructose, mannose, rhamnose, sucrose, ribose, xylose, sialic acid, maltose, amylose, inulin, fructooligosaccharides, galactooligosaccharides, mannan, lectin, pectin, starch, cellulose, heparin, hyaluronic acid, chitin, amylopectin, or glycogen. In some embodiments, the therapeutic agent is a sugar alcohol.

[0353] In some embodiments, the therapeutic agent is a lipid. The lipid may be hydrophobic or amphiphilic and may form a tertiary structure such as a liposome, vesicle, or membrane, or an insert into a liposome, vesicle, or membrane. The lipid may include a fatty acid, a glycerolipid, a glycerophospholipid, a sterol lipid, a prenol lipid, a sphingolipid, a glycolipid, a polyketide, or a sphingolipid. Examples of lipids produced by the cells described herein include anandamide, docosahexaenoic acid, aprostaglandin, leukotriene, thromboxane, eicosanoid, triglyceride, cannabinoid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, ceramide, sphingomyelin, cerebroside, ganglioside, estrogen, androsterone, testosterone, cholesterol, carotenoid, quinone, hydroquinone, or ubiquinone.

[0354] In some embodiments, the therapeutic agent is a small molecule. Small molecules can include natural products produced by cells. In some embodiments, the small molecule has low bioavailability or does not meet Lipinski's Rule of Five (a set of guidelines used to estimate whether a small molecule is likely to become an orally active drug in humans; see, e.g., Lipinski, CA et al (2001) Adv Drug Deliv 46:2-36). Exemplary small molecule natural products include antibacterial drugs (e.g., carumonam, daptomycin, fidaxomicin, fosfomycin, ispamycin, micronomycin sulfate, miocamycin, mupiocin, netilmicin sulfate, teicoplanin, thienamycin, rifamycin, erythromycin, vancomycin), antiparasitic drugs (e.g., artemisinin, ivermectin), anticancer drugs (e.g., doxorubicin, aclarubicin, aminolevulinic acid, aruglavin, omacetaxine, mepesuccinate, paclitaxel, pentostatin, peplomycin, romidepsin, trabectoside), and the like. trabectdin, actinomycin D, bleomycin, chromomycin A, daunorubicin, leucovorin, neocarzinostatin, streptozocin, trabectedin, vinblastine, vincristine), antidiabetic drugs (e.g., voglibose), central nervous system drugs (e.g., L-dopa, galantamine, zicontide), statins (e.g., mevastatin), antifungal drugs (e.g., fumagillin, cyclosporine), 1-deoxynojirimycin, and theophylline, sterols (cholesterol, estrogen, testosterone). Additional small molecule natural products are described in Newman, DJ and Cragg, M. (2016) J Nat Prod 79:629-661 and Butler, MS et al. (2014) Nat Prod Rep 31:1612-1661.

[0355] In some embodiments, the cells are engineered to synthesize non-protein or non-peptide small molecules. For example, in one embodiment, the cells may produce a statin (e.g., taurostatin, pravastatin, fluvastatin, or atorvastatin).

[0356] In some embodiments, the therapeutic agent is an antigen (e.g., a viral antigen, a bacterial antigen, a fungal antigen, a plant antigen, an environmental antigen, or a tumor antigen). Antigens are recognized by those skilled in the art as being immunostimulatory, i.e., capable of stimulating an immune response or providing effective immunity against the organism or molecule from which they are derived. Antigens can be nucleic acids, peptides, proteins, sugars, lipids, or combinations thereof.

[0357] Encapsulated cells, e.g., engineered or differentiated cells, e.g., engineered or differentiated cells described herein, may produce a single therapeutic agent or multiple therapeutic agents. In some embodiments, the cells produce a single therapeutic agent. In some embodiments, the hydrogel capsule encapsulates a cluster of cells comprising cells that produce a single therapeutic agent. In some embodiments, at least about 1 percent, or about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, or 99 percent of the cells in the cluster produce a single therapeutic agent (e.g., a therapeutic agent described herein). In some embodiments, the encapsulated cells produce multiple therapeutic agents, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 therapeutic agents. In some embodiments, the encapsulated cluster of cells comprises cells that produce multiple therapeutic agents. In some embodiments, at least about 1 percent, or about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, or 99 percent of the cells in the cluster produce multiple therapeutic agents (e.g., therapeutic agents described herein). These therapeutic agents may be associated or complexed. In some embodiments, the therapeutic agent is secreted or released from the cell in an active form. In some embodiments, the therapeutic agent is secreted or released from the cell in an inactive form, e.g., as a prodrug. In the latter case, the therapeutic agent may be activated by a downstream agent, such as an enzyme. In some embodiments, the therapeutic agent is maintained intracellularly rather than secreted or released from the encapsulated cell. For example, the therapeutic agent may be an enzyme involved in the detoxification or metabolism of an unwanted substance, where the detoxification or metabolism of the unwanted substance occurs intracellularly.

[0358] In some embodiments, the hydrogel capsules described herein contain mammalian cells in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 MmL -1 Contains at a concentration of

[0359] In some embodiments, the hydrogel capsules described herein contain mammalian cells in a volume of about 1 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 2 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 3 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 4 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 5 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 6 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 7 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 8 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 9 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 10 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 15 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 20 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 25 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 30 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 35 MmL -1In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 40 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 45 MmL -1 In some embodiments, the hydrogel capsules described herein contain mammalian cells at a concentration of about 50 MmL -1 Contains at a concentration of In some embodiments, the hydrogel capsules described herein contain mammalian cells in a volume of about 1 to 50 μL. -1 , 1 to 45 mL -1 , 1 to 40 mL -1 , 1 to 35 mL -1 , 1 to 30 mL -1 , 1 to 25 mL -1 , 1 to 20 mL -1 , 1 to 15 mL -1 , 1 to 10 mL -1 , 1 to 5 mL -1 , 5 to 50 mL -1 , 5 to 45 mL -1 , 5 to 40 mL -1 , 5 to 35 mL -1 , 5 to 30 mL -1 , 5 to 25 mL -1 , 5 to 20 mL -1 , 5-15MmL -1 , 5-10MmL -1 , 10-50MmL -1 , 10-45MmL -1 , 10-40MmL -1 , 10-35MmL -1 , 10-30MmL -1 , 10-25MmL -1 , 10-20MmL -1 , 10-15MmL -1 , 15-50MmL -1 , 15-45MmL -1 , 15-40MmL -1 , 15-35MmL -1 , 15-30MmL -1 , 15-25MmL -1 , 15-20MmL -1 , 20-50MmL-1 , 20-45MmL -1 , 20-40MmL -1 , 20-35MmL -1 , 20-30MmL -1 , or 20-25MmL -1 Contains in concentration.

[0360] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate comprises Compound 101 and the SLG100 alginate is unmodified, and wherein the inner compartment contains 5 to 25 mg of mammalian cells. -1 and (ii) an outer compartment comprising a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate comprises Compound 101 and the SLG100 alginate is unmodified.

[0361] In some embodiments, the hydrogel capsule comprises (i) an inner compartment comprising a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate comprises Compound 101 and the SLG100 alginate comprises Compound 205, and wherein the inner compartment contains 5 to 25 mg of mammalian cells. -1 and (ii) an outer compartment comprising a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate comprises Compound 101 and the SLG100 alginate comprises Compound 205.

[0362] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG100 alginate and 5-25 μM of mammalian cells. -1 and (ii) an outer compartment containing LG20, wherein LG20 comprises Compound 101 and Compound 205.

[0363] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and 5-25 μM of mammalian cells. -1 and (ii) an outer compartment containing LG20, wherein LG20 comprises Compound 101 and Compound 205.

[0364] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified LG20 alginate and 5-25 μM of mammalian cells. -1 and (ii) an outer compartment containing LG20, wherein LG20 comprises Compound 101 and Compound 205.

[0365] Treatment method Described herein are methods for preventing or treating a disease, disorder, or condition in a subject through administration or implantation of a hydrogel capsule comprising the polysaccharide polymers described herein. In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of the disease, disorder, or condition. In some embodiments, the methods described herein prevent or delay the onset of the disease, disorder, or condition. In some embodiments, the subject is a human.

[0366] In some embodiments, the disease, disorder, or condition affects a system of the body, such as, for example, the nervous system (e.g., the peripheral nervous system or the central nervous system), the vascular system, the skeletal system, the respiratory system, the endocrine system, the lymphatic system, the reproductive system, or the gastrointestinal tract. In some embodiments, the disease, disorder, or condition affects a part of the body, such as the blood, eyes, brain, skin, lungs, stomach, mouth, ears, legs, feet, hands, liver, heart, kidneys, bones, pancreas, spleen, large intestine, small intestine, spinal cord, muscles, ovaries, uterus, vagina, or penis.

[0367] In some embodiments, the disease, disorder, or condition is a neurodegenerative disease, diabetes (type 1 or type 2), heart disease, autoimmune disease, cancer, liver disease, lysosomal storage disease, a coagulation or clotting disorder, an orthopedic condition, or an amino acid metabolism disorder.

[0368] In some embodiments, the disease, disorder, or condition is an autoimmune disease. In some embodiments, the disease, disorder, or condition is diabetes (type 1 or type 2 diabetes). In one embodiment, the subject has or has been diagnosed with diabetes (e.g., type 1 or type 2 diabetes). The subject may have any biomarker or other diagnostic criteria associated with diabetes, such as a high blood glucose level (e.g., greater than 300 mg / dL, greater than 400 mg / dL), or a high hemoglobin A1C level (e.g., a hemoglobin A1C level greater than 5.9%, a hemoglobin A1C level greater than 6.5%, a hemoglobin A1C level greater than 7%).

[0369] In some embodiments, the disease, disorder, or condition is not Type I diabetes and / or is not Type II diabetes.

[0370] In some embodiments, the disease, disorder, or condition is a neurodegenerative disease. Exemplary neurodegenerative diseases include Alzheimer's disease, Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and cerebral palsy (CP), dentatorubral-pallidoluysian atrophy (DRPLA), neuronal intranuclear hyaline inclusion disease (NIHID), dementia with Lewy bodies, Down's syndrome, Hallervorden-Spatz disease, prion diseases, argyrophilic grain dementia, corticobasal degeneration, dementia pugilistica, diffuse neurofibrillary tangle disease, Gerstmann-Straussler-Scheinker disease, Jakob-Creutzfeldt disease, Niemann-Pick disease type 3, progressive supranuclear palsy, subacute sclerosing panencephalitis, spinocerebellar ataxia, Pick's disease, and dentatorubral-pallidoluysian atrophy.

[0371] In some embodiments, the disease, disorder, or condition is an autoimmune disease, such as scleroderma, multiple sclerosis, lupus, or an allergy.

[0372] In some embodiments, the disease is a liver disease, eg, hepatitis B, hepatitis C, cirrhosis, or NASH.

[0373] In some embodiments, the disease, disorder, or condition is cancer. Exemplary cancers include leukemia, lymphoma, melanoma, lung cancer, brain cancer (e.g., glioblastoma), sarcoma, pancreatic cancer, kidney cancer, liver cancer, testicular cancer, prostate cancer, or uterine cancer.

[0374] In some embodiments, the disease, disorder, or condition is an orthopedic condition. Exemplary orthopedic conditions include osteoporosis, osteonecrosis, Paget's disease, or fractures.

[0375] In some embodiments, the disease, disorder, or condition is a lysosomal storage disease. Exemplary lysosomal storage diseases include Gaucher disease (e.g., Type I, Type II, or Type III), Tay-Sachs disease, Fabry disease, Farber disease, Hurler syndrome (also known as mucopolysaccharidosis type I (MPS I)), Hunter syndrome, lysosomal acid lipase deficiency, Niemann-Pick disease, Salla disease, Sanfilippo syndrome (also known as mucopolysaccharidosis type IIIA (MPS3A)), multiple sulfatase deficiency, Maroteaux-Lamy syndrome, metachromatic leukodystrophy, Krabbe disease, Scheie syndrome, Hurler-Scheie syndrome, Sly syndrome, hyaluronidase deficiency, Pompe disease, Danon disease, gangliosidosis, or Morquio syndrome.

[0376] In some embodiments, the disease, disorder, or condition is a coagulation disorder or clotting disorder. Exemplary coagulation disorders or clotting disorders include hemophilia (e.g., hemophilia A or hemophilia B), von Willebrand disease, thrombocytopenia, uremia, Bernard-Soulier syndrome, factor XII deficiency, vitamin K deficiency, or congenital afibrinogenemia.

[0377] In some embodiments, the disease, disorder, or condition is an amino acid metabolism disorder, such as phenylketonuria, tyrosinemia (e.g., type 1 or type 2), alkaptonuria, homocystinuria, hyperhomocysteinemia, or maple syrup urine disease.

[0378] In some embodiments, the disease, disorder, or condition is a fatty acid metabolism disorder, eg, hyperlipidemia, hypercholesterolemia, galactosemia.

[0379] In some embodiments, the disease, disorder, or condition is a purine or pyrimidine metabolism disorder, e.g., Lesch-Nyhan syndrome.

[0380] The present invention further includes a method of identifying a subject having or suspected of having a disease, disorder, or condition described herein, and, upon such identification, administering to the subject an implantable element, or composition thereof, comprising cells (e.g., optionally encapsulated by an encapsulation component) and optionally modified with a compound of Formula (I) described herein. In one embodiment, the subject is a human. In one embodiment, the subject is a human. In one embodiment, the subject is an adult. In one embodiment, the subject is a child (e.g., a subject under 21 years of age, under 18 years of age, under 15 years of age, under 12 years of age, under 10 years of age, or under 6 years of age).

[0381] How to make particles The present disclosure further includes methods for making particles described herein, e.g., particles comprising a polysaccharide polymer comprising a first compartment, a second compartment, a photoactive cross-linking moiety, and a compound of Formula (I). In some embodiments in which the particles are hydrogel capsules, the method of making the hydrogel capsules includes contacting a plurality of droplets comprising first and second polymer solutions (e.g., each comprising a hydrogel-forming polymer) with an aqueous cross-linking solution. In one embodiment, the aqueous cross-linking solution includes an ionic cross-linking agent, e.g., a divalent cation such as calcium, barium, or magnesium. The droplets may be formed using any technique known in the art. In a further embodiment in which the particles are hydrogel capsules, the method of making the hydrogel capsules includes an irradiation step in which a solution comprising the polysaccharide polymer is exposed to ultraviolet light to initiate the photocross-linking reaction. In one embodiment, one or both of the first and second polymer solutions may further contain a photoinitiator.

[0382] Each compartment of the particles described herein can contain one or more of the following: an unmodified polymer, a polymer modified with one or both of a compound of Formula (I) and a photoactive cross-linking moiety, or a blend of an unmodified polymer and a modified polymer. Briefly, in carrying out the method for preparing particles configured as two-compartment hydrogel capsules, a certain amount of a first polymer solution (e.g., containing an unmodified polymer, a polymer modified with a compound of Formula (I), a photoactive cross-linking moiety, or a blend thereof, and optionally containing cells) is loaded into a first syringe connected to the inner lumen of a coaxial needle. The first syringe can then be connected to a syringe pump oriented vertically above a container containing an aqueous cross-linking solution, including a cross-linking agent, a buffer, and an osmotic agent. A certain amount of a second polymer solution (e.g., containing an unmodified polymer, a polymer modified with a compound of Formula (I), a photoactive cross-linking moiety, or a blend thereof, and optionally containing cells) is loaded into a second syringe connected to the outer lumen of the coaxial needle. The second syringe can then be connected to a syringe pump oriented horizontally relative to the vessel containing the crosslinking solution. A high-voltage power generator can then be connected to the top and bottom of the needle. The syringe pump and power generator can then be used to push the first and second polymer solutions through the syringes at settings determined to achieve a desired droplet velocity of the polymer solution into the crosslinking solution. Those skilled in the art can easily determine various combinations of needle lumen size, voltage range, flow rate, droplet velocity, and droplet distance to create a two-compartment hydrogel capsule composition in which the majority of capsules (e.g., at least 80%, 85%, 90%, or more) are within 10% of the target diameter and have a spherical shape. After the first and second volumes of polymer solution are depleted, the droplets can be allowed to crosslink in the crosslinking solution for a specific time, for example, about 5 minutes. Crosslinking can involve ionic crosslinking (e.g., by contacting the droplets with an ionic crosslinking agent, e.g., a divalent cation), and / or covalent crosslinking (e.g., by irradiating the droplets to activate a photoactive crosslinking agent, e.g., a methacrylate or methacrylamide).

[0383] Exemplary process parameters for preparing millicapsules (e.g., 1.5 mm diameter millicapsules) include the following: A coaxial needle is positioned above the surface of the crosslinking solution at a distance sufficient to provide a drop distance from the needle tip to the solution surface. In one embodiment, the distance between the needle tip and the solution surface is between 1 and 5 cm. In one embodiment, the first and second polymer solutions are extruded through the needle at a total flow rate of between 0.05 mL / min and 5 mL / min, or between 0.05 mL / min and 2.5 mL / min, or between 0.05 mL / min and about 1 mL / min, or between 0.05 mL / min and 0.5 mL / min, or between 0.1 mL / min and 0.5 mL / min. In one embodiment, the first and second polymer solutions are extruded through the needle at a total flow rate of about 0.05 mL / min, 0.1 mL / min, 0.15 mL / min, 0.2 mL / min, 0.25 mL / min, 0.3 mL / min, 0.35 mL / min, 0.4 mL / min, 0.45 mL / min, or 0.5 mL / min. In one embodiment, the flow rates of the first and second polymer solutions through the needle are substantially the same. In one embodiment, the flow rates of the first and second polymer solutions through the needle are different.

[0384] In one embodiment, the voltage of the instrument is between 1 kV and 20 kV, or between 1 and 15 kV, or between 1 kV and 10 kV, or between 5 kV and 10 kV. The voltage may be adjusted until a desired droplet velocity is achieved. In one embodiment, the droplet velocity of the instrument is between 1 droplet / 10 seconds and 50 droplets / 10 seconds, or between 1 droplet / 10 seconds and 25 droplets / 10 seconds.

[0385] In one embodiment, the number of non-particle debris on the surface of the crosslinking solution is determined. The particles that have fallen to the bottom of the crosslinking container can then be collected, for example, by transferring the crosslinking solution containing the particles to another container, leaving the non-particle debris on the surface of the solution in the original crosslinking container. The removed particles can then be allowed to settle, the crosslinking solution can be removed, and the particles can then be washed one or more times with a buffer solution (e.g., HEPES buffer). In one embodiment, one or more aliquots of the resulting particle composition (e.g., particle preparation) are inspected by microscopy to assess the quality of the composition, for example, the number of particle defects and satellite particles.

[0386] In some embodiments, the crosslinking solution further comprises a processing additive (e.g., a hydrophilic, non-ionic surfactant). The processing additive can reduce the surface tension of the crosslinking solution. Agents useful as processing additives in the present disclosure include polysorbate-type surfactants, copolymers of polyethylene oxide (PEO) and polypropylene oxide (PPO), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers, and non-ionic surfactants such as Tween® 20, Tween® 80, Triton® X-100, IGEPAL® CA-630, poloxamer 188, or poloxamer 407, or surfactants having substantially the same chemical and physical properties as those listed in the table of exemplary surfactants immediately below. [Table 17]

[0387] In some embodiments, the non-ionic surfactant is a poloxamer. In one embodiment, the processing additive comprises multiple surfactants, e.g., multiple hydrophilic surfactants. In some embodiments, the processing additive does not contain Tween® 20 (polysorbate 20) or Triton® X-100. In one embodiment, the processing additive is IGEPAL® CA-630 (polyethylene glycol sorbitan monooleate). In some embodiments, the processing additive is poloxamer 188.

[0388] In some embodiments, a processing additive (e.g., a surfactant) is present in the crosslinking solution at a concentration of at least 0.0001% or greater. In some embodiments, the crosslinking solution comprises at least 0.001%, 0.01%, or 0.1% of the processing additive. In some embodiments, the processing additive is present at a concentration selected from between about 0.001% and about 0.1%, about 0.005% and about 0.05%, about 0.005% and about 0.01%, and about 0.01% and about 0.5%. In one embodiment, the processing additive is a surfactant and is present at a concentration below the micelle concentration for the surfactant.

[0389] In some embodiments, the ionic crosslinker may be a single type of divalent cation, or a mixture of different types, e.g., Ba 2+ , Ca2 +、Sr2+の In some embodiments, the ionic crosslinker is BaCl2, e.g., at a concentration of 1 mM to 100 mM, or 7.5 mM to 20 mM. In some embodiments, the ionic crosslinker is CaCl2, e.g., at a concentration of 50 mM to 100 mM. In some embodiments, the ionic crosslinker is SrCl2, e.g., at a concentration of 37.5 mM to 100 mM. In some embodiments, the ionic crosslinker is a mixture of BaCl2 (e.g., 5 mM to 20 mM) and CaCl2 (e.g., 37.5 mM to 12.5 mM), or a mixture of BaCl2 (e.g., 5 mM to 20 mM) and SrCl2 (e.g., 37.5 mM to 12.5 mM).

[0390] In some embodiments, the ionic crosslinker is SrCl2 and the processing additive is Tween® 80 (or a surfactant with substantially the same chemical and physical properties listed in the Exemplary Surfactants Table) at a concentration of less than 0.1%, e.g., about 0.005% to 0.05%, about 0.005% to about 0.01%. In some embodiments, the concentration of SrCl2 is about 50 mM. In some embodiments, the ionic crosslinker is SrCl2 and the processing additive is poloxamer 188 at a concentration of 1%.

[0391] The type and concentration of the buffer in the aqueous crosslinking solution are selected to maintain the solution pH at approximately neutral, e.g., about 6.5 to about 7.5, about 7.0 to about 7.5, or about 7.0. In one embodiment, the buffer is compatible with the biological material to be encapsulated in the particles, e.g., cells. In some embodiments, the buffer in the aqueous crosslinking solution comprises HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid).

[0392] The osmolality adjusting agent in the aqueous crosslinking solution is selected to maintain the osmolality of the solution at a value similar to that of the polymer solution (which in some embodiments includes a suspension of cells), e.g., or with up to 20%, 10%, or 5% higher or lower variation. In some embodiments, the osmolality adjusting agent is mannitol at a concentration of 0.1 M to 0.3 M.

[0393] In some embodiments, the crosslinking solution comprises 25 mM HEPES buffer, 20 mM BaCl, 0.2 M mannitol, and 0.01% poloxamer 188.

[0394] In some embodiments, the crosslinking solution comprises 50 mM strontium chloride hexahydrate, 0.165 M mannitol, 25 mM HEPES, and 0.01% surfactant having substantially the same chemical and physical properties as listed in the Exemplary Surfactants Table: Tween 80.

[0395] In one embodiment, the processing additive is poloxamer 188, which is present in a detectable amount in the particle composition (e.g., particle preparation) after a washing step. Poloxamer 188 can be detected by any technique known in the art, for example, by partially or completely dissolving the particles in an aliquot of the composition by sodium sulfate precipitation and analyzing the supernatant by LC / MS.

[0396] The reduction in surface tension of the crosslinking solution can be assessed by any method known in the art, for example, by using a contact angle goniometer, or a tensiometer, for example, via the Dunouy ring method (see, e.g., Davarci et al (2017) Food Hydrocolloids 62:119-127).

[0397] Enumerated exemplary embodiments 1. A polysaccharide polymer comprising: (i) a photoactive cross-linking moiety; (ii) A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: A is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-, -C(O)O-, -C(O)-, -OC(O)-, -N(R C )-, -N(R C )C(O)-, -C(O)N(R C )-, -N(R C )N(R D )-, -NCN-, -N(R C )C(O)(C1-C6-alkylene)-, -N(R C )C(O)(C2-C6-alkenylene)-, -C(=N(R C )(R D ))O-, -S-, -S(O) x -, -OS(O) x -, -N(R C )S(O) x -, -S(O) x N(R C )-, -P(R F ) y -, -Si(OR A )2-, -Si(R G )(OR A )-, -B(OR A)-, or a metal, each of which is optionally linked to a linking group (e.g., a linking group described herein), and one or more R 1 and optionally replaced by L 1 , and L 3 is independently a bond, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is selected from one or more R 2 and optionally replaced by L 2 is a bond, M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 3 and optionally replaced by P is one or more R 4 is heteroaryl optionally substituted by Z is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 5 and optionally replaced by Each R A , R B , R C , R D , R E , R F , and R G are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, azido, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 6 and optionally replaced by or R C , and R D together with the nitrogen atom to which they are attached, form one or more R 6 forming a ring (e.g., a 5- to 7-membered ring) optionally substituted by Each R 1 , R 2 , R3 , R 4 , R 5 , and R 6 are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, oxo, -OR A1 , -C(O)OR A1 , -C(O)R B1 , -OC(O)R B1 , -N(R C1 )(R D1 ), -N(R C1 )C(O)R B1 , -C(O)N(R C1 ), SR E1 , S(O) x R E1 , -OS(O) x R E1 , -N(R C1 )S(O) x R E1 , -S(O) x N(R C1 )(R D1 ), -P(R F1 ) y , cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 7 and optionally replaced by Each R A1 , R B1 , R C1 , R D1 , R E1 , and R F1 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl may optionally be joined by one or more R 7 is replaced by Each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; x is 1 or 2, a compound of formula (I) wherein y is 2, 3, or 4.

[0398] 2. The polysaccharide polymer of embodiment 1, wherein the photoactive cross-linking moiety is covalently attached to a saccharide monomer within the polysaccharide polymer.

[0399] 3. The polysaccharide polymer of embodiment 2, wherein the photoactive cross-linking moieties are attached to carboxylate moieties in the saccharide monomers.

[0400] 4. The polysaccharide polymer of any one of embodiments 1 to 3, wherein the photoactive cross-linking moiety comprises an alkyl, alkenyl, alkynyl, ester, ketone, amine, or amide group.

[0401] 5. The polysaccharide polymer of any one of embodiments 1 to 3, wherein the photoactive cross-linking moiety comprises an alkyl group.

[0402] 6. The polysaccharide polymer of any one of embodiments 1 to 3, wherein the photoactive cross-linking moiety comprises an alkenyl group.

[0403] 7. The polysaccharide polymer of any one of embodiments 1 to 3, wherein the photoactive cross-linking moiety comprises an alkynyl group.

[0404] 8. The polysaccharide polymer of any one of embodiments 1 to 3, wherein the photoactive cross-linking moiety comprises an ester group.

[0405] 9. The polysaccharide polymer of any one of embodiments 1 to 3, wherein the photoactive cross-linking moiety comprises a ketone group.

[0406] 10. The polysaccharide polymer of any one of embodiments 1 to 3, wherein the photoactive cross-linking moiety comprises an amine group.

[0407] 11. The polysaccharide polymer of any one of embodiments 1 to 3, wherein the photoactive cross-linking moiety comprises an amide group.

[0408] 12. The polysaccharide polymer according to any one of embodiments 1 to 11, wherein the photoactive cross-linking moiety is capable of reacting with a second photoactive cross-linking moiety upon activation by light (e.g., ultraviolet light).

[0409] 13. The polysaccharide polymer of any one of embodiments 1 to 12, wherein the photoactive cross-linking moieties are present on the polysaccharide polymer at a density of at least about 1%, e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, as determined, e.g., by comparison to a reference standard (e.g., by LC-MS assay).

[0410] 14. The polysaccharide polymer according to any one of embodiments 1 to 13, wherein the photoactive cross-linking moieties are present on the polysaccharide polymer at a density of between 1% and 10%, e.g., 1% to 8%, 1% to 6%, or 1% to 4%, as determined, e.g., by comparison with a reference standard.

[0411] 15. The polysaccharide polymer according to any one of embodiments 1 to 14, wherein the photoactive cross-linking moieties are present on the polysaccharide polymer at a density of between 1% and 8%, as determined, for example, by comparison with a reference standard.

[0412] 16. The polysaccharide polymer according to any one of embodiments 1 to 15, wherein the photoactive cross-linking moieties are present on the polysaccharide polymer at a density of between 1% and 6%, e.g., as determined by comparison with a reference standard.

[0413] 17. The polysaccharide polymer according to any one of embodiments 1 to 16, wherein the photoactive cross-linking moieties are present on the polysaccharide polymer at a density of between 1% and 4%, as determined, for example, by comparison with a reference standard.

[0414] 18. The polysaccharide polymer of any one of embodiments 1-17, wherein the polysaccharide polymer is selected from agarose, alginate, amylose, amylopectin, arabinogalactan, cellulose, chitin, chitosan, dextran, fructan, fucoidan, galactan, galactomannan, glycogen, gellan gum, hyaluronic acid, hyaluronate, inulin, laminarin, maltodextrin, pectin, pullulan, xanthan gum, xylan, carrageenan, and raffinose.

[0415] 19. The polysaccharide polymer of any one of embodiments 1-18, wherein the polysaccharide polymer is not agarose, amylose, amylopectin, arabinogalactan, cellulose, chitin, chitosan, dextran, fructan, fucoidan, galactan, galactomannan, glycogen, gellan gum, hyaluronic acid, hyaluronate, inulin, laminarin, maltodextrin, pectin, pullulan, xanthan gum, xylan, carrageenan, and raffinose.

[0416] 20. The polysaccharide polymer according to any one of embodiments 1 to 19, wherein the polysaccharide polymer is selected from alginate, hyaluronate, and chitosan.

[0417] 21. The polysaccharide polymer of any one of embodiments 1 to 20, wherein the polysaccharide polymer is an alginate.

[0418] 22. The polysaccharide polymer according to any one of embodiments 1 to 21, wherein the polysaccharide polymer is hyaluronate.

[0419] 23. The polysaccharide polymer of any one of embodiments 1 to 22, wherein the polysaccharide polymer is chitosan.

[0420] 24. The polysaccharide polymer of embodiment 21, wherein the alginate is a high guluronic acid (G) alginate or a high mannuronic acid (M) alginate.

[0421] 25. The polysaccharide polymer of any one of embodiments 21-24, wherein the alginate is a high guluronic acid (G) alginate.

[0422] 26. The polysaccharide polymer of embodiment 21 or 24-25, wherein the alginate is a high mannuronic acid (G) alginate.

[0423] 27. The polysaccharide polymer of any of embodiments 21 or 24-26, wherein the alginate is not a high mannuronic acid (M) alginate.

[0424] 28. The polysaccharide polymer of any of embodiments 21 or 24-27, wherein the alginate is selected from low molecular weight alginates, medium molecular weight alginates, hig...

Claims

1. Alginate polymer, (i) Equation (IV): 【Chemistry 1】 [In the formula, X １ is non-existent, O, NR ３３ , or C(R ３４ａ ) (Caution ３４ｂ ) and R ３０ａ 、 R ３０ｂ 、 R ３１ 、 R ３２ 、 R ３３ 、 R ３４ａ 、 and R ３４ｂ each independently is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, -OR Ａ１ 、 -C(O)OR Ａ１ 、 -C(O)R Ｂ１ 、 -OC(O)R Ｂ１ 、 -N(R Ｃ１ )(R Ｄ１ ), -N(R Ｃ１ )(C(O)R Ｂ１ 、 -C(O)N(R Ｃ１ ), SR Ｅ１ 、 cycloalkyl, heterocyclyl, aryl, or heteroaryl, and Each R Ａ１ , R Ｂ１ , R Ｃ１ , R Ｄ１ , and R Ｅ１ These are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl has 1 to 6 R ７ It is optionally replaced by, Each R ７ [These are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.] The compound, or a pharmaceutically acceptable salt or tautomer thereof, (ii) Equation (I): 【Chemistry 2】 [In the formula, A is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-, -C(O)O-, -C(O)-, -OC(O)-, -N(R Ｃ )-,-N(R Ｃ )C(O)-, -C(O)N(R Ｃ )-,-N(R Ｃ )N(R Ｄ )-, -NCN-, -N(R Ｃ ) C(O)(C １ ~C ６ -Alkilen)-, -N(R Ｃ ) C(O)(C ２ ~C ６ -Alkenylene)-, -C(=N(R Ｃ ) (Caution Ｄ )) O-, -S-, -S(O) ｘ -, -OS(O) ｘ -, -N(R Ｃ ) S(O) ｘ -, -S(O) ｘ N(R) Ｃ )-,-P(R Ｆ ) ｙ -, -Si( OR Ａ ) ２ -, -Si(R Ｇ ) ( OR Ａ )-,-B(OR Ａ ) - or a metal, each of which is optionally linked to a bonding group, and one or more R １ It is optionally replaced by, L １ , and L ３ Each of them is independently a bond, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is one or more R ２ It is optionally replaced by, L ２ It is a combination, M is a heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which has one or more R ３ It is optionally replaced by, P is one or more R ４ It is a triazolyl that is optionally substituted by, Z is an alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of these is one or more R ５ It is optionally replaced by, Each R Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ , R Ｆ , and R Ｇ Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, azide, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R ６ It is optionally replaced by, or R Ｃ , and R Ｄ These, together with the nitrogen atom to which they are bonded, form one or more R ６ Forms a ring that is optionally substituted, Each R １ 、R ２ 、R ３ 、R ４ 、R ５ 、and R ６ are, independently, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, -OR Ａ１ 、-C(O)OR Ａ１ 、-C(O)R Ｂ１ 、-OC(O)R Ｂ１ 、-N(R Ｃ１ )(R Ｄ１ ), -N(R Ｃ１ )(C(O)R Ｂ１ 、-C(O)N(R Ｃ１ ), SR Ｅ１ 、S(O) ｘ R Ｅ１ 、-OS(O) ｘ R Ｅ１ 、-N(R Ｃ１ )(S(O) ｘ R Ｅ１ 、-S(O) ｘ N(R Ｃ１ )(R Ｄ１ ), -P(R Ｆ１ ), ｙ cycloalkyl, heterocyclyl, aryl, heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R ７ . Each R Ａ１ , R Ｂ１ , R Ｃ１ , R Ｄ１ , R Ｅ１ , and R Ｆ１ Each is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R ７ It is optionally replaced by, Each R ７ These are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl. x is either 1 or 2, y is 2, 3, or 4. The alginate polymer comprising a compound or a pharmaceutically acceptable salt thereof.

2. The compound of formula (IV) above, (a) Covalently bonded to the sugar monomer in the alginate polymer, and / or (b) Bonded to the carboxylate portion within the sugar monomer, The alginate polymer according to claim 1.

3. The compound of formula (IV) above, (a) at least about 1%, for example 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or a density greater than that, (b) Densities between 1% and 10%, for example, 1% to 8%, 1% to 6%, or 1% to 4% The alginate polymer according to claim 1, wherein the alginate polymer is present on the alginate polymer.

4. The alginate polymer according to claim 1, wherein the alginate is a high guluronic acid (G) alginate or a high mannuronic acid (M) alginate.

5. X １ However, NR ３３ or O, R ３０ａ , R ３０ｂ , R ３１ , and R ３２ The alginate polymer according to claim 1, wherein each of them is hydrogen.

6. The compound of formula (IV) above, (a) Table 1 【change】 Having a structure selected from, or a pharmaceutically acceptable salt thereof, (b) 【Transformation 3】 or selected from a pharmaceutically acceptable salt thereof, The alginate polymer according to claim 1.

7. The compound of formula (I) above, (a) Table 2 【change】 【change】 【change】 【change】 【change】 Having a structure selected from, or a pharmaceutically acceptable salt thereof, (b) 【Chemistry 4】 or selected from its pharmaceutically acceptable salts, (c) 【Transformation 5】 or a pharmaceutically acceptable salt thereof The alginate polymer according to claim 1.

8. A composition comprising the alginate polymer according to any one of claims 1 to 7.

9. A hydrogel capsule comprising the alginate polymer according to any one of claims 1 to 7.

10. (a) The hydrogel capsule comprises a single compartment containing the alginate polymer, (b) The hydrogel capsule comprises a plurality of compartments, one of which comprises the alginate polymer, or (c) The hydrogel capsule includes an inner compartment and an outer compartment, The hydrogel capsule according to claim 9.

11. The inner compartment comprises a first alginate polymer containing the compound of formula (IV), The hydrogel capsule according to claim 9, wherein the outer compartment comprises a second alginate polymer containing the compound of formula (IV).

12. The aforementioned hydrogel capsule, (a) Between 0.1 mm and 5 mm, (b) Between 1 mm and 5 mm, and / or (c) Between 1 mm and 2.5 mm A hydrogel capsule according to claim 9, having a diameter of [specify diameter].

13. The hydrogel capsule according to claim 9, wherein the hydrogel capsule encapsulates cells that produce a therapeutic agent.

14. A composition comprising the hydrogel capsule described in claim 9.

15. A method for producing a hydrogel capsule comprising the alginate polymer described in any one of claims 1 to 7.

16. A composition for use in the treatment of a subject having a disease, disorder, or pathological condition, comprising the hydrogel capsule described in claim 9.

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