Hydrogel capsules containing covalently photocrosslinked polysaccharides and island cells

Abstract

Modulation of the immune response may have beneficial effects on the fidelity and function of these devices. Novel compounds, compositions, and devices that achieve this goal are needed in the art. [Solution] Hydrogel capsules (e.g., alginate hydrogel capsules) comprising a polysaccharide polymer that can be covalently crosslinked with another part (e.g., another polysaccharide polymer), and island cells, as well as related compositions and uses thereof, are described herein.

Description

[Technical Field]

[0001] Priority Claim This application claims priority to U.S. Application No. 63 / 452,127, filed on 14 March 2023, and the disclosures of the aforementioned application are incorporated herein by reference in their entirety. [Background technology]

[0002] The function of implantable devices largely depends on the recipient's biological immune response pathway (Anderson et al., Semin. Immunol. 20:86-100 (2008); Langer, Adv. Mater. 21:3235-3236 (2009)). Modulation of the immune response may 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. [Overview of the project]

[0003] Hydrogel capsules (e.g., alginate hydrogel capsules), as well as related compositions and uses thereof, comprising (i) a polysaccharide polymer that can be covalently crosslinked with another part (e.g., another polysaccharide polymer), and (ii) island cells, are described herein. In one embodiment, the polysaccharide polymer comprises a photoactive crosslinked part, an example of which is a compound of formula (IV) or a pharmaceutically acceptable salt thereof. In one embodiment, the polysaccharide polymer comprises both a photoactive crosslinked part (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 may be present in a hydrogel capsule comprising one or more compartments, for example, in the outer compartment of the hydrogel capsule described herein, or in the inner compartment of the hydrogel capsule described herein, or both. In one embodiment, the polysaccharide polymer is covalently crosslinkable and ionically crosslinkable. Incorporating photoactive crosslinkers within polysaccharide polymers, and consequently incorporating them into hydrogel capsules, may allow for the modification of specific properties of the hydrogel capsules, including capsule diameter, stability, and integrity.

[0004] Details of one or more embodiments of the present disclosure are shown herein. Other features, purposes, and advantages of the present invention will become apparent from the modes for carrying out the invention, drawings, examples, and claims. [Brief explanation of the drawing]

[0005] [Figure 1] This shows a typical LC-UV chromatogram used to characterize the components of a photoactive crosslinking linker reaction. [Figure 2]A shows a typical image of a two-compartment alginate hydrogel capsule. This is an image of an alginate hydrogel capsule in which both the inner and outer compartments contain a blend of VLVG / SLG100 alginate. B is 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), and the inner compartment contains dextrin beads that mimic mammalian cells. C is an image of a hydrogel in which both the inner and outer compartments contain a blend of methacrylamide-modified VLVG / SLG100 (70 / 30), and the inner compartment contains dextrin beads that mimic mammalian cells. [Figure 3] Figures A-C show representative images of the alginate hydrogel capsules shown in Figures 2A-C after being stored in buffer solution for one month. [Figure 4A] Representative images comparing the size and stability of double-crosslinked alginate hydrogels prepared using a 7% photoactive crosslinking linker are shown. [Figure 4B] Representative images comparing the size and stability of double-crosslinked alginate hydrogels prepared using a 5% photoactive crosslinking linker are shown. [Figure 4C] Representative images comparing the size and stability of double-crosslinked alginate hydrogels prepared using a 3% photoactive crosslinking linker are shown. [Figure 4D] Representative images comparing the size and stability of double-crosslinked alginate hydrogels prepared using a 1.5% photoactive crosslinking linker are shown. [Figure 4E] Figures 4A to 4D are charts showing the corresponding fracture strengths of the alginate hydrogels. [Figure 5] This figure compares the average fracture strength of an exemplary hydrogel capsule containing a covalently crosslinked polymer with compound 101(2) to that of an ionically crosslinked alginate hydrogel(2) as described in Example 7. [Figure 6]This figure compares the average fracture strength of an exemplary hydrogel capsule containing a covalently crosslinked polymer with compound 111(2) to that of an ionically crosslinked alginate hydrogel(2) as described in Example 7. [Figure 7] A and B show exemplary microscopic images of hydrogel capsule 1 (A) and hydrogel capsule 2 (B) as described in Table 8. [Figure 8] Images A and B show exemplary microscopic images of a double-crosslinked alginate hydrogel capsule containing exemplary island cells. [Figure 9] This is a bar graph comparing the multiplicative changes in macrophage adhesion for various modified alginate hydrogel capsules described herein; (1): empty sphere; (2)-(5): bicrosslinked polymer hydrogels containing exemplary island cells. [Figure 10] Figures A and B show the percentage viability (A) and total cell number (B) of exemplary island cells encapsulated in double-crosslinked alginate hydrogel capsules. (1) and (3) were performed at room temperature, and (2) and (4) were performed at 4°C. [Figure 11] Figures A and B show the effects of UV exposure time (A) and UV intensity (B) on the fracture strength of exemplary modified alginate hydrogel capsules. [Figure 12] Figures A and B show the effects of UV exposure time (A) and UV intensity (B) on the viability of islet cells encapsulated in exemplary modified alginate hydrogel capsules. [Figure 13] This graph shows the effect of ultraviolet exposure on the release rate of the encapsulated dextran polymer from the exemplary modified alginate hydrogel capsules described herein. [Figure 14] A-C show the effect of in vivo residence time on compound retention (A), structural integrity (B), and mechanical strength (C) of the exemplary modified alginate hydrogel capsules described herein. Light gray represents double-crosslinked alginate hydrogel capsules, and dark gray represents ion-crosslinked alginate hydrogel capsules. [Figure 15](1) an empty sphere, (2) a double-crosslinked alginate hydrogel capsule containing exemplary island cells as described herein, and (3) a graph showing the relative PFO response to polystyrene beads. [Figure 16] Figures A and B are graphs showing the blood glucose levels of immunodeficient diabetic mice after administration of hydrogel capsules containing the double-crosslinked polymer and island cells described herein. [Figure 17A] This specification compares the effect of changing the batch size on the size of the two-compartment hydrogel capsules described herein. The hydrogel capsules contain the same composition as described in Example 9 (Hydrogel Capsule #1). [Figure 17B] This specification compares the effect of changing the batch size on the strength of the two-compartment hydrogel capsules described herein. The hydrogel capsules contain the same composition as described in Example 9 (Hydrogel Capsule #1). [Figure 17C] This specification compares the effect of changing the batch size on IgG absorption of the two-compartment hydrogel capsules described herein. The hydrogel capsules contain the same composition as described in Example 9 (Hydrogel Capsule #1). [Figure 18] A and B compare the effects on insulin diffusion (A) and IgG absorption (B) when the density of the compound of formula (IV) is changed in a two-compartment hydrogel capsule (hydrogel capsule #1) prepared according to the method of Example 9. Sample (1) refers to an ionic crosslinked sphere without a covalent crosslinking agent. Sample (2) refers to a double crosslinked sphere in which the inner and outer compartments contain alginates modified with compounds 101 and 205 (hydrogel capsule #2 of Example 9). Sample (3) refers to a double crosslinked sphere in which the inner and outer compartments contain alginates modified with compounds 101 and 205 (hydrogel capsule #2 of Example 9), and further contains exemplary pancreatic islet cells. [Figure 19]A-C show the effect of varying the density of the compound of formula (IV) on the strength (A), flexibility (B), and size (C) of the two-compartment hydrogel capsule, where (1; round) refers to the control hydrogel capsule, and (2; square), (3; triangular), and (4; rhombic) refer to hydrogel capsules with compound 205 reduced by 75%, 62%, and 50%, respectively. The hydrogel capsule contains the same composition as described in Example 9 (Hydrogel Capsule #1). [Figure 20A] The effect of varying the density of the compound of formula (IV) on the strength of the two-compartment hydrogel capsule (Figure 20A) is shown, where (1; circle) refers to the control hydrogel capsule, and (2; square) and (3; triangle) refer to hydrogel capsules with compound 205 reduced by 62% and 50%, respectively. Sample (4) refers to an ionic crosslinked sphere without a covalent crosslinking agent, sample (5) refers to a double crosslinked sphere (hydrogel capsule #2 of Example 9) containing alginates modified with compounds 101 and 205 in the inner and outer compartments, and (6) refers to a double crosslinked sphere (hydrogel capsule #2 of Example 9) containing alginates modified with compounds 101 and 205 in the inner and outer compartments, and further refers to a double crosslinked sphere containing exemplary islet cells. [Figure 20B] The effect of varying the density of the compound of formula (IV) on the flexibility of the two-compartment hydrogel capsule (Figure 20B) is shown, where (1; circle) refers to the control hydrogel capsule, and (2; square) and (3; triangle) refer to hydrogel capsules with compound 205 reduced by 62% and 50%, respectively. Sample (4) refers to an ionic crosslinked sphere without a covalent crosslinking agent, sample (5) refers to a double crosslinked sphere (hydrogel capsule #2 of Example 9) containing alginates modified with compounds 101 and 205 in the inner and outer compartments, and (6) refers to a double crosslinked sphere (hydrogel capsule #2 of Example 9) containing alginates modified with compounds 101 and 205 in the inner and outer compartments, and further refers to a double crosslinked sphere containing exemplary pancreatic islet cells. [Figure 20C]The effect of varying the density of the compound of formula (IV) on the size of the two-compartment hydrogel capsule (Figure 20C) is shown, where (1; circle) refers to the control hydrogel capsule, and (2; square) and (3; triangle) refer to hydrogel capsules with compound 205 reduced by 62% and 50%, respectively. Sample (4) refers to an ionic crosslinked sphere without a covalent crosslinking agent, sample (5) refers to a double crosslinked sphere (hydrogel capsule #2 of Example 9) containing alginates modified with compounds 101 and 205 in the inner and outer compartments, and (6) refers to a double crosslinked sphere (hydrogel capsule #2 of Example 9) containing alginates modified with compounds 101 and 205 in the inner and outer compartments, and further refers to a double crosslinked sphere containing exemplary islet cells. [Figure 20D] The effect of varying the density of the compound of formula (IV) on IgG absorption in two-compartment hydrogel capsules (Figure 20D) is shown, where (1; circle) refers to the control hydrogel capsule, 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 an ionic crosslinked sphere without covalent crosslinking linkers, sample (5) refers to a double crosslinked sphere (hydrogel capsule #2 of Example 9) containing alginates modified with compounds 101 and 205 in the inner and outer compartments, and (6) refers to a double crosslinked sphere (hydrogel capsule #2 of Example 9) containing alginates modified with compounds 101 and 205 in the inner and outer compartments, and further includes exemplary island cells. [Figure 21A]This study shows the effect of changes in UV irradiation conditions on the size of two-compartment hydrogel capsules. The hydrogel capsules tested are those described in Example 9 (Hydrogel Capsule #1). Sample (1) refers to an ionic crosslinked sphere without a covalent crosslinking agent. Sample (2) refers to a double crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9). Sample (3) refers to a double crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9), and further containing exemplary pancreatic islet cells. Sample (4) refers to an empty well control. [Figure 21B] This study shows the effect of changes in UV irradiation conditions on the strength of two-compartment hydrogel capsules. The hydrogel capsules tested are those described in Example 9 (Hydrogel Capsule #1). Sample (1) refers to an ionic crosslinked sphere without a covalent crosslinking agent. Sample (2) refers to a double crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9). Sample (3) refers to a double crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9), and further containing exemplary pancreatic islet cells. Sample (4) refers to an empty well control. [Figure 21C] This study demonstrates the effect of changes in UV irradiation conditions on the flexibility of two-compartment hydrogel capsules. The hydrogel capsules tested are those described in Example 9 (Hydrogel Capsule #1). Sample (1) refers to an ionic crosslinked sphere without a covalent crosslinking agent. Sample (2) refers to a double crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9). Sample (3) refers to a double crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9), and further containing exemplary pancreatic islet cells. Sample (4) refers to an empty well control. [Figure 21D]This study shows the effect of changes in UV irradiation conditions on IgG absorption in two-compartment hydrogel capsules. The hydrogel capsules tested are those described in Example 9 (Hydrogel Capsule #1). Sample (1) refers to an ionic crosslinked sphere without covalent crosslinking linkers. Sample (2) refers to a double crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9). Sample (3) refers to a double crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9), and further containing exemplary island cells. Sample (4) refers to an empty well control. [Figure 22] This specification shows the volume swelling rates of the exemplary two-compartment hydrogel capsules described herein in various culture media. The hydrogel capsules tested are those described in Example 9 (Hydrogel Capsule #1). [Figure 23A] This specification shows the effect of different alginate types in the inner compartment on the strength of the exemplary two-compartment hydrogel capsule described herein. The hydrogel capsule tested is the same as that described in Example 9 (Hydrogel Capsule #1), but with a modified alginate in the inner compartment. Sample (1) refers to an ionic crosslinked sphere without a covalent crosslinking agent. Sample (2) refers to a double-crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9). Sample (3) refers to a double-crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9), and further containing exemplary islet cells. Sample (4) refers to an empty well control. [Figure 23B]This specification demonstrates the effect of different alginate types in the inner compartment on the flexibility of the exemplary two-compartment hydrogel capsules described herein. The tested hydrogel capsules are those described in Example 9 (Hydrogel Capsule #1), but with a modified alginate in the inner compartment. Sample (1) refers to an ionic crosslinked sphere without a covalent crosslinking agent. Sample (2) refers to a double-crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9). Sample (3) refers to a double-crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9), and further containing exemplary islet cells. Sample (4) refers to an empty well control. [Figure 23C] This specification demonstrates the effect of different alginate types within the inner compartment on the viability of cells encapsulated in the exemplary two-compartment hydrogel capsules described herein. The hydrogel capsules tested are those described in Example 9 (Hydrogel Capsule #1), but with a modified alginate in the inner compartment. Sample (1) refers to an ionic crosslinked sphere without a covalent crosslinking agent. Sample (2) refers to a double-crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9). Sample (3) refers to a double-crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9), and further containing exemplary islet cells. Sample (4) refers to an empty well control. [Figure 23D]This specification demonstrates the effect of different alginate types within the inner compartment on IgG absorption by cells encapsulated in the exemplary two-compartment hydrogel capsules described herein. The tested hydrogel capsules are those described in Example 9 (Hydrogel Capsule #1), but with a modified alginate in the inner compartment. Sample (1) refers to an ionic crosslinked sphere without covalent crosslinking linkers. Sample (2) refers to a double-crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9). Sample (3) refers to a double-crosslinked sphere containing alginates modified with compounds 101 and 205 in the inner and outer compartments (Hydrogel Capsule #2 from Example 9), and further containing exemplary island cells. Sample (4) refers to an empty well control. [Figure 24] This is a line graph showing the barium release rate from exemplary alginate hydrogel capsules. Sample (1) refers to an ion-crosslinked sphere without covalent linkers, washed 15 times with buffer. Sample (2) refers to hydrogel capsule #1 of Example 9, washed 8 times with buffer. Sample (3) refers to hydrogel capsule #1 of Example 9, washed with EDTA. [Figure 25] This bar graph shows the residual barium in an exemplary alginate hydrogel capsule (Hydrogel Capsule #1 of Example 9) after increasing the number of washes with CMRL or HPLM medium. [Figure 26] This is a schematic diagram illustrating the indirect curing process. [Figure 27]A-C illustrate the effect of indirect covalent crosslinking on the strength (A), size (B), and insulin diffusion (C) of the exemplary two-compartment hydrogel capsules described herein. Samples (1), (2), and (3) refer to individual replicas of the hydrogel capsule described in Example 9 (Hydrogel Capsule #1). Sample (1) refers to an ionic crosslinked sphere in which no covalent crosslinking agent is present. Sample (2) refers to a double crosslinked sphere in which the inner and outer compartments contain alginates modified with compounds 101 and 205 (Hydrogel Capsule #2 of Example 9). Sample (3) refers to a double crosslinked sphere in which the inner and outer compartments contain alginates modified with compounds 101 and 205 (Hydrogel Capsule #2 of Example 9), and further contains exemplary pancreatic islet cells. [Figure 28] This is a schematic diagram illustrating exemplary architectures of the polymers and associated hydrogel capsules described herein. [Modes for carrying out the invention]

[0006] This disclosure provides a hydrogel capsule (e.g., an alginate hydrogel capsule) comprising (i) a photoactive crosslinked moiety and a polysaccharide polymer containing a compound of formula (I), and (ii) island cells, as well as related compositions thereof, hydrogel capsules containing the same, and methods for producing and using the same.

[0007] Abbreviations and Definitions To make this disclosure more easily understandable, certain technical and scientific terms used herein are specifically defined below. Unless otherwise specifically defined elsewhere in this document, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which the invention pertains.

[0008] As used herein, including in the attached claims, the singular forms of terms such as "a," "an," and "the" include the corresponding plural references unless the context otherwise clearly indicates.

[0009] When "about" or "approximately" is 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), it means that the described value is within an acceptable functional range for the defined parameter, as determined by those skilled in the art, and which depends in part on how the limits of the measuring system (including the acceptable error range for that measuring system) are measured or determined. For example, "about" may mean a range of 20% above and below the described 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 to 1.8 mm and encapsulate 4 to 6 M cells. As another non-limiting example, a preparation of about 100 devices (e.g., hydrogel capsules) may include preparations having 80 to 120 devices. In some embodiments, the term “about” means that a modified parameter may vary by 15%, 10%, or 5% above or below the numerical value described for that parameter. Alternatively, with respect to certain properties of the devices described herein, particularly such as the integrity of hydrogel capsules of non-fibrous compounds, the term “about” may mean within one order of magnitude above or below the enumerated value, for example, within 5 times, 4 times, 3 times, 2 times, or 1 time.

[0010] "To obtain" or "to acquire," as used herein, means to obtain 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" a value or physical entity. "Directly obtaining" means performing a process (e.g., performing an analytical method or protocol) in order to obtain a value or physical entity. "Indirectly obtaining" means receiving such value or physical entity from another party or source (e.g., a laboratory that is a third party that directly obtained the physical entity or value). Examples of directly obtaining a value or physical entity include performing a process that involves a physical change of the physical entity, or performing a process that involves the use of a machine or apparatus. An example of directly obtaining a value is obtaining a sample from a human subject. An example of directly obtaining a value is performing a process that uses a machine or device, e.g., obtaining fluorescence microscopy data using a fluorescence microscope.

[0011] When used herein, “administer,” “give administration,” or “give administration” means to implant, absorb, ingest, inject, or otherwise introduce into a subject an entity described herein (e.g., a hydrogel capsule, device, or preparation of a hydrogel capsule or device) or to provide such entity to a subject for administration.

[0012] As used herein, "non-fibrous" means a compound or material that reduces the foreign body response (FBR). For example, the amount of FBR induced in biological tissue by implanting a device (e.g., a hydrogel capsule) containing a non-fibrous compound (e.g., a hydrogel capsule containing a polymer covalently modified with the compounds listed in Table 3) into the tissue is less than the FBR induced by implanting a non-fibrous null reference device (i.e., a device lacking any non-fibrous compounds but with substantially the same composition (e.g., the same size, shape, and number of compartments)). In one embodiment, the degree of FBR is assessed by an immunological response in the tissue containing the implanted device (e.g., a hydrogel capsule), which may include, for example, protein adsorption, macrophages, multinucleated foreign body giant cells, fibroblasts, and angiogenesis, for which assays known in the art, such as those described in WO2017 / 075630, or Vegas, A., et al., Nature One or more assays / methods described in Biotechnol (see above) (e.g., subcutaneous cathepsin measurement of an embedded capsule), Masson's trichrome (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 cell deposits, quantification of 79 RNA sequences of known inflammatory factors and immune cell markers, or FACS analysis of macrophages and neutrophils in devices (e.g., capsules) recovered after 14 days in the intraperitoneal space of a suitable test subject (e.g., immunocompetent mice). In one embodiment, FBR is evaluated by measuring the levels in tissue containing the embedding of one or more biomarkers of the immune response (e.g., cathepsin, TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-4, CCL2, or CCL4).In some embodiments, the FBR induced by the device of the present invention (e.g., a hydrogel capsule containing a non-fibrous compound disposed on its outer 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 substantially identical to the claimed device (e.g., a hydrogel capsule that does not contain a non-fibrous compound but is otherwise substantially identical to the claimed capsule), except that it lacks means for reducing the FBR. In some embodiments, the FBR (e.g., the level of a biomarker) 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 longer.

[0013] As used herein, “cell” means an engineered cell or an unengineered cell. In one embodiment, a cell is an immortalized cell or an engineered cell derived from an immortalized cell. In one embodiment, a cell is a viable cell, and is viable, for example, as measured by any technique described herein or known in the art.

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

[0015] [Table 1]

[0016] When used herein, "CBP-polymer" means a polymer comprising at least one cell-binding peptide molecule covalently bonded 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 contain amino acids. 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., essentially composed of a single amino acid or a peptide of several identical or different amino acids), which is linked to the N-terminus or C-terminus of the CBP via a peptide bond. In one embodiment, the C-terminus of the amino acid linker is linked to the N-terminus of the CBP, and the N-terminus of the amino acid linker is linked 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) Represented as -CBP, this means the linker has one, two, three, or four glycine residues. In one embodiment, one or more 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 modifiable pendant carboxyl groups. In one embodiment, the number of polysaccharide moieties having covalently bonded CBP is less than any of the following values: 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%.

[0017] In one embodiment, the density of CBP modification in the CBP polymer is estimated by combustion analysis with respect to nitrogen percentage. In one embodiment, the CBP polymer is an RGD polymer (e.g., RGD-alginate), which is a polymer (e.g., alginate) covalently modified with linker-RGD molecules (e.g., a peptide essentially consisting of GRGD (SEQ ID NO: 62) or GRGDSP (SEQ ID NO: 60)), and the density of linker-RGD molecular modification (e.g., conjugation density), when determined using the assay described herein, 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. In one embodiment, the linker-RGD modification conjugation density in RGD-alginates (e.g., MMW alginates covalently modified with GRGDSP (SEQ ID NO: 60)) is such that, when determined by any assay capable of quantifying the amount of peptides conjugated to the polymer (e.g., the quantitative peptide conjugation assay described herein), it contains 0.1-1.0, 0.2-0.8, 0.3-0.7, and 0.4-0.6 micromoles of linker-RGD moieties per gram of RGD-polymer in a solution with a viscosity of 80-120 cP. Unless otherwise expressly stated or readily apparent from the context, the specifically described numerical concentrations, concentration ranges, densities, or density ranges of CBP in CBP-polymers refer to the concentration or density of conjugated CBP molecules, i.e., not to include any residual free (e.g., unconjugated) CBP that may be present in the CBP-polymer.

[0018] "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 that it has 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. A conservative amino acid substitution refers to substituting an amino acid with an amino acid that has similar properties (e.g., charge, side chain size, hydrophobic / hydrophilic, skeletal conformation, and stiffness) and has minimal impact on the biological activity of the resulting substituted peptide or polypeptide. A table of functionally similar conservative amino acid substitutions is well known in the art, and exemplary substitutions grouped by functional characteristics are shown in Table 2 below.

[0019] [Table 2]

[0020] "Crosslinking," and its variations such as "crosslinking" or "x-linking," as used herein, refers to at least one chemical bond (e.g., an ionic bond or a covalent bond) between two or more polymers. In some embodiments, if two or more chemical bonds are present, crosslinking refers to a mixture of both covalent and ionic bonds. In some embodiments, if two or more chemical bonds are present, crosslinking refers to different types of covalent bonds (e.g., covalent bonds containing different or orthogonal functional groups). In some embodiments, if two or more chemical bonds are present, crosslinking refers to the same type of covalent bond (e.g., covalent bonds containing the same functional group). In some embodiments, if two or more chemical bonds are present, crosslinking refers to the same type of ionic bond (e.g., the same ion, e.g., Ba 2+ This refers to an ionic bond (including ions).

[0021] When used herein in relation to cells, "derived from" refers to cells obtained from tissue, cell lines, or, optionally, cells that subsequently produce cells induced by culture, passage, differentiation, induction, etc. For example, mesenchymal stem cells may originate from mesenchymal tissue and, as a result, can differentiate into various cell types.

[0022] As used herein, “differential volume” refers to the volume of one compartment within a device described herein, excluding the space occupied by another compartment(s). For example, in a two-compartment device having an inner compartment and an 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.

[0023] As used herein, “effective amount” means an amount of a device, device composition, or component of a device or device composition sufficient to induce a biological response, such as a plurality of hydrogel capsules containing islet cells (e.g., manipulated islet cells), or an agent produced by islet cells (e.g., a therapeutic agent). As will be understood by those skilled in the art, the effective amount may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the therapeutic agent, composition, or device (e.g., hydrogel capsules, particles), the condition being treated, the mode of administration, and the age and health of the subject. The effective amount encompasses both therapeutic and prophylactic treatments. For example, to mitigate FBR, an effective amount of the compound of formula (I) may reduce fibrosis or halt the growth or spread of fibrous tissue on or near an implanted device.

[0024] When used herein, "endogenous nucleic acid" refers to nucleic acids that are naturally present in the cells of interest.

[0025] When used herein, "endogenous polypeptide" refers to a polypeptide that is naturally present in the cells of interest.

[0026] "Manipulated cell," as used herein, is a cell having modifications not present in nature and typically includes a nucleic acid sequence (e.g., DNA, or RNA) (e.g., exogenous nucleic acid sequence) or polypeptide that is not present (or present at different levels) in otherwise similar cells under similar conditions of non-manipulated cells. In one embodiment, the manipulated cell includes an exogenous nucleic acid (e.g., a vector or altered chromosomal sequence). In one embodiment, the manipulated cell includes an exogenous polypeptide. In one embodiment, the manipulated cell includes an exogenous nucleic acid sequence (e.g., a sequence, e.g., DNA or RNA) that is not present in similar unmanipulated cells. In one embodiment, the exogenous nucleic acid sequence is chromosomal, for example, an exogenous nucleic acid sequence is an exogenous sequence located within an endogenous chromosomal sequence. In one embodiment, the exogenous nucleic acid sequence is chromosomal or extrachromosomal, for example, a non-integrated vector. In one embodiment, the exogenous nucleic acid sequence includes an RNA sequence, for example, mRNA. In one embodiment, the exogenous nucleic acid sequence includes a chromosomal or extrachromosomal exogenous nucleic acid sequence containing a sequence expressed as RNA, e.g., mRNA or regulatory RNA. In one embodiment, the exogenous nucleic acid sequence includes a chromosomal or extrachromosomal exogenous nucleic acid sequence containing a sequence encoding or expressed as a polypeptide. In one embodiment, the exogenous nucleic acid sequence includes a first chromosomal or extrachromosomal exogenous nucleic acid sequence that modulates the conformation or expression of a second nucleic acid sequence, the second amino acid sequence may be exogenous or endogenous. For example, the engineered cell may contain an exogenous nucleic acid that controls the expression of an endogenous sequence. In one embodiment, the engineered cell contains polypeptides present at levels or distributions different from those found in similar unengineered cells. In one embodiment, the engineered cell includes island cells engineered to produce RNA or polypeptides. For example, the engineered cell may contain an exogenous nucleic acid sequence containing a chromosomal or extrachromosomal exogenous nucleic acid sequence containing a sequence expressed as RNA (e.g., mRNA or regulatory RNA).In one embodiment, the manipulated cell (e.g., an island cell) contains an exogenous nucleic acid sequence, including a chromosome or extrachromosomal nucleic acid sequence containing a sequence encoding a polypeptide or a sequence expressed as a polypeptide. In one embodiment, the polypeptide is encoded by a codon-optimized sequence to achieve higher polypeptide expression than that of the naturally occurring coding sequence. The codon-optimized sequence may be generated using commercially available algorithms, examples of which include GeneOptimizer (ThermoFisher Scientific), OptimumGene® (GenScript, Piscataway, NJ, USA), GeneGPS® (ATUM, Newark, California, USA), or Java® Codon Adaptation Tool (JCat, www.jcat.de, Grote, A. et al., Nucleic Acids Research, Vol 33, Issue suppl_2, pp. W526-W531 (2005)).

[0027] As used herein, "exogenous nucleic acid" refers to a nucleic acid that is not naturally present in the cells of interest.

[0028] Where used herein, "exogenous polypeptide" refers to a polypeptide that is not naturally present in the target cell, e.g., the manipulated cell. References to specific amino acid positions in a sequence mean the position of that amino acid in the reference amino acid sequence (e.g., the sequence of the fully matured (after signal peptide cleavage) wild-type protein (unless otherwise specified)) and do not preclude variations at other positions in the reference amino acid sequence (e.g., the presence of deletions, insertions, and / or substitutions).

[0029] As used herein, “island cells” means any cells, including any naturally occurring, any synthetically created, or modified cells, that are intended to reproduce, mimic, or otherwise express (some or all) the function of Langerhans islet cells. The term “island cells” includes glucose-responsive insulin-producing cells derived from stem cells (e.g., from induced pluripotent stem cell lines).

[0030] As used herein, "photoactive" refers to a compound or moiety that can form reactive species after activation by light (e.g., light of a specific wavelength). In one embodiment, a photoactive compound is chemically inert under standard experimental conditions but becomes reactive upon activation by light. A "photoactive crosslinker" is a crosslinker compound that is activated for crosslinking upon activation by light.

[0031] As used herein, "polymer composition" refers to a composition (e.g., a solution, a mixture) comprising one or more polymers. As a class, "polymer" includes homopolymers, heteropolymers, copolymers, block polymers, and block copolymers, which may be both natural and synthetic. Homopolymers contain one type of building block or monomer, while copolymers contain more than one type of monomer.

[0032] As used herein, "polypeptide" refers to a polymer comprising amino acid residues linked via peptide bonds and having at least two, and (in some embodiments) at least 10, 50, 75, 100, 150, or 200 amino acid residues.

[0033] As used herein, “prevention,” “prevent,” and “prevention” refer to a treatment that involves administering or applying a therapy to eliminate the physical signs of a disease, disorder, or condition (e.g., type 1 diabetes) before the onset of the disease, disorder, or condition (e.g., type 1 diabetes), such example being the administration of a cell-encapsulated device composition (e.g., as described herein). In some embodiments, “prevention,” “prevent,” and “prevention” require that the signs or symptoms of the disease, disorder, or condition have not yet developed or been observed. In some embodiments, the treatment includes prevention, while in other embodiments it does not.

[0034] When “sequence identity” or “percent identity” is used herein to refer to two nucleotide sequences or two amino acid sequences, it means that the two sequences are identical within the region specifically described, or, if the two sequences are compared and aligned for maximum match across a comparison window or a specified region, it means that they have identical nucleotides or amino acids in the specifically described percentage of nucleotide or amino acid positions. 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 specifically described 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.

[0035] As used herein, "sphere" means a sphere (e.g., a perfectly round ball) or a device (e.g., a hydrogel capsule or other particle) having a curved surface that forms a sphere-like shape, which may have waves and undulations on its surface. Spheres and sphere-like objects can be mathematically defined by a circular, elliptical, or combined rotation around each of three vertical axes a, b, and c. In a sphere, the three axes are of equal length. Typically, a sphere-like shape is an ellipsoid (with respect to its averaged surface) with semi-principal 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 semi-principal axes.

[0036] When the term “ellipsoid” is used herein to refer to a device (e.g., a hydrogel capsule or other particle), it means that the device (i) has a perfect, or classical, flattened, or oblate ellipsoid shape, or (ii) has a surface that substantially forms an ellipsoid, which may have waves and undulations and / or be an ellipse (with respect to its averaged surface) with semi-principal axes within 100% of each other.

[0037] As used herein, “Subject” 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 child subject (e.g., infant, child, adolescent), 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., mouse, dog, primate (e.g., crab-eating macaque or rhesus macaque)). In one embodiment, the subject is a commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog) or a bird (e.g., a commercially relevant bird, for example, chicken, duck, goose, or turkey). In a given embodiment, the animal is a mammal. The animal may be male or female and may be at any stage of development. The non-human animal may be a transgenic animal.

[0038] As used herein, "total volume" refers to the volume within one compartment of a multi-compartment device, including the space occupied by other compartments. 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.

[0039] As used herein, “treatment,” “to treat,” and “to treat” refer to one or more of the symptoms, signs, or underlying causes of a disease, disorder, or condition (e.g., type 1 diabetes) that are present, reversed, alleviated, delayed onset, or inhibited progression. In one embodiment, treating includes reducing, reversing, alleviating, delayed onset, or inhibiting progression of the symptoms of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delayed onset, or inhibiting progression of the signs of a disease, disorder, or condition (e.g., type 1 diabetes). In one embodiment, treating includes reducing, reversing, alleviating, reducing, or delayed onset of the underlying causes of a disease, disorder, or condition (e.g., type 1 diabetes). In some embodiments, “treatment,” “to treat,” and “to treat” require that the signs or symptoms of a disease, disorder, or condition are present or observed. In other embodiments, the treatment may be administered in the absence of signs or symptoms of the disease or condition (e.g., in prophylactic treatment). For example, the treatment may be administered to a susceptible individual before the onset of symptoms (e.g., taking into account a history of symptoms and / or in terms of genetic or other susceptibility factors). The treatment may also be continued after the symptoms have subsided, for example, to delay or prevent relapse. In some embodiments, the treatment includes prophylaxis, while in other embodiments it does not.

[0040] "VLVG" or "VLVG alginate" refers to an ultra-low viscosity sodium alginate having an average molecular weight of less than approximately 75 kDa and containing more than 60% gluronate units (i.e., having a gluronate-to-mannuronate ratio of 1.5 or greater).

[0041] "SG100" or "SG100 alginate" refers to sodium alginate having an average molecular weight of approximately 150-250 kDa and containing more than 60% gluronate units (i.e., having a gluronate-to-mannuronate ratio of 1 or more).

[0042] Selected chemical definitions The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The identification follows the Ed. (inside cover), and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional sites and reactivity, are based on Thomas Sorrell, *Organic Chemistry*, University Science Books, Sausalito, 1999, and 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 This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0043] Abbreviations used herein have their usual meanings in the fields of chemistry and biology. Chemical structures and formulas shown herein are prepared according to standard rules for valency known in the fields of chemistry.

[0044] When a range of values ​​is enumerated, it is intended to include each value within the range, as well as any secondary ranges. 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.

[0045] As used herein, "alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C24"). 24 "Alkyl" refers to 1 to 12 carbon atoms ("C1 to C12"). In some embodiments, an alkyl group is a group of 1 to 12 carbon atoms. 12 Alkyl), 1 to 10 carbon atoms ("C1-C") 12"(alkyl)", having 1 to 8 carbon atoms ("C1-C8 alkyl"), 1 to 6 carbon atoms ("C1-C6 alkyl"), 1 to 5 carbon atoms ("C1-C5 alkyl"), 1 to 4 carbon atoms ("C1-C4 alkyl"), 1 to 3 carbon atoms ("C1-C3 alkyl"), 1 to 2 carbon atoms ("C1-C2 alkyl"), or 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 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-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Each example of an alkyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, substituted with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl").

[0046] As used herein, "alkenyl" refers to a group of a straight-chain or branched-chain hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C 24 alkenyl"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2-C 10C2-C4 alkenyl groups have 2-8 carbon atoms ("C2-C8 alkenyl"), 2-6 carbon atoms ("C2-C6 alkenyl"), 2-5 carbon atoms ("C2-C5 alkenyl"), 2-4 carbon atoms ("C2-C4 alkenyl"), 2-3 carbon atoms ("C2-C3 alkenyl"), or 2 carbon atoms ("C2 alkenyl"). 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), and butadienyl (C4). Examples of C2-C6 alkenyl groups include the aforementioned C 2-4 This includes alkenyl groups and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Each example of an alkenyl group may be independently and optionally substituted, that is, it may be unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"), examples of which include 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0047] As used herein, the term “alkynyl” refers to a radical of a linear or branched hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2- 24 The term "alkenyl" refers to an alkenyl group. In some embodiments, the alkynyl group consists of 2 to 10 carbon atoms ("C2-C2"). 10The C2-C4 alkynyl group has 2-8 carbon atoms ("C2-C8 alkynyl"), 2-6 carbon atoms ("C2-C6 alkynyl"), 2-5 carbon atoms ("C2-C5 alkynyl"), 2-4 carbon atoms ("C2-C4 alkynyl"), 2-3 carbon atoms ("C2-C3 alkynyl"), or 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). Each example of an alkynyl group may be independently and optionally substituted, that is, it may be unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"), examples of which include 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0048] As used herein, the term “heteroalkyl” refers to an acyclic stable linear or branched chain, or a combination thereof, comprising 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 may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S, and Si may be present at any position in the heteroalkyl group. Examples of 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)2-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, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. C R D When discussing such things, it is natural to use the terms heteroalkyl and -CH2O or -NR. C R D These terms are neither redundant nor mutually exclusive. Rather, specific heteroalkyl groups are described to provide clarity. Therefore, the term "heteroalkyl" refers to specific heteroalkyl groups, e.g., -CH2O, -NR C R D This specification should not be interpreted as excluding the like. Each example of a heteroalkyl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"), examples of which include, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0049] The terms “alkylene,” “alkenylene,” “alkynylene,” or “heteroalkylene,” unless otherwise specified, refer to a divalent group derived from an alkyl, alkenyl, alkynyl, or heteroalkyl group, either alone or as part of another substituent. Alkylene, alkenylene, alkynylene, or heteroalkylene groups may be described, for example, as C1-C6 member alkylene, C2-C6 member alkenylene, C2-C6 member alkynylene, or C1-C6 member heteroalkylene, where “member” refers to a non-hydrogen atom within the group. In the case of heteroalkylene groups, the heteroatom may also occupy either or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not indicated 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-.

[0050] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C6~C6~C6"). 14 This refers to an aryl group ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl (1-naphthyl and 2-naphthyl, etc.). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). The aryl group is, for example, C6-C 10They may be described as member aryls, where the term "member" refers to a non-hydrogen ring atom within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example of an aryl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").

[0051] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system ("5-10 membered heteroaryl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems in which the heteroaryl ring as defined above is fused with one or more aryl groups having a bond site on either the aryl or heteroaryl ring, in such examples, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), the bond site can be on either ring, i.e., on the ring containing a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryls, where the term "member" refers to a non-hydrogen ring atom within the moiety.

[0052] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Each example of the heteroaryl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl").

[0053] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Exemplary seven-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, benzofuranil, benzoisofuranil, benzimimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolidinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0054] As used herein, the terms “arylene” and “heteroarylene” mean a divalent group derived from an aryl and a heteroaryl, respectively, either alone or as part of another substituent.

[0055] As used herein, "cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C3-C 10 A cycloalkyl group refers to a radical of a non-aromatic cyclic hydrocarbon group that does not have a heteroatom. In some embodiments, a cycloalkyl group may have 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"), or 5 to 10 ring carbon atoms ("C5-C6 cycloalkyl"). 10 A cycloalkyl group has a cycloalkyl group. A cycloalkyl group may be described, for example, as a C4-C7 member cycloalkyl group, where the term "member" refers to a non-hydrogen ring atom within the group. Examples of 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), and cyclohexadienyl (C6). Examples of 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), etc. 10 Cycloalkyl groups include, but are not limited to, the aforementioned C3-C8 cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10) and others are included. As the above examples show, in certain embodiments, the cycloalkyl group may be monocyclic ("monocyclic cycloalkyl") or may contain condensed, crosslinked, or spirocyclic systems, such as bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes cyclic systems in which the cycloalkyl ring defined above is condensed with one or more aryl groups (where the bond site is on the cycloalkyl ring). In such examples, the number of carbons still refers to the number of carbons in the cycloalkyl cyclic system. Each example of a cycloalkyl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl").

[0056] As used herein, "heterocyclyl" refers to a 3- to 10-membered non-aromatic ring radical having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the bond site may be a carbon atom or a nitrogen atom, as the valence allows. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl"), fused, bridging, or spirocyclic, for example, bicyclic ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. The term "heterocyclyl" also includes ring systems in which the heterocyclyl ring defined above is fused with one or more cycloalkyl groups (where the bond site is either on the cycloalkyl ring or the heterocyclyl ring), or ring systems in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups (where the bond site is on the heterocyclyl ring). In such examples, the number of ring members still refers to the number of ring members in the heterocyclyl ring system. A heterocyclyl group can be described, for example, as a 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms in that part, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each example of a 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 a given embodiment, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0057] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0058] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azildinyl, oxyranyl, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianil, and dioxanil. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl or thiomorpholinyl-1,1-dioxide. Exemplary seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxekanyl, and thiokanyl. Examples of five-membered heterocyclyl groups condensed to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0059] When used herein, "amino" refers to radical-NR 70 R 71 (In the formula, R 70 and R 71 These are, independently, hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, C4-C 10 Heterocyclyl, C6-C 10 Aryl, and C5-C 10 It refers to a heteroaryl compound. In some embodiments, amino refers to NH2.

[0060] As used herein, "cyano" refers to the group -CN.

[0061] As used herein, "halo" or "halogen" means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, either independently or as part of another substituent, unless otherwise described.

[0062] As used herein, "hydroxy" refers to the -OH group.

[0063] Alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted, as defined herein (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 group). Generally, the term "substituted" means, whether preceded by the term "optionally," that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, such substituents that, when substituted, result in a stable compound, such compounds are those that do not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a “substituted” group has substituents at one or more substituted positions of the group, and if multiple positions in any particular structure are substituted, the substituents are either the same or different at each position. The term “substituted” is intended to include substitution at all acceptable substituents of an organic compound, such as any substituent described herein, resulting in the formation of a stable compound. This disclosure intends any such combination to result in a stable compound. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any preferred substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable site.

[0064] Two or more substituents can optionally bond to form aryl, heteroaryl, cycloalkyl, or heterocyclyl groups. Such so-called ring-forming substituents are typically, but not necessarily, bonded to a cyclic base structure. In one embodiment, the ring-forming substituent is bonded to an adjacent member of the base structure. For example, two ring-forming substituents bonded to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituent is bonded to a single member of the base structure. For example, two ring-forming substituents bonded to a single member of a cyclic base structure form a spiro-ring structure. In yet another embodiment, the ring-forming substituent is bonded to a non-adjacent member of the base structure.

[0065] The compounds of formula (I) described herein may contain one or more chiral centers and thus 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 in the form of a mixture of stereoisomers, including racemic mixtures and mixtures in which one or more stereoisomers are concentrated. The isomers may be isolated from the mixture 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 may 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). This disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0066] As used herein, a pure enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer-rich). That is, the "S" form of the compound is substantially free of the "R" form of the compound, and is therefore enantiomer-rich in the "R" form. The terms "pure as an enantiomer" or "pure enantiomer" indicate that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% enantiomers. In a given embodiment, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0067] The compounds of formula (I) described herein may also include one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium), and 3 It can be any isotopic form containing H (T or tritium); C is 12 C, 13 C, and 14 It can be any isotopic form containing C; O is 16 O and 18 It can be any isotopic form containing O; etc.

[0068] The term “pharmaceutically acceptable salt” means that salts of active compounds are prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. If the compound of formula (I) used to prepare the devices of this disclosure contains a relatively acidic functional group, a base addition salt may be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either in its raw state 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. If the compounds used in this disclosure contain a relatively basic functionality, an acid addition salt may be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either in its raw state or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric 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, and methanesulfonic acid. Also included are salts of amino acids (e.g., arginate salts) and salts of organic acids (e.g., glucuronic acid or galacturonic acid) (see, for example, Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds used in the devices of this disclosure (e.g., particles, hydrogel capsules) include both basic and acidic functionalities, allowing the compounds to be converted to either a base or an acid addition salt. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in this disclosure.

[0069] As used herein, “polysaccharide” refers to a polymer of monosaccharides or disaccharide carbohydrates linked together by glycosidic bonds. Polysaccharides may be linear or branched. Exemplary monosaccharides include glucose, galactose, mannose, allose, altrose, talose, idose, growth, fructose, ribose, arabinose, lyxose, xylose, rhamnose, glucuronic acid, galacturonic acid, mannuronic acid, and guluronic acid. Exemplary polysaccharides include alginates, 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).

[0070] The devices of this disclosure may contain compounds of formula (I) in prodrug form. Prodrugs are compounds that readily undergo chemical changes under physiological conditions to provide compounds useful for preparing the devices in this disclosure. Additionally, prodrugs can be converted into useful compounds of formula (I) by chemical or biochemical methods in an ex vivo environment.

[0071] Certain compounds of formula (I) described herein may exist in solvated forms, including non-solvated and hydrated forms. Typically, the solvated forms are equivalent to the non-solvated forms and are included within the scope of this disclosure. Certain compounds of formula (I) described herein may exist in polycrystalline or amorphous forms. Typically, all physical forms are equivalent for the uses intended by this disclosure and are intended within the scope of this disclosure.

[0072] The term "solvate" typically refers to the form of a compound associated with a solvent through solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, and diethyl ether. The compounds described herein may be prepared, for example, in crystalline form or solvated. Preferred solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates.

[0073] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules in a compound hydrate is within a certain ratio to the number of compound molecules in the hydrate. Therefore, a compound hydrate can be represented, for example, by the general formula R × x H₂O, where R is the compound and x is a number greater than 0.

[0074] As used herein, the term “tautomer” refers to a compound whose structurally interchangeable form is altered by the substitution of hydrogen atoms and electrons. Thus, the two structures may also be in equilibrium with the transfer of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with either an acid or a base. Tautomeristic forms may be relevant to achieving the optimal chemical reactivity and biological activity of the compound of interest.

[0075] [ka] When used herein, the symbol refers to a connection to an entity, such as a polymer (e.g., a hydrogel-forming polymer such as alginate), or to the surface of an embeddable device, such as a particle or hydrogel capsule. [ka] The connection represented by may refer to a direct bond with an entity (e.g., a polymer (e.g., alginate) or an embeddable element), or to a linkage with an entity via a binding group. “Binding group,” as used herein, refers to the portion of a compound of formulas (I) to (IV) for linkage to an entity (e.g., a hydrogel capsule or an embeddable device as described herein), and may include any binding chemistry known in the art. A list of exemplary binding groups can be found in Bioconjugate Techniques (3 rd This is outlined in (ed., Greg T. Hermanson, Waltham, MA: Elsevier, Inc., 2013), which is incorporated herein by reference in its entirety. In some embodiments, the binding group is 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 and y is independently as described herein. In some embodiments, the bonding group includes amines, ketones, esters, amides, alkyls, alkenyls, alkynyls, or thiols. In some embodiments, the bonding group is a crosslinking linker. In some embodiments, the bonding group is -C(O)(C1~C6-alkylene)-, where alkylene is R 1 It is replaced by R 1 This is as described herein. In some embodiments, the bonding group is -C(O)(C1-C6-alkylene)-, and the alkylene is substituted with 1-2 alkyl groups (e.g., 1-2 methyl groups). In some embodiments, the bonding group is -C(O)C(CH3)2-. In some embodiments, the bonding group is -C(O)(methylene)-, and the alkylene is substituted with 1-2 alkyl groups (e.g., 1-2 methyl groups). In some embodiments, the bonding group is -C(O)CH(CH3)-. In some embodiments, the bonding group is -C(O)C(CH3)-.

[0076] The terms “covalent,” “covalent bond,” and “covalent linkage,” 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 (CH bond), carbon atoms (CC bond), carbon atoms and oxygen atoms (CO bond), and carbon atoms and nitrogen (CN bond). Depending on the identity of the atoms, a covalent bond may be a single bond, a double bond, or a triple bond. That is, a covalent bond may involve the sharing of one pair, two pairs, or three pairs of electrons.

[0077] As used herein, the terms “ionic,” “ionic bond,” and “ionic linkage” refer to a type of chemical bond involving Coulomb attraction between adjacent atoms (i.e., ions) with opposite charges.

[0078] Modified polysaccharide polymers The polysaccharide polymers described herein are covalently modified with covalently photoactive crosslinked linker moieties. In one embodiment, the polysaccharide polymer may be linear, branched, or crosslinked polysaccharide polymers, or polysaccharide polymers of a selected molecular weight range, degree of polymerization, viscosity, or melt flow rate. Branched polysaccharide polymers may include one or more of the following types: star polymers, comb polymers, brush polymers, dendrimerized polymers, graftco(polymers), ladder polymers, and dendrimers. 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 polymer. The polysaccharide polymer may be a thermoresponsive polymer, such as a gel (e.g., becoming solid or liquid upon exposure to heat or a specific temperature) or a photocrosslinkable polymer. In some embodiments, the polysaccharide polymer is a photocrosslinkable polymer. In some embodiments, the polysaccharide polymer may be biodegradable, for example, containing unstable bonds or being dissociated by enzymes, such as lyases. In some embodiments, the polysaccharide polymer is composed of a single type of repeating monomer units. 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., polymer blends). In some embodiments, the polysaccharide polymer may be composed of mannuronic acid and guluronic acid monomers.

[0079] In some embodiments, the polysaccharide polymer is a naturally occurring polymer or a synthetic polymer. In some embodiments, the polysaccharide polymer is a naturally occurring polysaccharide or a synthetic polysaccharide. In one embodiment, the polysaccharide polymer is cellulose, an example of which is carboxymethylcellulose. In one embodiment, the polysaccharide polymer is polylactide, polyglycoside, or polycaprolactone. In one embodiment, the polysaccharide polymer is hyaluronate, for example, sodium hyaluronate. In one embodiment, the polymer is collagen, elastin, or gelatin. In one embodiment, the polysaccharide polymer is chitin.

[0080] In some embodiments, the polysaccharide polymer is a hydrogel-forming polymer. Hydrogel-forming polymers contain a hydrophilic structure and are therefore capable of holding large amounts of water within a three-dimensional network. Hydrogel-forming polymers may include polymers that form homopolymer hydrogels, copolymer hydrogels, or multipolymer interpenetrating polymer hydrogels, and may be essentially amorphous, semicrystalline, or crystalline, as described, for example, in Ahmed (2015) J Adv Res 6:105-121. Exemplary hydrogel-forming polymers include proteins (e.g., collagen), gelatin, polysaccharides (e.g., starch, alginates, hyaluronates, agarose), and synthetic polysaccharides.

[0081] Examples of polysaccharides include alginates, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, amylose, chitin, chitosan, or their derivatives or variants (e.g., those described in Laurienzo (2010), Mar Drugs 9:2435-65). Examples of polysaccharide polymers include heparin, chondroitin sulfate, dermatan, dextran, or carboxymethylcellulose. In some embodiments, the polysaccharide polymer is a cell surface polysaccharide.

[0082] In some embodiments, the polysaccharide polymer is an alginate. The 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 containing 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 containing 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 and optionally has a G:M ratio of ≥1.5. In some embodiments, the alginate has an approximate molecular weight of 75 kDa to 150 kDa and optionally has a G:M ratio of 1.5 or higher. In some embodiments, the alginate has an approximate molecular weight of 150 to 250 kDa and optionally has a G:M ratio of 1.5 or higher.

[0083] A polysaccharide polymer (e.g., any of the polymers described herein, e.g., any of the alginates described herein) comprising a sugar moiety having the structure of formula (I), or a pharmaceutically acceptable salt thereof, may be modified in one or more monomer units. In some embodiments, at least 0.5 percent of the sugar 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 sugar monomers have the structure of formula (I)). In some embodiments, 0.5 to 50%, 10 to 90%, 10 to 50%, or 25 to 75% of the sugar monomers of the polysaccharide polymer have the structure of formula (I). In some embodiments, 1 to 20% of the sugar monomers of the polysaccharide polymer have the structure of formula (I). In some embodiments, 1 to 10% of the sugar monomers of the polysaccharide polymer have the structure of formula (I). In some embodiments, 1 to 50% of the sugar monomers have the structure of formula (I).

[0084] In some embodiments, the polysaccharide polymer (if it contains sugar monomers having the structure of formula (I)) includes 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 is determined by elemental analysis and corresponds to the amount of compound of formula (I) in the modified polymer.

[0085] In some embodiments, the polysaccharide polymer (if it contains a sugar monomer having the structure of formula (I)) includes an increase in %N (compared to the unmodified polymer) of 0.1 to 10%N by weight, where %N is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0086] In some embodiments, the polysaccharide polymer (if it contains a sugar monomer having the structure of formula (I)) includes an increase in %N (compared to the unmodified polymer) of 0.1 to 2%N by weight, where %N is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0087] In some embodiments, the polysaccharide polymer (if it contains a sugar monomer having the structure of formula (I)) includes an increase in %N (compared to the unmodified polymer) of 2-4%N by weight, where %N is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0088] In some embodiments, the polysaccharide polymer (if it contains a sugar monomer having the structure of formula (I)) includes an increase in %N (compared to the unmodified polymer) of 4-8%N by weight, where %N is determined by elemental analysis and corresponds to the amount of compound of formula (I) in the modified polymer.

[0089] In some embodiments, the polysaccharide polymers described herein (e.g., alginates) each comprise a sugar monomer having one or more of the formulas (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).

[0090] In some embodiments, the polysaccharide polymer (e.g., alginate) is modified with the compounds shown in Table 3. In some embodiments, the polymer (e.g., alginate) modified with the compound of formula (I) is not the 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.

[0091] Non-fibrous compound In some embodiments, the polysaccharide polymer described herein comprises at least one non-fibrous compound of formula (I):

Chemical formula

[0092] In some embodiments, the compound of formula (I) is the compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, where 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 linked to a bonding group (e.g., the bonding groups described herein) and one or more R 1 It is optionally replaced by L 1 and L 3 Each of them is independently bonded, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is one or more R2 It is optionally replaced by L 2 is a bond, and M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is one or more R 3 P is optionally replaced by one or more R 4 A heteroaryl is optionally substituted by Z, where Z is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which 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 either optionally replaced by R C and R D Together with the bonded nitrogen atom, it forms one or more R 6 A ring (e.g., a 5- to 7-membered ring) is formed by the optional substitution of each R. 1 , R 2 , R 3 , R 4 , R 5 and R 6 These are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, and -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 , 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 These are cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 It is optionally replaced by each R A1 , R B1 , R C1 , R D1 , R E1 and R F1 These are 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 x is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, where x is 1 or 2 and y is 2, 3, or 4.

[0093] 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 A is independently hydrogen or alkyl. In some embodiments, A is -NH-. In some embodiments, A is -N(R C )C(O)(C1-C6-alkylene)-, and alkylene is R 1 It is replaced 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(CH3)2-. In some embodiments, A is -N(R C )C(O)(methylene)-, R 1 is an alkyl group (e.g., methyl). In some embodiments, A is -NHC(O)CH(CH3)-. In some embodiments, A is -NHC(O)C(CH3)-.

[0094] In some embodiments, for formulas (I) and (Ia), L 1is 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 a C1-C6 alkyl group. In some embodiments, L 1 is -CH2-, -CH(CH3)-, -CH2CH2CH2, or -CH2CH2-. In some embodiments, L 1 It is either -CH2 or -CH2CH2-.

[0095] 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 C1-C 12 It is alkyl. In some embodiments, L 3 is a C1-C6 alkyl group. In some embodiments, L 3 is -CH2-. In some embodiments, L 3 is a heteroalkyl group. In some embodiments, L 3 is one or more R 2 C1-C arbitrarily substituted with (for example, oxo) 12 It is heteroalkyl. In some embodiments, L 3 is one or more R 2 It is a C1-C6 heteroalkyl group optionally substituted with (for example, oxo). In some embodiments, L 3 These are -C(O)OCH2-, -CH2(OCH2CH2)2-, -CH2(OCH2CH2)3-, CH2CH2O-, or -CH2O-.

[0096] In some embodiments, L 3 It is -CH2O-.

[0097] 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, 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 an aryl compound. In some embodiments, M is a phenyl compound. In some embodiments, M is an unsubstituted phenyl compound. In some embodiments, M is... [ka] In some embodiments, M is R 7 (For example, one R 7 It is a phenyl substituted with ). In some embodiments, M is [ka] In some embodiments, R 7 This is CF3.

[0098] In some embodiments, for formulas (I) and (Ia), P is absent, a heterocyclyl, or a heteroaryl. In some embodiments, P is absent. In some embodiments, for formulas (I) and (Ia), P is a tricyclic, bicyclic, or monocyclic heteroaryl. In some embodiments, P is a monocyclic heteroaryl. In some embodiments, P is a nitrogen-containing heteroaryl. In some embodiments, P is a monocyclic, nitrogen-containing heteroaryl. In some embodiments, P is a five-membered heteroaryl. In some embodiments, P is a five-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] That is the case.

[0099] In some embodiments, P is a 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-dioxydyl.

[0100] In some embodiments, P is [ka] That is the case.

[0101] In some embodiments, for formula (I) or (Ia), Z is alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, Z is a heterocyclyl. In some embodiments, Z is a monocyclic or bicyclic heterocyclyl. In some embodiments, Z is an 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 four-membered oxygen-containing heterocycline. In some embodiments, Z is [ka] That is the case.

[0102] In some embodiments, Z is a bicyclic oxygen-containing heterocycline. In some embodiments, Z is phthalic anhydride. In some embodiments, Z is a sulfur-containing heterocycline. In some embodiments, Z is a six-membered sulfur-containing heterocycline. In some embodiments, Z is a six-membered heterocycline containing a nitrogen atom and a sulfur atom. In some embodiments, Z is thiomorpholinyl-1,1-dioxydyl. In some embodiments, Z is [ka] In some embodiments, Z is a nitrogen-containing heterocycline. In some embodiments, Z is a 6-membered nitrogen-containing heterocycline. In some embodiments, Z is [ka] That is the case.

[0103] In some embodiments, Z is a bicyclic heterocycline. In some embodiments, Z is one or more R 5 It is a bicyclic nitrogen-containing heterocycline optionally substituted with . In some embodiments, Z is 2-oxa-7-azaspiro[3.5]nonanyl. In some embodiments, Z is [ka] In some embodiments, Z is 1-oxa-3,8-diazaspiro[4.5]decan-2-one. In some embodiments, Z is [ka] That is the case.

[0104] In some embodiments, Z is an aryl compound in formulas (I) and (Ia). In some embodiments, Z is a monocyclic aryl compound. In some embodiments, Z is a phenyl compound. In some embodiments, Z is a monosubstituted phenyl compound (e.g., one R). 5 In some embodiments, Z is one R 5 It is a monosubstituted phenyl whose nitrogen-containing group is. In some embodiments, Z is one R 5 It is a monosubstituted phenyl whose NH2 is. In some embodiments, Z is one R 5 It is a monosubstituted phenyl whose oxygen-containing group is. In some embodiments, Z is one R 5 is a monosubstituted phenyl that is an oxygen-containing heteroalkyl. In some embodiments, Z is one R 5 It is a monosubstituted phenyl whose OCH3 is. In some embodiments, Z is one R 5 It is a monosubstituted phenyl with the ortho position. In some embodiments, Z is one R 5 It is a monosubstituted phenyl with the meta position. In some embodiments, Z is one R 5 It is a monosubstituted phenyl compound with the para position.

[0105] In some embodiments, Z is alkyl in formulas (I) and (Ia). In some embodiments, Z is C1-C 12 It is alkyl. In some embodiments, Z is C1-C 10 It is alkyl. In some embodiments, Z is C1-C8 alkyl. In some embodiments, Z is 1 to 5 R 5 It is a C1-C8 alkyl group substituted with R. In some embodiments, Z is one R 5 It is a C1-C8 alkyl group substituted with R. In some embodiments, Z is one R 5It is a C1-C8 alkyl substituted with R 5 These include alkyl, heteroalkyl, halogen, oxo, and -OR A1 , -C(O)OR A1 , -C(O)R B1 -OC(O)R B1 , or -N(R C1 )(R D1 )

[0106] In some embodiments, Z is one R 5 It is a C1-C8 alkyl substituted with R 5 is -OR A1 or -C(O)OR A1 In some embodiments, Z is one R 5 It is a C1-C8 alkyl substituted with R 5 is -OR A1 Alternatively, it is -C(O)OH. In some embodiments, Z is -CH3.

[0107] In some embodiments, Z is a heteroalkyl group in formulas (I) and (Ia). In some embodiments, Z is C1-C 12 It is heteroalkyl. In some embodiments, Z is C1-C 10 It is a heteroalkyl group. In some embodiments, Z is a C1-C8 heteroalkyl group. In some embodiments, Z is a C1-C6 heteroalkyl group. In some embodiments, Z is one or more R groups. 5 It is a nitrogen-containing heteroalkyl that is optionally substituted with R. In some embodiments, Z is 1 to 5 R 5 It is a nitrogen- and sulfur-containing heteroalkyl substituted with . In some embodiments, Z is N-methyl-2-(methylsulfonyl)ethane-1-aminyl.

[0108] In some embodiments, Z is -OR A or -C(O)OR A In some embodiments, Z is -OR A(For example, -OH, or -OCH3). In some embodiments, Z is -OCH3. In some embodiments, Z is -C(O)OR A (For example, -C(O)OH).

[0109] In some embodiments, Z is hydrogen.

[0110] In some embodiments, L 2 This is a bond between P and L 3 In some embodiments, L 2 is a bond, P is a heteroaryl, and L 3 is a bond, and Z is hydrogen. In some embodiments, P is a heteroaryl and L 3 Z is a heteroalkyl group, and Z is an alkyl group.

[0111] In some embodiments, the compound of formula (I) is the compound of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof, wherein ring M 1 However, these are cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which has 1 to 5 R 3 It is optionally substituted in the ring Z 1 However, 1 to 5 R 5 A cycloalkyl, heterocyclyl, aryl, or heteroaryl molecule optionally substituted with R 2a , R 2b , R 2c , and R 2d Each of these 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 2dEach of them combines to form an oxo group, and X is absent, N(R) 10 )(R 11 ), O, or S, R C The R is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has 1 to 6 R 6 It is optionally replaced by each R 3 , R 5 , and R 6 However, 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 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 10 , and R 11 Each of these independently consists of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, and -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 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7However, independently, each m and n is 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] However, this refers to the bonding group or connection to the polymer as described herein. In some embodiments, each R 3 , and R 5 Each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally and independently substituted with a halogen, oxo, cyano, cycloalkyl, or heterocyclyl.

[0112] In some embodiments, the compound of formula (Ib) is the compound of formula (Ibi): [ka] or a pharmaceutically acceptable salt thereof, wherein ring M 2 is one or more R 3 An aryl or heteroaryl that is optionally substituted with ring Z 2 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 2a , R 2b , R 2c and R 2d Each of them is independently hydrogen, alkyl, or heteroalkyl, or R 2a and R 2b or R 2c and R 2d Each of them together forms an oxo group, where X is absent, O or S, and each R 3 and R 5 These are independently alkyl, heteroalkyl, halogen, oxo, and -OR A1 , -C(O)OR A1 or -C(O)R B1Each alkyl and heteroalkyl group is optionally substituted with a halogen, or two R groups. 5 Together, they form a ring Z 2 It forms a condensed 5-6 member ring, and each R A1 and R B1 is independently hydrogen, alkyl, or heteroalkyl, m and n are independently 1, 2, 3, 4, 5, or 6, and p is 0, 1, 2, 3, 4, 5, or 6. [ka] This refers to connection to a binding group or polymer as described herein.

[0113] In some embodiments, the compound of formula (Ibi) is the compound of formula (Ib-ii): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 However, it is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 2c , and R 2d Each of them is independently hydrogen, alkyl, or heteroalkyl, or R 2c , and R 2d However, together they form an oxo group, and each R 3 , and R 5 However, independently, alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 Each alkyl and heteroalkyl group is optionally substituted with a halogen, and each R A1 , and R B1 However, independently, they are hydrogen, alkyl, or heteroalkyl, and each of p and q is independently 0, 1, 2, 3, 4, 5, or 6. [ka] However, this refers to the binding group or connection to the polymer as described herein.

[0114] In some embodiments, the compound of formula (I) is the compound of formula (Ic): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 However, R is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound. 2c , and R 2d Each of them is independently hydrogen, alkyl, or heteroalkyl, or R 2c , and R 2d However, together they form an oxo group, and each R 3 , and R 5 However, independently, alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 Each alkyl and heteroalkyl group is optionally substituted with a halogen, and each R A1 , and R B1 However, each of the following 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] However, this refers to the binding group or connection to the polymer as described herein.

[0115] In some embodiments, the compound of formula (I) is the compound of formula (Id): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where X is absent, O, or S, and R 2a , R 2b , R 2c , and R 2d Each of them is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b , or R 2c , and R 2d Each of them combines to form an oxo group, and each R 5 However, independently, alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 Each alkyl and heteroalkyl group is optionally substituted with a halogen, and each R A1 , and R B1 However, independently, each of m and n is hydrogen, alkyl, or heteroalkyl, and 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] However, this refers to the binding group or connection to the polymer as described herein.

[0116] In some embodiments, the compound of formula (I) is the compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof (wherein ring Z) 2 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; X is absent, O, or S; R 2a , R 2b , R 2c , and R 2d Each of them is independently hydrogen, alkyl, or heteroalkyl, or R 2a and R 2b or R 2c and R2d Each of them together forms an oxo group; each R 5 These are independently alkyl, heteroalkyl, halogen, oxo, and -OR A1 , -C(O)OR A1 , or -C(O)R B1 and; each R A1 and R B1 m is independently hydrogen, alkyl, or heteroalkyl; each of m and n is independently 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; [ka] (This refers to connection to a bonding group or polymer as described herein.)

[0117] In some embodiments, the compound of formula (I) is the compound of formula (If): [ka] or a pharmaceutically acceptable salt thereof, wherein M is one or more R 3 an alkyl group optionally substituted with, where ring P has one or more R 4 A heteroaryl that is optionally substituted with L 3 However, one or more R 2 an alkyl or heteroalkyl group optionally substituted with, where Z is alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of these is one or more R groups. 5 It is optionally replaced by R 2a , and R 2b Each of them is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b However, together they form an oxo group, and each R 2 , R 3 , R 4 , and R 5 However, independently, alkyl, heteroalkyl, halogen, oxo, -ORA1 , -C(O)OR A1 , or -C(O)R B1 And each R A1 , and R B1 However, each element is independently hydrogen, alkyl, or heteroalkyl, and n is independently 1, 2, 3, 4, 5, or 6. [ka] However, this refers to the binding group or connection to the polymer as described herein.

[0118] In some embodiments, the compound of formula (I) is the compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, where M is a bond, alkyl or aryl, and alkyl and aryl are one or more R 3 It is optionally replaced by L 3 is one or more R 2 an alkyl or heteroalkyl group optionally substituted with Z, where Z is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -OR A Alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are one or more R 5 It is optionally replaced by R A is hydrogen, and R 2a and R 2b Each of them is independently hydrogen, alkyl, or heteroalkyl, or R 2a and R 2b They combine to form an oxo group, and each R 2 , R 3 and R 5 These are independently alkyl, heteroalkyl, halogen, oxo, and -OR A1 , -C(O)OR A1 or -C(O)R B1 And each R A1and R B1 n is independently hydrogen, alkyl, or heteroalkyl, and n is independently 1, 2, 3, 4, 5, or 6. [ka] This refers to connection to a binding group or polymer as described herein.

[0119] In some embodiments, the compound of formula (II) is the compound of formula (II-a): [ka] or a pharmaceutically acceptable salt thereof, in the formula L 3 However, it is alkyl or heteroalkyl, and each of these is one or more R 2 It is optionally substituted with hydrogen, alkyl, heteroalkyl, or -OR A Alkyl and heteroalkyl groups consist of one or more R 5 It is optionally replaced by R 2a , and R 2b Each of them is independently hydrogen, alkyl, or heteroalkyl, or R 2a , and R 2b However, together they form an oxo group, and each R 2 , R 3 , and R 5 However, independently, alkyl, heteroalkyl, halogen, oxo, -OR A1 , -C(O)OR A1 , or -C(O)R B1 And R A However, it is hydrogen, and each R A1 , and R B1 However, each element is independently hydrogen, alkyl, or heteroalkyl, and n is independently 1, 2, 3, 4, 5, or 6. [ka] However, this refers to connection to a bonding group or polymer as described herein.

[0120] In some embodiments, the compound of formula (I) is the compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, where Z 1 The R is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of these has 1 to 5 R 5 It is optionally replaced by R 2a , R 2b , R 2c , and R 2d Each of them independently is 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 However, together they form an oxo group, R C The elements are hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and each of the alkyl, alkenyl, alkynyl, or heteroalkyl has 1 to 6 R 6 It is optionally replaced by R 3 , R 5 , and R 6 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And each R A1 , and R B1 However, each is independently hydrogen, alkyl, or heteroalkyl, and each m and n is independently 1, 2, 3, 4, 5, or 6, and q is an integer from 0 to 25. [ka] However, this refers to the binding group or connection to the polymer as described herein.

[0121] In some embodiments, the compound of formula (III) is the compound of formula (III-a): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 However, these are cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which has 1 to 5 R 5 It is optionally replaced by R 2a , R 2b , R 2c , and R 2d Each of them is independently hydrogen, alkyl, heteroalkyl, halo, or R 2a , and R 2b , or R 2c , and R 2d However, together they form an oxo group, R 3 , and R 5 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And each R A1 , and R B1 Each of the elements is independently hydrogen, alkyl, or heteroalkyl, m and n are independently 1, 2, 3, 4, 5, or 6, o and p are independently 0, 1, 2, 3, 4, or 5, and q is an integer between 0 and 25. [ka] However, this refers to the binding group or connection to the polymer as described herein.

[0122] In some embodiments, the compound of formula (III-a) is the compound of formula (III-b): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 2 However, these are cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which has 1 to 5 R 5 It is optionally replaced by R 2a , R 2b , R 2c , and R 2d Each of them is independently hydrogen, alkyl, heteroalkyl, halo, or R 2a , and R 2b , or R 2c , and R 2d However, together they form an oxo group, R 3 , and R 5 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And each R A1 , and R B1 Each of the elements is independently hydrogen, alkyl, or heteroalkyl, m and n are independently 1, 2, 3, 4, 5, or 6, o and p are independently 0, 1, 2, 3, 4, or 5, and q is an integer between 0 and 25. [ka] However, this refers to the binding group or connection to the polymer as described herein.

[0123] In some embodiments, the compound of formula (III-a) is the compound of formula (III-c): [ka] or a pharmaceutically acceptable salt thereof, where X is C(R')(R”), N(R'), or S(O) x And each of R' and R'' is independently hydrogen, alkyl, halogen, or cycloalkyl, and R 2a , R 2b , R 2c , and R 2dEach of them is independently hydrogen, alkyl, heteroalkyl, or halo, or R 2a , and R 2b , or R 2c , and R 2d However, together they form an oxo group, R 3 , and R 5 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And each R A1 , and R B1 However, each element is independently hydrogen, alkyl, or heteroalkyl, m and n are 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] However, this refers to the binding group or connection to the polymer as described herein.

[0124] In some embodiments, the compound of formula (III-c) is the compound of formula (III-d): [ka] or a pharmaceutically acceptable salt thereof, where X is C(R')(R”), N(R'), or S(O) x And each of R' and R'' is independently hydrogen, alkyl, halogen or cycloalkyl, and R 2a , R 2b , R 2c and R 2d Each of them is independently hydrogen, alkyl, heteroalkyl or halo, or R 2a and R 2b or R 2c and R 2d They combine to form an oxo group, R 3 and R 5Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR A1 , -C(O)OR A1 or -C(O)R B1 And each R A1 and R B1 x is independently hydrogen, alkyl, or heteroalkyl, m and n are 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] This refers to connection to a binding group or polymer as described herein.

[0125] In some embodiments, the compound of formula (I) is the compound of formula (III-e): [ka] or a pharmaceutically acceptable salt thereof, where Z 1 These are alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which has 1 to 5 R 5 It is optionally replaced by R 2a , R 2b , R 2c , and R 2d Each of them independently is 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 Each of them combines to form an oxo group, R C The elements are hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and each of the alkyl, alkenyl, alkynyl, or heteroalkyl has 1 to 6 R 6 It is optionally replaced by R 3, R 5 , and R 6 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And each R 12 However, independently, each R is deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino, and each R A1 , and R B1 However, each element is independently hydrogen, alkyl, or heteroalkyl, m and n are independently 1, 2, 3, 4, 5, or 6, q is an integer from 0 to 25, and w is 0 or 1. [ka] However, this refers to the binding group or connection to the polymer as described herein.

[0126] In some embodiments, the compound of formula (I) is the compound of formula (III-f): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 1 However, these are cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which has 1 to 5 R 5 It is optionally replaced by R 2a , R 2b , R 2c , and R 2d Each of them is independently hydrogen, alkyl, heteroalkyl, halo, or R 2a , and R 2b , or R 2c , and R 2d However, together they form an oxo group, R C The elements are hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl, and each of the alkyl, alkenyl, alkynyl, or heteroalkyl has 1 to 6 R 6 It is optionally replaced by R 3, R 5 , and R 6 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And each R 12 However, independently, each R is deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino, and each R A1 , and R B1 Each of the elements is independently hydrogen, alkyl, or heteroalkyl, m and n are independently 1, 2, 3, 4, 5, or 6, o and p are independently 0, 1, 2, 3, 4, or 5, q is an integer between 0 and 25, and w is 0 or 1. [ka] However, this refers to the binding group or connection to the polymer as described herein.

[0127] In some embodiments, the compound of formula (I) is the compound of formula (III-g): [ka] or a pharmaceutically acceptable salt thereof, wherein ring Z 1 However, these are cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which has 1 to 5 R 5 It is optionally replaced by R C However, 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), where each alkyl and alkenyl has 1 to 6 R 6 It is optionally replaced by R 2a , R 2b , R 2c , and R 2dEach of them is independently hydrogen, or alkyl, or R 2a , and R 2b , or R 2c , and R 2d However, together they form an oxo group, R 3 , R 5 , and R 6 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And R 12 However, each R is hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino, and each R A1 , and R B1 However, each 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] However, this refers to the binding group or connection to the polymer as described herein.

[0128] In some embodiments, the compound of formula (I) is the compound of formula (III-h): [ka] or a pharmaceutically acceptable salt thereof, where R C However, 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), where each alkyl and alkenyl has 1 to 6 R 6 It is optionally replaced by R 2a , R 2b , R 2c , and R 2dEach of them is independently hydrogen, alkyl, or R 2a , and R 2b , or R 2c , and R 2d However, together they form an oxo group, R 3 , R 5 , and R 6 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And R 12 However, each R is hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino, and each R A1 , and R B1 However, each element is independently hydrogen, alkyl, or heteroalkyl, m and n are 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] However, this refers to the binding group or connection to the polymer as described herein.

[0129] In some embodiments, the compound of formula (I) is the compound of formula (III-i): [ka] or a pharmaceutically acceptable salt thereof, where X is C(R')(R”), N(R'), or S(O) x And each of R' and R'' is independently hydrogen, alkyl, or halogen, and R C However, 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), where each alkyl and alkenyl has 1 to 6 R6 It is optionally replaced by R 2a , R 2b , R 2c , and R 2d Each of them is independently hydrogen, or alkyl, or R 2a , and R 2b , or R 2c , and R 2d However, together they form an oxo group, R 3 , R 5 , and R 6 Each of these can independently be alkyl, heteroalkyl, halogen, oxo, or -OR. A1 , -C(O)OR A1 , or -C(O)R B1 And R 12 However, each R is hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, halo, cyano, nitro, or amino, and each R A1 , and R B1 However, each element is independently hydrogen, alkyl, or heteroalkyl, m and n are 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] However, this refers to the binding group or connection to the polymer as described herein.

[0130] In some embodiments, the compound is the compound of formula (I). In some embodiments, L 2 It is a bond between P and L 3 It is, independently, non-existent.

[0131] In some embodiments, the compound is the compound of formula (Ia). In some embodiments of formula (II-a), L 2 is a bond, P is a heteroaryl, and L 3 is a bond, and Z is hydrogen. In some embodiments, P is a heteroaryl and L 3is a heteroalkyl group, and Z is an alkyl group. In some embodiments, L 2 It is a bond between P and L 3 In some embodiments, L 2 is a bond, P is a heteroaryl, and L 3 is a bond, and Z is hydrogen. In some embodiments, P is a heteroaryl and L 3 Z is a heteroalkyl group, and Z is an alkyl group.

[0132] In some embodiments, the compound is the compound of formula (Ib). In some embodiments, P is absent, and L 1 It is -NHCH2, and L 2 is a bond, M is an aryl (e.g., phenyl), and L 3 is -CH2O, and Z is a heterocycline (e.g., nitrogen-containing heterocycline, e.g., thiomorpholinyl-1,1-dioxide).

[0133] In some embodiments of equation (Ib), P is absent, and L 1 It is -NHCH2, and L 2 M is a combination, M is non-existence, L 3 is a bond, and Z is a heterocyclyl (e.g., oxygen-containing heterocyclyl, e.g., tetrahydropyranil, tetrahydrofuranil, oxetanil, or oxiranil).

[0134] In some embodiments, the compound is a compound of formula (Ibi). In some embodiments of formula (Ibi), R 2a , and R 2b Each of them is independently hydrogen or CH3, and R 2c , and R 2d Each of them is independently a hydrogen, m is 1 or 2, n is 1, X is O, p is 0, M 2 is one or more R 3 Phenyl is optionally substituted with R 3is -CF3, Z 2 These are heterocyclines (e.g., oxygen-containing heterocyclines, e.g., tetrahydropyranil, tetrahydrofuranil, oxetanil, or oxiranil).

[0135] In some embodiments, the compound is the compound of formula (Ib-ii). In some embodiments of formula (Ib-ii), R 2a , R 2b , R 2c , and R 2d Each of them is independently a hydrogen, q is 0, p is 0, m is 1, Z 2 These are heterocyclines (e.g., oxygen-containing heterocyclines, e.g., tetrahydropyranil).

[0136] In some embodiments, the compound is a compound of formula (Ic). In some embodiments of formula (Ic), R 2c , and R 2d Each of them is independently a hydrogen atom, m is 1, p is 1, q is 0, R 5 is -CH3, and Z is a heterocycline (e.g., nitrogen-containing heterocycline, e.g., piperazinyl).

[0137] 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 Each of them is independently a hydrogen atom, m is 1, n is 3, X is O, p is 0, and Z is a heterocycline (e.g., an oxygen-containing heterocycline, e.g., tetrahydropyranil, tetrahydrofuranil, oxetanil, or oxyranil).

[0138] In some embodiments, the compound is the compound of formula (If). In some embodiments of formula (If), R 2a , and R 2bEach of them is independently hydrogen, n is 1, M is -CH2-, P is a nitrogen-containing heteroaryl (e.g., imidazolyl), and L 3 Z is -C(O)OCH2- and Z is CH3.

[0139] In some embodiments, the compound is the compound of formula (II-a). In some embodiments of formula (II-a), R 2a , and R 2b Each of them is independently a hydrogen, n is 1, q is 0, L 3 Z is -CH2(OCH2CH2)2, and Z is -OCH3.

[0140] In some embodiments of equation (II-a), R 2a and R 2b Each of them is independently a hydrogen, n is 1, L 3 is a bond or -CH2, and Z is hydrogen or -OH.

[0141] In some embodiments, the compound is the compound of formula (III). In some embodiments of formula (III), R 2a , R 2b , R 2c , and R 2d Each of them is independently a hydrogen atom, m is 1, n is 2, q is 3, p is 0, R C is hydrogen, Z 1 R 5 It is a heteroalkyl group that is optionally substituted with (for example, -N(CH3)(CH2CH2)S(O)2CH3).

[0142] In some embodiments, the compound is the compound of formula (III-b). In some embodiments of formula (III-b), R 2a , R 2b , R 2c , and R 2d Each of them is independently a hydrogen, m is 0, n is 2, q is 3, p is 0, Z 2 This is one R 5It is an aryl (e.g., phenyl) substituted with (e.g., -NH2).

[0143] In some embodiments, the compound is the compound of formula (III-b). In some embodiments of formula (III-b), R 2a , R 2b , R 2c , and R 2d Each of them is independently a hydrogen atom, m is 1, n is 2, q is 3, p is 0, R C is hydrogen, Z 2 These are heterocyclines (e.g., nitrogen-containing heterocyclines, nitrogen-containing spiroheterocyclines, e.g., 2-oxa-7-azaspiro[3.5]nonanyl).

[0144] In some embodiments, the compound is the compound of formula (III-d). In some embodiments of formula (III-d), R 2a , R 2b , R 2c , and R 2d Each of them 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. In some embodiments of formula (III-d), R 2a , and R 2b Each of them is independently a hydrogen atom, m is 1, n is 2, q is 1, 2, 3, or 4, p is 0, and X is S(O)2.

[0145] 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).

[0146] In some embodiments, the compound of formula (I) is not a compound disclosed in WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 019391, WO 2017 / 075630, US2012-0213708, US 2016-0030359, or US 2016-0030360.

[0147] In some embodiments, the compound of formula (I) comprises the compounds shown in Table 3 or pharmaceutically acceptable salts thereof. In some embodiments, the outer surface and / or one or more compartments within the device described herein comprises the small molecule compounds shown in Table 3 or pharmaceutically acceptable salts thereof.

[0148] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7]

[0149] The conjugate of any of the compounds in Table 3 with a polymer (e.g., alginate) may be carried out as described in Example 2 of WO 2019 / 195055, or by any other suitable chemical reaction.

[0150] 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 selected from pharmaceutically acceptable salts thereof.

[0151] In some embodiments, the devices described herein are [ka] It contains the compound of either of these compounds, or a pharmaceutically acceptable salt of either compound.

[0152] In some embodiments, the devices described herein are [ka] It contains the compound of either of these compounds, or a pharmaceutically acceptable salt of either compound.

[0153] In some embodiments, the devices described herein are [ka] The compounds include the compounds of these compounds, or pharmaceutically acceptable salts of any of these compounds.

[0154] In some embodiments, the compound of formula (I) (e.g., compound 101 in Table 3) is covalently bonded to an alginate (e.g., an alginate having approximately MW < 75 kDa and a G:M ratio of 1.5 or greater) at a conjugate density of at least 2.0% and less than 9.0%, or 3.0% to 8.0%, 4.0 to 7.0%, 5.0 to 7.0, or 6.0 to 7.0 or about 6.8, as determined by combustion analysis for nitrogen percentage, as described in WO2020 / 069429.

[0155] Photoactive crosslinking linker and photoinitiator Hydrogel capsules containing a polysaccharide polymer covalently bonded to a photoactive crosslinker, as well as compositions and methods of use thereof, are described herein. The photoactive crosslinker includes a moiety that is activated upon exposure to light. The light may include light of any wavelength from infrared to X-ray energy. In some embodiments, the light includes 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 includes visible light (e.g., 400 nm to 700 nm). The photoactive crosslinker often includes at least one unsaturated functional group that can undergo free radical polymerization. In some embodiments, the photoactive crosslinker includes an alkenyl group (e.g., C2-C2). 12 The alkenyl group (C2-C8 alkenyl) is included. In some embodiments, the photoactive crosslinker is an alkynyl group (e.g., C2-C8 alkenyl). 12This includes alkynyls (C2-C8 alkynyls). The moieties that can be activated upon exposure to radiation include aromatic groups, alkenyl groups, alkynyl groups, and azide groups. Exemplary alkenyl compounds that can act as photoactive crosslinkers include alkenic acids (such as acrylates, methacrylates, acrylamides, and methacrylamides), as well as their corresponding acid chlorides and anhydrides. In some embodiments, the photoactive crosslinker includes an acrylate group. In some embodiments, the photoactive crosslinker includes a methacrylate group. In some embodiments, the photoactive crosslinker includes an acrylamide group. In some embodiments, the photoactive crosslinker includes a methacrylamide group. Other exemplary alkenyl compounds include enols (e.g., 2-propen-1-ol), halogenated alkenyls (e.g., allyl chloride), organometallic alkenyl compounds (e.g., magnesium vinyl bromide), and aryl compounds (e.g., styrene). Examples of photoactive crosslinkers include acrylates, methacrylates, ethylene glycol dimethyl acrylate, divinylbenzene, 1,3-diisopropylbenzene, and N,N'-methylenebiscrylamide. In one embodiment, the photoactive crosslinker is a bifunctional crosslinker, i.e., it 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.

[0156] In one embodiment, the photoactive crosslinker has the structure of formula (IV): [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein X 1 However, non-existence, O, NR 33 , or C(R 34a )(R 34b ) and R 30a , R30b , R 31 , R 32 , R 33 , R 34a , and R 34b Each of these can independently be 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, each R A1 , R B1 , R C1 , R D1 , and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7 However, they are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0157] In one embodiment, X 1 is O, R 30a , R 30b , R 31 and R 32 Each of them is hydrogen, R 32 is a heteroalkyl group (e.g., propylamine, e.g., -CH2CH2CH2NH2). In one embodiment, X 1 is O, R 30a , R 30b , R 31 , and R 32 Each of them is hydrogen, R 32is a heteroalkyl (e.g., ethylamine, e.g., -CH2CH2NH2). In one embodiment, the photoactive crosslinking linker of formula (IV) is a methacrylate. In one embodiment, X 1 It does not exist, R 32 is a halo (for example, chloroform), and R 30a , R 30b , and R 31 Each of them is hydrogen. In one embodiment, the photoactive crosslinker of formula (IV) is acryloyl chloride.

[0158] In one embodiment, X 1 , NR 33 (For example, NH) and R 30a , R 30b , R 31 and R 32 Each of these is hydrogen. In one embodiment, the photoactive crosslinking linker of formula (IV) is acrylamide.

[0159] In one embodiment, the photoactive crosslinker of formula (IV) has the structure of formula (IV-a): [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein R 30a , R 30b , R 31 , R 32 , and R 35 Each of these can independently be 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, each R A1 , R B1, R C1 , R D1 , and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7 However, they are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0160] In one embodiment, the photoactive crosslinker of formula (IV) has the structure of formula (IV-b): [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein R 30a , R 30b , R 31 , R 32 , R 36a , and R 36b Each of these can independently be 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, each R A1 , R B1 , R C1 , R D1 , and R E1However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7 However, independently, they are alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, and R 35 n is hydrogen, alkyl, heteroalkyl, halo, cyano, nitro, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and n is 1, 2, 3, 4, 5, or 6.

[0161] In one embodiment, the photoactive crosslinker of formula (IV) has the structure of formula (IV-c): [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein R 30a , R 30b , and R 31 However, independently, 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, R 32 However, alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR A1 , -C(O)R B1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, each R A1 , RB1 , R C1 , R D1 , and R E1 are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with 1 to 6 R 7 s, and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0162] In one embodiment, the photoactive cross-linking linker of formula (IV) has the structure of formula (IV-d): [Chemical formula] or a pharmaceutically acceptable salt or tautomer thereof, and each of R 30a , R 30b , R 31 , R 32 , R 36a , and R 36b is independently 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 [[ID= 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 , RB1 , R C1 , R D1 , and R E1 are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 6 R 7 s, 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.

[0163] In some embodiments, the photoactive crosslinking linker is a compound of Table 4.

[0164]

Table 4-1

Table 4-2

[0165] The photoactive crosslinking linker may 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 can form reactive species in an excited state. A variety of free radical initiators, readily identifiable to those skilled in the art, may be employed in the implementation 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-hydroxycyclohexylphenyl 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-morpholine-4-ylphenyl)butan-1-one (i.e., Irgacure 369), and 2-methyl-1-(4-methylsulfanylphenyl)-2-morpholine-4-ylpropan-1-one (i.e., Irgacure 907) comprises 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.

[0166] In visible light polymerization, a system of dyes and cocatalysts may be used. Exemplary visible light photoinitiators include 2-(2,4,5,7-tetrabromo-3-hydroxy-6-oxoxanthene-9-yl)benzoic acid (i.e., eosin Y), erythrosine, riboflavin, rose bengal, methylene blue, and thionine. 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 thionine. To increase the polymerization rate, small amounts of comonomers can be optionally added to the crosslinking reaction. Suitable examples of 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 triacrylate, pentaerythritol trimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, tripropylene glycol diacrylate, tripropylene glycol dimethacrylate, glyceryl acrylate, glyceryl methacrylate, and the like.

[0167] In some embodiments, the photoinitiator is a thermally activated photoinitiator.

[0168] Photoactive crosslinking linkers can be used in the presence of a single photoinitiator or multiple photoinitiators. Multiple photoinitiators may include 2, 3, 4, 5, 6, 7, 8, or more photoinitiators.

[0169] In one embodiment, the covalently crosslinked portions may be present on the polysaccharide polymer at densities of at least 1%, for example, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or higher, as determined, for example, by an LC-UV assay. In one embodiment, the covalently crosslinked portions may be present on the polysaccharide polymer at densities of less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or higher, as determined, for example, by an LC-UV assay. In one embodiment, covalently crosslinked portions may be present on the polysaccharide polymer at densities exceeding 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 an LC-UV assay.

[0170] The modified polysaccharide may contain a photoactive crosslinker moiety. The photoactive crosslinker (e.g., compounds of formulas (IV) to (IV-d)) may be covalently bonded to the polysaccharide (e.g., alginate). The modified polysaccharide polymer (e.g., modified alginate polymer) may be crosslinked to another polymer. In one embodiment, the polysaccharide polymer is modified with more than one type of photoactive crosslinker.

[0171] In one embodiment, the polysaccharide is modified with a group capable of undergoing free radical polymerization. In one embodiment, the polysaccharide is modified with a compound of formula (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] It is modified by.

[0172] In one embodiment, the modified polysaccharide is a compound of formula (V): [ka] or a pharmaceutically acceptable salt or tautomer thereof, where T and U are independently 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 of these can independently be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, or -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, R 32 and R 35 Each of them is hydrogen, alkyl, heteroalkyl, halo, cyano, nitro, amino, 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 alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7These are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, and the photoactive crosslinking linker has the structure of formula (IV), (IV-a), (IV-b), (IV-c), or (IV-d).

[0173] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Va): [ka] or having a pharmaceutically acceptable salt or tautomer thereof, wherein each of T and U is independently C(R) 40 )(R 41 ), O or 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 of these can independently be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, or -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 R A1 , R B1 , R C1 , R D1 and R E1is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with 1 to 6 R 7 and each R 7 is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl or heterocyclyl.

[0174] In one embodiment, the modified polysaccharide polymer of formula (V) has a structure of formula (V-b):

Chemical formula

[0175] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Vc): [ka] or a pharmaceutically acceptable salt or 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 of these can independently be 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 ), SRE1 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, each R A1 , R B1 , R C1 , R D1 , and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7 However, independently, n is alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, where n is 1, 2, 3, 4, 5, or 6.

[0176] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Vd): [ka] or a pharmaceutically acceptable salt or 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 of these can independently be 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, each R A1 , R B1 , R C1 , R D1 , and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7 The elements are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, where n is 1, 2, 3, 4, 5, or 6.

[0177] In one embodiment, the modified polysaccharide polymer has the structure of formula (VI): [ka] or comprising a pharmaceutically acceptable salt or tautomer thereof, wherein W, T 1 , T 2 , U 1 , and U 2 Each of these independently, 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 of these can independently be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, -OR A1 , -C(O)ORA1 , -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 R A1 , R B1 , R C1 , R D1 , and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7 The elements are independently alkyl, alkenyl, lukinyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, p is an integer between 1 and 100, the non-fibrous compound has the 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 crosslinking linker has the structure of formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), or (IV-e).

[0178] In one embodiment, the modified polysaccharide polymer has the structure of formula (Vi-ai): [ka] or comprising a pharmaceutically acceptable salt or tautomer thereof, wherein W, T 1 , U 1 , and U 2Each of these independently, 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 of these is independently 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, each R A1 , R B1 , R C1 , R D1 , and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl has 1 to 6 R7 It is optionally replaced by each R7 However, independently, they are 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 Cm and n are as defined in formula (Ib), p is an integer between 1 and 100, and the photoactive crosslinker has the structure of formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), or (IV-e).

[0179] In one embodiment, the modified polysaccharide polymer of formula (V) has the structure of formula (Va-ii): [ka] or comprising a pharmaceutically acceptable salt or tautomer thereof, wherein W, T 1 , U 1 and U 2 Each of these independently 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 of these can independently be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, or -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 R A1 , R B1 , R C1 , R D1 and R E1These are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of 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, and the variable Z 1 , R 2a , R 2b , R 2c , R 2d , 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 the structure of formula (IV), (IV-a), (IV-b), (IV-c), (IV-d), or (IV-e).

[0180] In one embodiment, the modified polysaccharide polymer has the structure of formula (Vi-bi): [ka] or comprising a pharmaceutically acceptable salt or tautomer thereof, wherein W, X 1 , T 2 , U 1 and U 2 Each of these independently 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 44Each of these can independently be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, or -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 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 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, and the non-fibrous compounds have the 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).

[0181] In one embodiment, the modified polysaccharide polymer has the structure of formula (Vi-ci): [ka] or comprising a pharmaceutically acceptable salt or tautomer thereof, wherein X 1 , U 1 , U 2Each of , and W independently, 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 of these can independently be 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, each R A1 , R B1 , R C1 , R D1 , and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7 However, independently, they are alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl, and the variable M 1 , Z 1 , R 2a , R 2b , R 2c , R2d X, R C m and n are as defined in equation (Ib), and p is an integer between 1 and 100.

[0182] In one embodiment, the modified polysaccharide polymer has the structure of formula (Vi-c-ii): [ka] or comprising a pharmaceutically acceptable salt or tautomer thereof, wherein W, X 1 , Y 1 , and Y 2 Each of these independently, 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 of these can independently be 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, each R A1 , R B1 , R C1 , R D1 , and R E1However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl has 1 to 6 R 7 It is optionally replaced by each R 7 However, independently, they are 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 equation (III-f), and p is an integer between 1 and 100.

[0183] In one embodiment, the modified polysaccharide polymer of formula (VI) is a compound selected from Table 5:

[0184] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0185] In one embodiment, the modified polysaccharide polymer is [ka] or selected from pharmaceutically acceptable salts thereof.

[0186] The polysaccharide polymers described herein may be modified with any preferred functional group (e.g., a carboxyl group or a hydroxyl group). 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 both a carboxyl group and a hydroxyl group. In one embodiment, the polysaccharide polymer described herein may be modified on one or more functional groups with a compound of formula (I) and / or a compound of formula (IV).

[0187] In one embodiment, the degree of modification (i.e., the percentage of functional groups of the polymer modified with the photoactive crosslinker) is approximately 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 percentage 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 greater than 99%. In one embodiment, the degree of modification (i.e., the percentage 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 less than 99%.

[0188] In some embodiments, the polysaccharide polymers described herein retain enough unreacted carboxylic acid groups to enable ionic crosslinking, for example, when the polymer is used to prepare hydrogel capsules having double crosslinks. In some embodiments, the polysaccharide polymers described herein do not have a degree of modification of more than 10% of the carboxylic acid groups. In some embodiments, the polysaccharide polymers described herein do not have a degree of modification of more than 5% of the carboxylic acid groups. In some embodiments, the polysaccharide polymers described herein do not have a degree of modification of more than 5%, 6%, 7%, 8%, 9%, or 10% of the carboxylic acid groups.

[0189] In one embodiment, the polysaccharide polymer described herein is modified with one, two, three or more specific compounds. In one embodiment, the polysaccharide polymer described herein is modified with a photoactive crosslinker (e.g., a compound of formula (IV)) and a compound of formula (I). In one embodiment, the polysaccharide polymer described herein is modified with a photoactive crosslinker. In one embodiment, the polysaccharide polymer described herein is modified with a compound of formula (I). In a preferred embodiment, the polysaccharide polymer described herein is modified with both a photoactive crosslinker and a compound of formula (I). In one embodiment, the polysaccharide polymer described herein is modified with both a photoactive crosslinker (e.g., compound 201) and a compound of formula (I) (e.g., the compounds in Table 3).

[0190] In one embodiment, the polysaccharide polymer described herein is [ka] and are modified with the compounds in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and are modified with the compounds in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and are modified with the compounds in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and are modified with the compounds in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and are modified with the compounds in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and are modified with the compounds in Table 3. In one embodiment, the polysaccharide polymer described herein is [ka] and are modified with the compounds in Table 3. In one embodiment, the polysaccharide polymer described herein is modified with the compounds in Table 3.

[0191] In one embodiment, the polysaccharide polymer described herein is [ka] It is an alginate modified with both of the compounds. In one embodiment, the polysaccharide polymer described herein is [ka] It is an alginate modified with both of the compounds.

[0192] In some embodiments, the polysaccharide polymer described herein is an alginate (e.g., VLVG alginate or SLG-100 alginate, e.g., low viscosity alginate, e.g., high G:M ratio alginate) and is modified with a photoactive crosslinking linker and a compound of formula (I) (e.g., from Table 3). 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 contain 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 contain 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 contain an anti-CD28 antibody. In one embodiment, the polysaccharide polymer described herein is modified with the compound of formula (I) and the compound of formula (IV) and does not contain major histocompatibility peptides. In one embodiment, the polysaccharide polymer described herein is modified with the compound of formula (I) and the compound of formula (IV) and does not contain heparin, anti-CD3 antibody, anti-CD28 antibody, or major histocompatibility peptides.

[0193] Polysaccharides (e.g., alginates) can be modified on 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).

[0194] Characteristics of hydrogels and hydrogel capsules This disclosure further features hydrogels and hydrogel capsules comprising both (i) a polysaccharide polymer as described herein and (ii) island cells (e.g., multiple island cells). The hydrogels and hydrogel capsules are crosslinked by photoactive crosslinking groups (i.e., covalent crosslinking), or by, for example, divalent cations (e.g., Ba 2+They may also be produced by ion crosslinking in the presence of ). In one embodiment, the hydrogel capsules or hydrogel capsules described herein are produced by photoactive crosslinking. In one embodiment, the hydrogel capsules or hydrogel capsules described herein are produced by photoactive crosslinking and ion crosslinking (also referred to herein as double 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.

[0195] Polysaccharide polymers described herein, including photoactive crosslinker moieties, may undergo further polymerization, for example, by reacting with compatible functional groups on the same or different polymers. In one embodiment, a crosslinked polymer may be formed by reacting a first polymer with a second polymer, which is modified to contain thiol groups and a second polymer modified to contain alkene groups. In some embodiments, the hydrogel capsules are formed by covalent crosslinking of unsaturated functional groups by a chain growth polymerization process. In one embodiment, the hydrogel capsules are formed through covalent crosslinking of unsaturated functional groups on a first polymer with unsaturated functional groups on a second polymer. In a preferred embodiment, the hydrogel capsules are formed through covalent crosslinking of alkenyl functional groups on a first polymer with alkenyl functional groups on a second polymer. In other embodiments, the hydrogel capsules are formed by covalent crosslinking of unsaturated functional groups by a step growth polymerization process. In one embodiment, the stepwise polymerization process involves a reaction between one or more unsaturated functional groups (e.g., alkenyl groups) of one polysaccharide chain and a thiolated functional group of another polymer chain.

[0196] The hydrogel capsules described herein are formed by crosslinking one or more types of polysaccharide polymers. In one embodiment, the hydrogel capsule comprises only a polysaccharide polymer. In one embodiment, the hydrogel capsule comprises a polysaccharide polymer of the same type (e.g., an alginate polymer). In one embodiment, the hydrogel capsule is formed by polymerization of two identical polysaccharides. In one embodiment, the hydrogel capsule is formed by polymerization of two different polysaccharides. In one embodiment, the hydrogel capsule comprises multiple polymers (e.g., multiple polysaccharide polymers). In one embodiment, the hydrogel capsule comprises one polysaccharide polymer and a non-polysaccharide polymer.

[0197] The hydrogel capsules described herein are formed by crosslinking one or more types of polysaccharide polymers. In one embodiment, the hydrogel capsule comprises only a polysaccharide polymer. In one embodiment, the hydrogel capsule comprises a polysaccharide polymer of the same type, e.g., an alginate polymer. In one embodiment, the hydrogel capsule is formed by polymerization of two identical polysaccharides. In one embodiment, the hydrogel capsule is formed by polymerization of two different polysaccharides. In one embodiment, the hydrogel capsule comprises multiple polymers (e.g., multiple polysaccharide polymers). In one embodiment, the hydrogel capsule comprises one polysaccharide polymer and a non-polysaccharide polymer.

[0198] The hydrogel capsules described herein may be homogeneous, that is, they may not contain non-polysaccharide polymers. In one embodiment, the hydrogel capsules described herein do not contain polymers selected from polyacrylamide, poly(vinyl alcohol), poly(ethylene oxide), polyethylene glycol (PEG), and polyphosphazene. In one embodiment, the hydrogel capsules do not contain poly(vinyl alcohol). In one embodiment, the hydrogel capsules do not contain poly(ethylene oxide). In one embodiment, the hydrogel capsules do not contain polyethylene glycol (PEG). In one embodiment, the hydrogel capsules do not contain polyphosphazene.

[0199] In one embodiment, the hydrogel capsule is a two-compartment hydrogel capsule. In one embodiment, the hydrogel capsule includes 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 polysaccharides. In one embodiment, the inner compartment is formed from the polysaccharide of formula (Vb), and the outer compartment is formed from the polysaccharide of formula (Vb). In one embodiment, the inner compartment is formed from the polysaccharide of formula (Vd), and the outer compartment is formed from the polysaccharide of formula (Vd). In one embodiment, the inner compartment is formed from the polysaccharide of formula (Vci), and the outer compartment is formed from the 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 substance (e.g., the compounds 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 in Table 1, and the outer compartment is formed from a polysaccharide modified with a compound of formula (Vb), (Vd), or (VI-ci).

[0201] This disclosure features a hydrogel capsule containing a double-crosslinked polysaccharide for encapsulating island cells (such as engineered island cells, corpuscular island cells, or stem cell-derived island cells). The island cells can express a therapeutic agent (e.g., insulin) when the hydrogel is implanted in a subject (e.g., a human or other mammalian subject). Furthermore, the hydrogel capsule further includes at least one means (as defined herein) for reducing fasting bone regeneration (FBR). In one embodiment, the means for reducing FBR includes a non-fibrous compound as defined herein. In one embodiment, the double-crosslinked polysaccharide polymer may further include at least one cell-binding peptide (CBP) (as defined herein). The cells can express a therapeutic agent in a subject, e.g., a human or other mammalian subject, upon implantation of a device (e.g., a hydrogel capsule) containing the double-crosslinked polysaccharide polymer. Furthermore, the device includes at least one means (as defined herein) for reducing FBR. 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 bonded to the double-crosslinked polysaccharide polymer.

[0202] In some embodiments, the device (e.g., a hydrogel capsule) further comprises an unmodified polysaccharide polymer. In some embodiments, the unmodified polysaccharide polymer is an unmodified alginate. In some embodiments, the alginate is a high guluronic acid (G) alginate containing 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 containing 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 or higher.

[0203] In some embodiments, the device (e.g., hydrogel capsule)-modified polysaccharide polymer is a non-fibrous polymer, an example of which is a non-fibrous alginate containing an alginate chemically modified with the compound of formula (I). The alginate in the non-fibrous alginate polymer may be identical to or different from any unmodified alginate present in the device. In one embodiment, the density (e.g., amount of conjugate) 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 (determined, e.g., by combustion analysis for nitrogen percentage). In one embodiment, the amount of compound 101 causes an increase in %N (compared to unmodified alginate) of approximately 0.5% to 2%, 2% to 4%N, approximately 4% to 6%N, approximately 6% to 8%, or approximately 8% to 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 may be porous or non-porous. The pores within the polysaccharide hydrogel capsule (e.g., formed from an alginate hydrogel) 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 one preferred embodiment, the hydrogels and hydrogel capsules described herein are porous. In some embodiments, the average pore diameter is approximately 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 approximately 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 greater than 20 nm. In some embodiments, the average pore diameter is approximately 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 less than 20 nm.

[0205] In some embodiments, the average pore sizes of the first and second compartments of a particle (e.g., a hydrogel capsule) are substantially identical. In some embodiments, the average pore sizes of the first and second compartments of a 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 device (e.g., the average pore size of the first compartment and / or the average pore size of the second compartment) depends on a number of factors, such as the material(s) in each compartment, the presence and density of a photoactive crosslinking linker, and the presence and density of a compound of formula (I).

[0206] The hydrogel capsules described herein should not have pores large enough 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 larger than 75 μm. In some embodiments, the hydrogel capsules described herein do not have pore sizes larger 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 larger than 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 permeability of undesirable molecules from outside the capsule (determined, e.g., by a dextran permeability assay). 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 approximately 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, 105 kDa, 110 kDa, 115 kDa, 120 kDa, 125 kDa, 130 kDa, 135 kDa, 140 kDa, 145 kDa, or 150 kDa. In some embodiments, the average molecular weight permeability is greater than approximately 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, 105 kDa, 110 kDa, 115 kDa, 120 kDa, 125 kDa, 130 kDa, 135 kDa, 140 kDa, 145 kDa, or 150 kDa. In some embodiments, the average molecular weight permeability is approximately 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, 105 kDa, 110 kDa, 115 kDa, 120 kDa, 125 kDa, 130 kDa, 135 kDa, 140 kDa, 145 kDa, or less than 150 kDa.

[0208] In some embodiments, the hydrogel capsules described herein may be characterized by an absolute breaking strength (e.g., crush 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 are approximately 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, 4 It has an absolute strength of 10g, 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. In some embodiments, the hydrogel capsules described herein are available in 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, and 41g. It has an absolute strength of 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 greater than 800g.In some embodiments, the hydrogel capsules described herein are available in 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, and 41g. It has an absolute strength of 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 less than 800g.

[0209] This disclosure features particles (e.g., hydrogel capsules) comprising a first compartment, a second compartment, and a photoactive crosslinked moiety as 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 crosslinked moiety is covalently bonded to a polysaccharide polymer present in the first and / or second compartments. The particles (e.g., hydrogel capsules) may be spherical or have any other shape. The particles (e.g., hydrogel capsules) may contain materials such as metals, metal alloys, ceramics, polymers, fibers, inert materials, and combinations thereof. The particles (e.g., hydrogel capsules) may consist entirely of one type of material, or may contain a number of other materials in the second (outer) compartment and the first (inner) compartment.

[0210] In one embodiment, the present disclosure features a hydrogel capsule comprising a first compartment, a second compartment, and a compound of formula (I) (e.g., as described herein). In some embodiments, the first compartment is modified with the compound of formula (I). In some embodiments, the second compartment is modified with the compound of formula (I). In some embodiments, both the first and second compartments are independently modified with the compound of formula (I).

[0211] In some embodiments, the particles (e.g., hydrogel capsules) have a maximum linear dimension (LLD) (e.g., average diameter) or size that exceeds 1 millimeter (mm), preferably 1.5 mm or more. In some embodiments, the diameter or size of the particles (e.g., hydrogel capsules) may be as large as 10 mm. For example, the sizes of the hydrogel capsules described herein are 0.5mm-10mm, 1mm-10mm, 1mm-8mm, 1mm-6mm, 1mm-5mm, 1mm-4mm, 1mm-3mm, 1mm-2mm, 1mm-1.5mm, 1.5mm-8mm, 1.5mm-6mm, 1.5mm-5mm, 1.5mm-4mm, 1.5mm-3mm, 1.5mm-2mm, 2mm-8mm, 2mm-7mm, 2mm-6mm, 2mm-5mm, 2mm-4mm, 2mm-3mm, 2.5mm-8mm, 2.5mm-7mm, 2.5mm-6mm, 2.5mm-5mm, 2.5mm-4mm, 2.5mm-3mm, and 3mm. The sizes are in the range of 1mm to 8mm, 3mm to 7mm, 3mm to 6mm, 3mm to 5mm, 3mm to 4mm, 3.5mm to 8mm, 3.5mm to 7mm, 3.5mm to 6mm, 3.5mm to 5mm, 3.5mm to 4mm, 4mm to 8mm, 4mm to 7mm, 4mm to 6mm, 4mm to 5mm, 4.5mm to 8mm, 4.5mm to 7mm, 4.5mm to 6mm, 4.5mm to 5mm, 5mm to 8mm, 5mm to 7mm, 5mm to 6mm, 5.5mm to 8mm, 5.5mm to 7mm, 5.5mm to 6mm, 6mm to 8mm, 6mm to 7mm, 6.5mm to 8mm, 6.5mm to 7mm, 7mm to 8mm, or 7.5mm to 8mm. In some embodiments, the particles (e.g., hydrogel capsules) have an average diameter or size of 1mm to about 8mm. In some embodiments, the particle (e.g., hydrogel) capsules have an average diameter or size of 1 mm to 4 mm. In some embodiments, the particle (e.g., hydrogel capsules) have an average diameter or size of 1 mm to 2 mm. In some embodiments, the particle (e.g., hydrogel capsules) have an average diameter or size of 1.5 mm to 2 mm.

[0212] In some embodiments, the particles (e.g., hydrogel capsules) have a maximum linear dimension (LLD) (e.g., average diameter) or size of 1 millimeter (mm) or less. In some embodiments, the size of the particles (e.g., hydrogel capsules) is in the 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.

[0213] In some embodiments, the second (outer) compartment completely encloses 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 means 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 100 nm or more, and may be about 1 mm in size. For example, the thickness of the outer compartment in the particles described herein may 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.

[0214] In some embodiments, the particles (e.g., hydrogel capsules) include at least one pore or opening, for example, to allow free flow of the material. In some embodiments, the average pore size of the hydrogel capsules is about 0.1 μm to about 10 μm. For example, the average pore size may be 0.1μm~10μm, 0.1μm~5μm, 0.1μm~2μm, 0.15μm~10μm, 0.15μm~5μm, 0.15μm~2μm, 0.2μm~10μm, 0.2μm~5μm, 0.25μm~10μm, 0.25μm~5μm, 0.5μm~10μm, 0.75μm~10μm, 1μm~10μm, 1μm~5μm, 1μm~2μm, 2μm~10μm, 2μm~5μm, or 5μm~10μm. In some embodiments, the average pore size of the hydrogel capsule is approximately 0.1μm~10μm. In some embodiments, the average pore size of the hydrogel capsule is approximately 0.1μm~5μm. In some embodiments, the average pore size of the hydrogel capsule is approximately 0.1 μm to 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 the same. 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 approximately 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 hydrogel capsule (e.g., the average pore size of the first compartment and / or the average pore size of the second compartment) depends on several factors, including the material(s) in each compartment, as well as the presence and density of the compound of formula (I).

[0215] In some embodiments, the hydrogel capsule contains an alginate. The 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 containing 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 containing 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) may be, for example, at least 5% w / w, e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more, and less than 20%, e.g., 20%, 15%, 10%, 5%, 1%, 0.5%, 0.1%, or less than a lower percentage.

[0216] In some embodiments, both the first and second compartments contain the same polymer. In some embodiments, the first and second compartments contain different polymers. In some embodiments, the first compartment contains alginate. In some embodiments, the second compartment contains alginate. In some embodiments, both the first and second compartments contain 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 contains alginate and the second compartment contains a different polymer (e.g., polysaccharide, e.g., hyaluronate or chitosan). In some embodiments, the second compartment contains alginate and the first compartment contains a different polymer (e.g., polysaccharide, e.g., hyaluronate or chitosan).

[0217] Both the first and second compartments may contain a single component (e.g., one polymer) or two or more components (e.g., a blend of polymers). In some embodiments, the first compartment contains only alginates (e.g., chemically modified alginates, or a blend of unmodified and chemically modified alginates). In some embodiments, the second compartment contains only alginates (e.g., chemically modified alginates, or a blend of unmodified and chemically modified alginates). In some embodiments, both the first and second compartments independently contain only alginates (e.g., chemically modified alginates, or a blend of unmodified and chemically modified alginates).

[0218] In some embodiments, the first and second compartments contain a blend of polymers (i.e., a mixture of polymers). In some embodiments, the first (inner) compartment contains a blend of polymers. In some embodiments, the second (outer) compartment contains a blend of polymers. In some embodiments, the first and second compartments contain the same blend of polymers. In some embodiments, the first and second compartments contain different blends of polymers. In some embodiments, at least one polymer in the blend containing 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 containing 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 containing the second (outer) compartment is covalently modified with both a photoactive crosslinker and a non-fibrous compound.

[0219] In some embodiments, the first compartment contains a blend of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more polymers. In some embodiments, the first compartment contains a blend of 2 polymers. In some embodiments, the first compartment contains a blend of 3 polymers. In some embodiments, the first compartment contains a blend of 4 polymers. In some embodiments, the first compartment contains a blend of 5 polymers. In some embodiments, the first compartment contains a blend of 6 polymers. In some embodiments, the first (inner) compartment contains a blend of 7 polymers. In some embodiments, the first (inner) compartment contains a blend of 8 polymers. In some embodiments, the first (inner) compartment contains a blend of 9 polymers. In some embodiments, the first (inner) compartment contains a blend of 10 polymers.

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

[0221] In some embodiments, the first compartment contains a polymer blend, and the second compartment does not contain a polymer blend.

[0222] In some embodiments, the first compartment does not contain a polymer blend, and the second compartment contains a polymer blend. In some embodiments, the first compartment contains a single type of polymer, and the second compartment contains a polymer blend.

[0223] In some embodiments, the first and second compartments contain a blend of polymers, where the polymers in the blend are any two miscible polymers.

[0224] In some embodiments, the first and second compartments contain a blend of polymers, the polymers being selected from the group consisting of alginates, hyaluronates, and chitosan.

[0225] In some embodiments, the first compartment and the second compartment comprise a blend of polymers, the polymers being selected from the group consisting of alginates, hyaluronates, and chitosan.

[0226] In some embodiments, the first and second compartments contain a blend of alginate polymers.

[0227] In some embodiments, the first and second compartments comprise a blend of alginate polymers, the alginate polymers being selected from high guluronic acid alginate and high mannuronic acid alginate. In some embodiments, the first compartment comprises a blend of alginate polymers, the alginate polymers being selected from high guluronic acid alginate and high mannuronic acid alginate. In some embodiments, the second compartment comprises a blend of alginate polymers, the alginate polymers being selected from high guluronic acid alginate and high mannuronic acid alginate.

[0228] In some embodiments, the first and second compartments comprise a blend of alginate polymers, the alginate polymer being selected from low molecular weight alginate, medium molecular weight alginate, high molecular weight alginate, and ultra-high molecular weight alginate.

[0229] In some embodiments, the first and second compartments contain a blend of alginate polymers, which 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, 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 contains a blend of alginate polymers, which 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.

[0230] In some embodiments, the first and second compartments contain 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 approximately 75:25. In some embodiments, the ratio of the two alginate polymers in the blend is approximately 70:30. In some embodiments, the ratio of the two alginate polymers in the blend is approximately 65:35. In some embodiments, the ratio of the two alginate polymers in the blend is approximately 60:40. In some embodiments, the ratio of the two alginate polymers in the blend is approximately 55:45. In some embodiments, the ratio of the two alginate polymers in the blend is approximately 50:50.

[0231] In some embodiments, the first and second compartments contain 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 greater than 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 approximately 75:25. In some embodiments, the ratio of the two alginate polymers in the blend is greater than approximately 70:30. In some embodiments, the ratio of the two alginate polymers in the blend is greater than approximately 65:35. In some embodiments, the ratio of the two alginate polymers in the blend is greater than approximately 60:40. In some embodiments, the ratio of the two alginate polymers in the blend is greater than approximately 55:45. In some embodiments, the ratio of the two alginate polymers in the blend is greater than approximately 50:50.

[0232] In some embodiments of the present invention, the first and second compartments comprise a blend of VLVG alginate and SLG100 alginate. In some embodiments of the present invention, the first compartment comprises a blend of VLVG alginate and SLG100 alginate. In some embodiments of the present invention, the second compartment comprises a blend of VLVG alginate and SLG100 alginate.

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

[0234] In some embodiments, the polymer in one or both of the first and second compartments is (i) a low molecular weight alginate, e.g., with approximately MW < 75 kDa and a G:M ratio of 1.5 or higher; (ii) a medium molecular weight alginate, e.g., with approximately MW 75 to 150 kDa and a G:M ratio of 1.5 or higher; (iii) a high molecular weight alginate, e.g., with approximately MW 150 to 250 kDa and a G:M ratio of 1.5 or higher; 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, for example, a 70:30 or 60:40 blend of CM-LMW-Alg-101:U-HMW-Alg, which can be prepared as described in the following examples.

[0235] In some embodiments, the particles (e.g., hydrogel capsules) contain an alginate, and the 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).

[0236] In some embodiments, the polymer in a first compartment of the particle (e.g., hydrogel capsule) is modified with one compound of formula (I), and the polymer in a second compartment of the particle (e.g., hydrogel capsule) is modified with a different compound of formula (I). In some embodiments, the particle (e.g., hydrogel capsule) comprises a mixture of a polymer modified with the compound of formula (I) and an unmodified polymer (e.g., a polymer not modified with the compound of formula (I)). In some embodiments, the first compartment comprises a mixture of a polymer modified with the compound of formula (I) and an unmodified polymer (e.g., a polymer not modified with the compound of formula (I)). In some embodiments, the second compartment comprises a mixture of a polymer modified with the compound of formula (I) and an unmodified polymer (e.g., a polymer not modified with the compound of formula (I)).

[0237] Hydrogel Capsules The polymer of the particles described herein (e.g., hydrogel capsules) may be modified on one or more monomers of the polymer with a compound of formula (I) or a pharmaceutically acceptable salt thereof. The modified polymer of the particle may be present in a first (inner) compartment of the particle (e.g., hydrogel capsule), a second (outer) compartment of the particle (e.g., hydrogel capsule), or both the first (inner) and second (outer) compartments of the particle (e.g., hydrogel capsule). 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 polymer monomer is modified with the compound of formula (I) (for example, 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 polymer monomer is modified with the compound of formula (I)). In some embodiments, 0.5% to 50%, 10% to 90%, 10% to 50%, or 25% to 75% of the polymer monomer is modified with the compound of formula (I). In some embodiments, 1% to 20% of the polymer monomer is modified with the compound of formula (I). In some embodiments, 1% to 10% of the polymer monomer is modified with the compound of formula (I).

[0238] In some embodiments, the polymer (e.g., alginate) (when modified with a compound of formula (I) (e.g., compound 101 in Table 3)) includes an increase in %N of any of the following values ​​(compared to the unmodified polymer (e.g., alginate)) on a weight basis: (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, (ii) by weight (iii) 0.1% to 10% by weight, (iv) 0.1% to 2% 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, and (x) 8% to 9% N by weight (in all cases, N% is determined by combustion analysis (for example, as described in Example 2 herein) and corresponds to the amount of compound of formula (I) in the modified polymer).

[0239] The particles (e.g., hydrogel capsules) (e.g., a first or second compartment therein) may contain the compound of formula (I) in an amount that confers specific characteristics to the particles. For example, the hydrogel capsule surface (e.g., outside the outer compartment) may contain a concentration or density of the compound of formula (I) so that the hydrogel capsule becomes non-fibrous in the object (i.e., reduces the foreign body response). In one embodiment, the hydrogel capsule surface contains an alginate chemically modified with a non-fibrous effective amount of compound 101. In one embodiment, the non-fibrous effective amount of compound 101 causes an increase in %N (compared to the unmodified alginate) of about 0.5% to 2%, 2% to 4%N, about 4% to 6%N, about 6% to 8%, or about 8% to 10%N), where %N is determined by combustion analysis (e.g., as described in Example 2 herein) and corresponds to the amount of compound 101 in the modified alginate.

[0240] In one embodiment, a hydrogel capsule is mechanically tested using a TA.XT plus Texture Analyzer (Stable Micro Systems, Surrey, United Kingdom) with a 5mm probe attached to a 5kg load cell. Each capsule is placed on a platform and compressed from above by the probe at a fixed speed of 0.5mm / second. Contact between the probe and the capsule is detected when a rebound force of 1g is measured. The probe then moves 90% of the distance between the probe and the platform, compressing the capsule to its rupture point. The probe's resistance to the compressive force can be measured and plotted as a function of probe displacement (force-displacement curve). Typically, the capsule slightly breaks before completely rupturing, and the force acting on the probe slightly decreases. The analysis macro can be programmed to detect the first decrease of 0.25–0.5g in the force-displacement curve. The force applied by the probe at this point is called the initial rupture force. In one embodiment, the desired mechanical strength of the particles described herein (e.g., two-compartment hydrogel capsules) is such that the initial destructive force is greater than 1, 1.5, 2, 2.5, or 3 grams, or at least 2 grams.

[0241] In one embodiment, the desired mechanical strength of the hydrogel capsule is its ability to remain intact at a desired point in time after being implanted in a target, for example, both the outer and inner compartments of the particles (e.g., hydrogel capsules) removed from the target are visibly intact even after being recovered from an immunocompetent mouse, as observed by an optical microscope (e.g., by bright-field imaging as described in the examples herein).

[0242] In one embodiment, the surface of the hydrogel capsule comprises an alginate chemically modified with compound 101 in an amount that imparts both non-fibrous properties and desired mechanical strength to the particles, for example, the concentration or density of compound 101 in the modified alginate causing an increase in %N (compared to the unmodified alginate) of any of the following values: (i) 1% to 3% by weight, (ii) 2% to 4% N by weight, (iii) 4% to 8% N by weight, (iv) 5% to 9% N by weight, (v) 6% to 9% N by weight, (vi) 6% to 8% N by weight, (vii) 7% to 9% N by weight, and (ix) 8% to 9% N by weight (in all cases, N% is determined by combustion analysis (e.g., as described in Example 2 herein) and corresponds to the amount of compound of formula (I) in the modified alginate).

[0243] If a hydrogel capsule (for example, in a first or second compartment therein) contains an alginate, the alginate can be chemically modified with the compound of formula (I) using any suitable method known in the art. For example, the carboxylic acid moiety of the alginate can be activated to bond with one or more amine-functionalized compounds to obtain an alginate modified with the compound of formula (I). The alginate polymer may be dissolved in water (30 mL / gram polymer) or treated with 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.5 eq) and N-methylmorpholine (1 eq). To this mixture, a solution of the compound of formula (I) dissolved in a buffer or solvent (e.g., acetonitrile (0.3 M)) may be added. The reaction mixture may be heated (e.g., at 55°C for 16 hours), then cooled to room temperature and concentrated by rotary evaporation. The residue may then be dissolved in a buffer or solvent (e.g., water). The mixture may then be filtered, for example, through a cyano-modified silica gel (Silicycle) bed, and the filtered cake may be washed with water. The resulting solution may then be dialyzed against a buffer or water for 24 hours (10,000 MWCO membrane), in which case the buffer or water may be changed at least once, at least twice, at least three times, or more times. The resulting solution may then be concentrated, for example, by freeze-drying, to obtain the desired chemically modified alginate.

[0244] In some embodiments, the hydrogel capsule comprises: (i) an inner compartment containing a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate contains compound 101 and the SLG100 alginate is unmodified; and (i) an outer compartment containing a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate contains compound 101 and the SLG100 alginate is unmodified.

[0245] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate contains compound 101 and the SLG100 alginate contains compound 205, and (ii) an outer compartment containing a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate contains compound 101 and the SLG100 alginate contains compound 205.

[0246] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 200.

[0247] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 201.

[0248] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 202.

[0249] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 203.

[0250] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 204.

[0251] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 205.

[0252] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 214.

[0253] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 215.

[0254] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 216.

[0255] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 217.

[0256] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 218.

[0257] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 219.

[0258] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 200.

[0259] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 201.

[0260] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 202.

[0261] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 203.

[0262] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 204.

[0263] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 205.

[0264] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 214.

[0265] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 215.

[0266] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 216.

[0267] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 217.

[0268] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 218.

[0269] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 101 and compound 219.

[0270] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 201.

[0271] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 202.

[0272] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 203.

[0273] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 204.

[0274] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 205.

[0275] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 214.

[0276] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 215.

[0277] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 216.

[0278] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 217.

[0279] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 218.

[0280] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 101 and compound 219.

[0281] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 200.

[0282] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 201.

[0283] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 202.

[0284] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 203.

[0285] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 204.

[0286] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 205.

[0287] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 214.

[0288] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 215.

[0289] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 216.

[0290] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 217.

[0291] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 218.

[0292] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 219.

[0293] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 200.

[0294] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 201.

[0295] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 202.

[0296] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 203.

[0297] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 204.

[0298] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 205.

[0299] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 214.

[0300] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 215.

[0301] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 216.

[0302] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 217.

[0303] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 218.

[0304] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified LG20 alginate and (ii) an outer compartment containing LG20 containing compound 114 and compound 219.

[0305] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 201.

[0306] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 202.

[0307] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 203.

[0308] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 204.

[0309] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 205.

[0310] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 214.

[0311] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 215.

[0312] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 216.

[0313] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 217.

[0314] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 218.

[0315] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing an unmodified SLG100 alginate and (ii) an outer compartment containing SLG100 containing compound 114 and compound 219.

[0316] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 101 and compound 205.

[0317] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 101 and compound 200.

[0318] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 101 and compound 201.

[0319] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 101 and compound 202.

[0320] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 101 and compound 203.

[0321] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 101 and compound 204.

[0322] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 101 and compound 206.

[0323] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 114 and compound 205.

[0324] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 114 and compound 200.

[0325] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 114 and compound 201.

[0326] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 114 and compound 202.

[0327] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 114 and compound 203.

[0328] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 114 and compound 204.

[0329] In some embodiments, the hydrogel capsule comprises (i) an inner compartment containing unmodified SLG20 alginate and (ii) an outer compartment containing LG20 alginate modified with compound 114 and compound 206.

[0330] Cells and therapeutic agents The particles described herein (e.g., hydrogel capsules) contain islet cells. In some embodiments, the islet cells produce insulin. In some embodiments, the islet cells are engineered to produce insulin. In some embodiments, the islet cells are engineered to produce another therapeutic agent (e.g., a protein or polypeptide, e.g., an antibody, protein, enzyme or growth factor). In some embodiments, the islet cells are located in a first compartment. In some embodiments, the islet cells are located in a second compartment. In some embodiments, the islet cells are located in the first compartment, and the second compartment does not contain islet cells.

[0331] The particles described herein (e.g., hydrogel capsules) may be configured to release the therapeutic agent described herein (e.g., insulin). In some embodiments, the therapeutic agent is a biological substance. In some embodiments, the therapeutic agent is insulin.

[0332] Particles (e.g., hydrogel capsules) (e.g., those described herein) may be provided as preparations or compositions 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 hydrogel capsules in the preparation or composition have the properties described herein (e.g., average diameter or average pore size).

[0333] In one embodiment, the particles described herein (e.g., hydrogel capsules) comprise a plurality of island cells. In one embodiment, the plurality of island cells are in the form of a cell suspension before being encapsulated within the hydrogel capsules described herein. The cells in the suspension may take the form of single cells (e.g., derived from monolayer cell culture), or in another form, for example, arranged on a microcarrier (e.g., beads or a matrix), or as a three-dimensional aggregate of cells (e.g., cell clusters or spheroids). The cell suspension may contain a plurality of cell clusters (e.g., as spheroids) or microcarriers.

[0334] In some embodiments, the particles of the Disclosure (e.g., hydrogel capsules) reduce immune cell adhesion compared to an untreated control (e.g., substantially identical particles (e.g., hydrogel capsules) lacking the compound of formula (I)). In one embodiment, the particles (e.g., hydrogel capsules) reduce macrophage adhesion compared to an untreated control. In one embodiment, the reduction in macrophage adhesion is about 1 to 10 times less than that of the untreated control. In one embodiment, the reduction in macrophage adhesion is about 1 to 8 times less than that of the untreated control. In one embodiment, the reduction in macrophage adhesion is about 1 to 7 times less than that of the untreated control. In one embodiment, the reduction in macrophage adhesion is about 1 to 6 times less than that of the untreated control. In one embodiment, the reduction in macrophage adhesion is about 1 to 5 times less than that of the untreated control.

[0335] The hydrogels or particles of this disclosure (e.g., hydrogel capsules) enable encapsulated island cells (e.g., genetically engineered cells) to maintain viability (e.g., determined by a cell viability assay). In some embodiments, the hydrogel capsules enable encapsulated island cells to maintain viability for at least 7 days, at least 1 month, or at least 1 year.

[0336] This disclosure features particles (e.g., hydrogel capsules) that comprise (i) a polysaccharide polymer as described herein, and (ii) islet cells that produce, or can produce, a therapeutic agent (e.g., insulin) for the prevention or treatment of a disease, disorder, or condition (e.g., type 1 diabetes). In one embodiment, the islet cells are naturally occurring islet cells and not, for example, engineered. In one embodiment, the islet cells are engineered islet cells. In one embodiment, the islet cells are engineered to sense stimuli, such as chemical signals, and to express a therapeutic agent in response to those stimuli. In one embodiment, the islet cells are differentiated from stem cells (e.g., induced pluripotent stem cells), and the differentiated cells can produce a therapeutic agent (e.g., insulin) either continuously or in response to stimuli. In some embodiments, the therapeutic agent is insulin (e.g., insulin A chain, insulin B chain, or proinsulin). In some embodiments, the islet cells described herein produce insulin.

[0337] In some embodiments, the therapeutic agent is secreted or released from islet cells in an active form (e.g., insulin). In some embodiments, the therapeutic agent (e.g., insulin) is secreted or released from cells in an inactive form, for example, as a prodrug.

[0338] In some embodiments, the hydrogel capsules described herein are approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 M mL -1 It contains mammalian cells at this concentration.

[0339] In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 1 ml -1 It contains at a concentration of approximately 2 MmL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 2 MmL -1 It contains at a concentration of approximately 3 MmL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 3 MmL -1 It contains at a concentration of approximately 4 MmL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 4 MmL -1 It contains at a concentration of approximately 5 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 5 mL -1 It contains at a concentration of approximately 6 ml. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 6 ml -1 It contains at a concentration of approximately 7 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 7 mL -1 It contains at a concentration of approximately 8 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 8 mL -1 It contains at a concentration of approximately 9 MmL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 9 MmL -1 It contains at a concentration of approximately 10 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 10 mL -1 It contains at a concentration of approximately 15 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 15 mL -1 It contains at a concentration of approximately 20 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 20 mL -1 It contains at a concentration of approximately 25 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 25 mL -1 It contains at a concentration of approximately 30 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 30 mL -1 It contains at a concentration of approximately 35 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 35 mL -1It contains at a concentration of approximately 40 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 40 mL -1 It contains at a concentration of approximately 45 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 45 mL -1 It contains at a concentration of approximately 50 mL. In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 50 mL -1 It contains at this concentration.

[0340] In some embodiments, the hydrogel capsules described herein contain mammalian cells in approximately 1 to 50 ml -1 , 1-45 ml -1 , 1-40 ml -1 , 1-35 ml -1 , 1-30 ml -1 , 1-25 ml -1 , 1-20 ml -1 , 1-15 ml -1 , 1-10 ml -1 , 1-5 ml -1 5-50 ml -1 5-45 ml -1 5-40 ml -1 5-35 ml -1 5-30 ml -1 , 5-25 ml -1 5-20 ml -1 5-15 ml -1 5-10 ml -1 , 10-50 ml -1 , 10-45 ml -1 , 10-40 ml -1 , 10-35 ml -1 , 10-30 ml -1 , 10-25 ml -1 , 10-20 ml -1 , 10-15 ml -1 , 15-50 ml -1 , 15-45 ml -1 , 15-40 ml -1 , 15-35 ml -1 , 15-30 ml -1 , 15-25 ml -1, 15-20 ml -1 , 20-50 ml -1 , 20-45 ml -1 , 20-40 ml -1 , 20-35 ml -1 20-30 ml -1 , or 20-25 ml -1 It contains by concentration.

[0341] In some embodiments, the hydrogel capsule contains (i) a blend of VLVG alginate and SLG100 alginate, and 5-25 M mL -1 (i) an inner compartment containing mammalian cells at a concentration of , wherein the VLVG alginate contains compound 101 and the SLG100 alginate is unmodified, and (i) an outer compartment containing a blend of VLVG alginate and SLG100 alginate, wherein the VLVG alginate contains compound 101 and the SLG100 alginate is unmodified, and the outer compartment comprises

[0342] In some embodiments, the hydrogel capsule contains (i) a blend of VLVG alginate and SLG100 alginate, and 5-25 M mL -1 (i) an inner compartment containing mammalian cells at a concentration of (i) compound 101, and SLG100 alginate containing compound 205, and an outer compartment containing a blend of VLVG alginate and SLG100 alginate, where VLVG alginate contains compound 101, and SLG100 alginate contains compound 205.

[0343] In some embodiments, the hydrogel capsule contains (i) unmodified SLG100 alginate and 5-25 M mL -1 (ii) an inner compartment containing mammalian cells at a concentration of (ii) and an outer compartment containing LG20 containing compound 101 and compound 205.

[0344] In some embodiments, the hydrogel capsule contains (i) unmodified SLG20 alginate and 5-25 M mL -1(ii) an inner compartment containing mammalian cells at a concentration of (ii) and an outer compartment containing LG20 containing compound 101 and compound 205.

[0345] In some embodiments, the hydrogel capsule contains (i) unmodified LG20 alginate and 5-25 M mL -1 (ii) an inner compartment containing mammalian cells at a concentration of (ii) and an outer compartment containing LG20 containing compound 101 and compound 205.

[0346] Treatment method Methods for preventing or treating a disease, disorder, or condition in a subject by administering or implanting a hydrogel capsule comprising (i) a polysaccharide polymer described herein and (ii) island cells. In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of a disease, disorder, or condition (e.g., type 1 diabetes). In some embodiments, the methods described herein prevent or delay the onset of a disease, disorder, or condition (e.g., type 1 diabetes). In some embodiments, the subject is a human.

[0347] In some embodiments, a disease, disorder, or condition affects a system of the body, such as 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, a 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.

[0348] In some embodiments, the disease, disorder, or condition is an autoimmune disease. In some embodiments, the disease, disorder, or condition is diabetes mellitus (type 1 or type 2).

[0349] This disclosure further includes a method for identifying a subject who has or is suspected of having one of the diseases, disorders or conditions described herein (e.g., type 1 diabetes), and a method for administering to such a subject a hydrogel capsule comprising (i) a polysaccharide polymer described herein and (ii) islet cells, for example, the hydrogel capsule being optionally modified with a compound of formula (I) or a composition thereof. In one embodiment, the subject has or has been diagnosed with diabetes (e.g., type 1 diabetes). The subject may have any biomarkers or other diagnostic criteria associated with diabetes, such as hyperglycemic levels (e.g., greater than 300 mg / dL, greater than 400 mg / dL) or hyperhemoglobin A1C levels (e.g., greater than 5.9%, greater than 6.5%, greater than 7%). In one embodiment, the subject is human. In one embodiment, the subject is adult. In one embodiment, the target population is children (for example, those under 21, under 18, under 15, under 12, under 10, or under 6 years old).

[0350] Method for producing particles This disclosure further includes methods for producing hydrogel capsules as described herein, examples of which include hydrogel capsules comprising a polysaccharide polymer containing a first compartment, a second compartment, a photoactive crosslinking moiety, and a compound of formula (I). In some embodiments, the method for producing hydrogel capsules comprises contacting a plurality of droplets containing a first polymer solution and a second polymer solution (e.g., each containing a hydrogel-forming polymer) with an aqueous crosslinking solution. In one embodiment, the aqueous crosslinking solution comprises an ionic crosslinking agent, examples of which include divalent cations (such as calcium, barium, and magnesium). The droplets can be formed using any technique known in the art. In a further embodiment, where the particles are hydrogel capsules, the method for producing hydrogel capsules comprises an irradiation step in which a solution containing a polysaccharide polymer is exposed to ultraviolet light to initiate a photocrosslinking reaction. In one embodiment, one or both of the first polymer solution and the second polymer solution may further contain a photoinitiator.

[0351] Each compartment of the hydrogel capsule described herein may contain any one or more of the following: an unmodified polymer, a polymer modified with one or both of the compound of formula (I) and / or the photoactive crosslinked moiety, or a blend of the unmodified polymer and the modified polymer. Briefly, in carrying out a method for preparing a hydrogel capsule configured as a two-compartment hydrogel capsule, a certain amount of a first polymer solution (e.g., containing an unmodified polymer, a polymer modified with the compound of formula (I), a photoactive crosslinked moiety, or a blend thereof, optionally containing cells) is filled into a first syringe connected to the lumen of a coaxial needle. The first syringe may then be connected to a syringe pump oriented vertically above a vessel containing an aqueous crosslinking solution containing a crosslinking agent, a buffer, and an osmotic pressure adjusting agent. A certain amount of a second polymer solution (e.g., containing an unmodified polymer, a polymer modified with the compound of formula (I), a photoactive crosslinked moiety, or a blend thereof, optionally containing cells) is filled into a second syringe connected to the outer lumen of a coaxial needle. Next, a second syringe may be connected to a syringe pump oriented horizontally to a vessel containing the crosslinking solution. Then, a high-voltage power generator may be connected to the top and bottom of the needle. The syringe pump and power generator can then be used to extrude the first and second polymer solutions through the syringe 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 produce two-compartment hydrogel capsule compositions in which most (e.g., at least 80%, 85%, 90%, or more) capsules are within 10% of the target size and have a spherical shape. After the first and second volumes of polymer solution have been used up, the droplets may be crosslinked in the crosslinking solution for a specific time (e.g., about 5 minutes). Crosslinking may involve ionic crosslinking (e.g., by contacting a droplet with an ionic crosslinking agent (e.g., a divalent cation)) and / or covalent crosslinking (e.g., by irradiating a droplet to activate a photoactive crosslinking agent (e.g., methacrylate or methacrylamide)).

[0352] Exemplary process parameters for preparing a millicapsule composition (e.g., a millicapsule with a diameter of 1.5 mm) include: positioning a coaxial needle above the surface of the crosslinked solution at a distance sufficient to provide a dropping 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 polymer solution and the second polymer solution are extruded through the needle at a total flow rate of 0.05 mL / min to 5 mL / min, or 0.05 mL / min to 2.5 mL / min, or 0.05 mL / min to about 1 mL / min, or 0.05 mL / min to 0.5 mL / min, or 0.1 mL / min to 0.5 mL / min. In one embodiment, the first polymer solution and the second polymer solution are extruded through the needle at a total flow rate of approximately 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 polymer solution and the second polymer solution through the needle are substantially the same. In one embodiment, the flow rates of the first polymer solution and the second polymer solution through the needle are different.

[0353] In one embodiment, the voltage of the device is between 1kV and 20kV, or 1 and 15kV, or 1kV and 10kV, or 5kV and 10kV. The voltage may be adjusted until a desired droplet velocity is reached. In one embodiment, the droplet velocity of the device is between 1 droplet / 10 seconds and 50 droplets / 10 seconds, or between 1 droplet / 10 seconds and 25 droplets / 10 seconds.

[0354] In one embodiment, the number of non-particulate debris on the surface of the crosslinking solution is determined. The hydrogel capsules that have fallen to the bottom of the crosslinking vessel may then be collected, for example, by transferring the crosslinking solution containing the hydrogel capsules to another container, leaving any non-particulate debris on the surface of the solution in the original crosslinking vessel. The removed hydrogel capsules may then be precipitated, and after the crosslinking solution has been removed, the hydrogel capsules may be washed once or multiple times with a buffer (e.g., HEPES buffer). In one embodiment, one or more aliquots of the obtained hydrogel capsule composition (e.g., hydrogel capsule preparations) are examined under a microscope to evaluate the quality of the composition (e.g., hydrogel capsule defects and the number of satellite hydrogel capsules).

[0355] In some embodiments, the crosslinked solution further comprises process additives (e.g., hydrophilic, nonionic surfactants). Process additives may reduce the surface tension of the crosslinked solution. Useful agents as process additives in this disclosure include polysorbate 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 nonionic surfactants, examples of which include Tween® 20, Tween® 80, Triton® X-100, IGEPAL® CA-630, poloxamer 188 or poloxamer 407, or surfactants having substantially identical chemical and physical properties listed in the exemplary surfactant table immediately below.

[0356] [Table 6]

[0357] In some embodiments, the nonionic surfactant is poloxamer. In one embodiment, the process additive contains more than one surfactant (e.g., more than one hydrophilic surfactant). In some embodiments, the process additive does not contain Tween® 20 (polysorbate 20) or Triton® X-100. In one embodiment, the process additive is IGEPAL® CA-630 (polyethylene glycol sorbitan monooleate). In some embodiments, the process additive is poloxamer 188.

[0358] In some embodiments, process additives (e.g., surfactants) are present in the crosslinking solution at a concentration of at least 0.0001%. In some embodiments, the crosslinking solution contains at least 0.001%, 0.01%, or 0.1% of process additives. In some embodiments, the process additives are present at concentrations selected from about 0.001% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, and about 0.01% to about 0.5%. In one embodiment, the process additive is a surfactant and is present at a concentration below the critical micelle concentration for the surfactant.

[0359] In some embodiments, the ionic crosslinking agent is a single type of divalent cation, or a mixture of different types, for example, Ba 2+ Ca 2+ Sr 2+ It includes one or more of the following. In some embodiments, the ionic crosslinking agent is BaCl2, for example, in a concentration of 1 mM to 100 mM, or 7.5 mM to 20 mM. In some embodiments, the ionic crosslinking agent is CaCl2, for example, in a concentration of 50 mM to 100 mM. In some embodiments, the ionic crosslinking agent is SrCl2, for example, in a concentration of 37.5 mM to 100 mM. In some embodiments, the ionic crosslinking agent is a mixture of BaCl2 (for example, 5 mM to 20 mM) and CaCl2 (for example, 37.5 mM to 12.5 mM), or a mixture of BaCl2 (for example, 5 mM to 20 mM) and SrCl2 (for example, 37.5 mM to 12.5 mM).

[0360] In some embodiments, the ionic crosslinking agent is SrCl2, and the process additive is Tween® 80 (or a surfactant having substantially the same chemical and physical properties as those listed in the Exemplary Surfactants Table) at a concentration of less than 0.1%, for example, about 0.005% to 0.05%, or about 0.005% to about 0.01%. In some embodiments, the concentration of SrCl2 is about 50 mM. In some embodiments, the ionic crosslinking agent is SrCl2, and the process additive is poloxamer 188 at a concentration of 1%.

[0361] The type and concentration of the buffer in the aqueous crosslinking solution are selected to maintain the solution pH at approximately neutral, for example, 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 encapsulated in particles (e.g., cells). In some embodiments, the buffer in the aqueous crosslinking solution contains HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid).

[0362] The osmotic pressure regulator in the aqueous crosslinked solution is selected to maintain the osmotic pressure of the solution at a value similar to that of a polymer solution (including, in some embodiments, a cell suspension), for example, or with higher or lower fluctuations of up to 20%, 10%, or 5%. In some embodiments, the osmotic pressure regulator is mannitol at a concentration of 0.1 M to 0.3 M.

[0363] In some embodiments, the crosslinking solution comprises 25 mM HEPES buffer, 20 mM BaCl2, 0.2 M mannitol, and 0.01% poloxamer 188.

[0364] 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 identical chemical and physical properties as listed in Tween 80's Exemplary Surfactants Table.

[0365] In one embodiment, the process additive is poloxamer 188, which is present in the particulate composition (e.g., the particle preparation) in a detectable amount after the washing step. Poloxamer 188 may be detected by any technique known in the art, for example, by partially or completely dissolving the particles in the aliquots of the composition by sodium sulfate precipitation and analyzing the supernatant by LC / MS.

[0366] The reduction in surface tension of the crosslinked solution may be evaluated by any method known in the art, for example, by using a contact angle goniometer or tensionometer, or by the Dunouy ring method (see, for example, Davarci et al (2017) Food Hydrocolloids 62:119-127).

[0367] Listed exemplary embodiments 1. A polysaccharide polymer, (i) Photoactive crosslinked portion, (ii) Compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, 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)(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 bonding group (e.g., the bonding groups described herein) and one or more R 1 It is optionally replaced by; L 1 and L 3 Each of them is independently bonded, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is one or more R 2 It is optionally replaced by; L 2 is a combination; M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of these is one or more R 3 It is arbitrarily replaced by; P is one or more R 4 A heteroaryl that is arbitrarily substituted by; Z is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of these is one or more R 5 It is arbitrarily replaced by; Each R A , R B , R C , R D , R E , R F , and R G These are 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 6It is arbitrarily replaced with; or R C and R D These, together with the nitrogen atom to which they are bonded, form one or more R 6 It forms an arbitrarily substituted ring (e.g., a 5- to 7-membered ring); Each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 These are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, and -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 These are cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 It is optionally replaced by; Each R A1 , R B1 , R C1 , R D1 , R E1 , and R F1Each 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 arbitrarily 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; A polysaccharide polymer containing a compound where y is 2, 3, or 4.

[0368] 2. The polysaccharide polymer according to Embodiment 1, wherein the photoactive crosslinked portion is covalently bonded to a sugar monomer in the polysaccharide polymer.

[0369] 3. The polysaccharide polymer according to Embodiment 2, wherein the photoactive crosslinked portion is bonded to the carboxylate portion within the sugar monomer.

[0370] 4. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the photoactive crosslinked portion comprises an alkyl, alkenyl, alkynyl, ester, ketone, amine, or amide group.

[0371] 5. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the photoactive crosslinked portion contains an alkyl group.

[0372] 6. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the photoactive crosslinked portion contains an alkenyl group.

[0373] 7. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the photoactive crosslinked portion contains an alkynyl group.

[0374] 8. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the photoactive crosslinked portion contains an ester group.

[0375] 9. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the photoactive crosslinked portion contains a ketone group.

[0376] 10. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the photoactive crosslinked portion contains an amine group.

[0377] 11. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the photoactive crosslinked portion contains an amide group.

[0378] 12. The polysaccharide polymer according to any one of Embodiments 1 to 11, wherein the photoactive crosslinked portion can react with a second photoactive crosslinked portion when activated by light (e.g., ultraviolet light).

[0379] 13. The polysaccharide polymer according to any one of Embodiments 1 to 12, wherein the photoactive crosslinked portion is present on the polysaccharide polymer at a density of at least about 1%, for example, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or greater, as determined, for example, by comparison with a reference standard (for example, by an LC-MS assay).

[0380] 14. The polysaccharide polymer according to any one of Embodiments 1 to 13, wherein the photoactive crosslinked portion is present on the polysaccharide polymer at a density between 1% and 10%, for example, 1% to 8%, 1% to 6%, or 1% to 4%, determined, for example, by comparison with a reference standard.

[0381] 15. The polysaccharide polymer according to any one of Embodiments 1 to 14, wherein the photoactive crosslinked portion is present on the polysaccharide polymer at a density between 1% and 8%, determined, for example, by comparison with a reference standard.

[0382] 16. The polysaccharide polymer according to any one of Embodiments 1 to 15, wherein the photoactive crosslinked portion is present on the polysaccharide polymer at a density between 1% and 6%, determined, for example, by comparison with a reference standard.

[0383] 17. The polysaccharide polymer according to any one of Embodiments 1 to 16, wherein the photoactive crosslinked portion is present on the polysaccharide polymer at a density between 1% and 4%, determined, for example, by comparison with a reference standard.

[0384] 18. The polysaccharide polymer according to any one of Embodiments 1 to 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.

[0385] 19. The polysaccharide polymer according to any one of Embodiments 1 to 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.

[0386] 20. The polysaccharide polymer according to any one of Embodiments 1 to 19, wherein the polysaccharide polymer is selected from alginate, hyaluronate, and chitosan.

[0387] 21. The polysaccharide polymer according to any one of Embodiments 1 to 20, wherein the polysaccharide polymer is an alginate.

[0388] 22. The polysaccharide polymer according to any one of Embodiments 1 to 21, wherein the polysaccharide polymer is hyaluronate.

[0389] 23. The polysaccharide polymer according to any one of Embodiments 1 to 22, wherein the polysaccharide polymer is chitosan.

[0390] 24. The polysaccharide polymer according to Embodiment 21, wherein the alginate is a high guluronic acid (G) alginate or a high mannuronic acid (M) alginate.

[0391] 25. The polysaccharide polymer according to any one of Embodiments 21 to 24, wherein the alginate is a high guluronic acid (G) alginate.

[0392] 26. The polysaccharide polymer according to Embodiment 21 or 24-25, wherein the alginate is high mannuronic acid (G) alginate.

[0393] 27. The polysaccharide polymer according to Embodiment 21 or any of Embodiments 24-26, wherein the alginate is not high mannuronic acid (M) alginate.

[0394] 28. The polysaccharide polymer according to any one of Embodiments 21 or 24-27, wherein the alginate is selected from low molecular weight alginate, medium molecular weight alginate, high molecular weight alginate, and ultra-high molecular weight alginate.

[0395] 29. The polysaccharide polymer according to any one of Embodiments 21 or 24-28, wherein the alginate is a low molecular weight alginate.

[0396] 30. The polysaccharide polymer according to any one of Embodiments 21 or 24-29, wherein the alginate is a medium molecular weight alginate.

[0397] 31. The polysaccharide polymer according to any one of Embodiments 21 or 24-30, wherein the alginate is a high molecular weight alginate.

[0398] 32. The polysaccharide polymer according to Embodiment 21 or any of Embodiments 24-31, wherein the alginate is an ultra-high molecular weight alginate.

[0399] 33. The polysaccharide polymer according to any one of Embodiments 21 or 24-32, wherein the alginate is selected from low viscosity alginate, medium viscosity alginate, high viscosity alginate, and ultra-high viscosity alginate.

[0400] 34. The polysaccharide polymer according to any one of Embodiments 21 or 24-33, wherein the alginate is a low-viscosity alginate.

[0401] 35. The polysaccharide polymer according to any one of Embodiments 21 or 24-34, wherein the alginate is a medium-viscosity alginate.

[0402] 36. The polysaccharide polymer according to any one of Embodiments 21 or 24-35, wherein the alginate is a high-viscosity alginate.

[0403] 37. The polysaccharide polymer according to Embodiment 21 or any of Embodiments 24 to 36, wherein the alginate is an ultra-high viscosity alginate.

[0404] 38. The polysaccharide polymer according to any one of Embodiments 21 or 24-37, wherein the alginate has a purity of more than 90%, for example, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more than 99.9%, as determined by high-performance liquid chromatography.

[0405] 39. The polysaccharide polymer according to any one of Embodiments 21 or 24-38, wherein the alginate has a purity of more than 95%.

[0406] 40. The polysaccharide polymer according to any one of Embodiments 21 or 24-39, wherein the alginate has a purity of more than 98%.

[0407] 41. The polysaccharide polymer according to any one of Embodiments 21 or 24-40, wherein the alginate has a purity of more than 99%.

[0408] 42. The polysaccharide polymer according to Embodiment 21 or any of Embodiments 24-41, wherein the alginate has a purity of more than 99.5%.

[0409] 43. The polysaccharide polymer according to any one of Embodiments 21 or 24-42, wherein the alginate has an endotoxin level of less than 50 EU / g.

[0410] 44. The polysaccharide polymer according to Embodiment 21 or any of Embodiments 24 to 43, wherein the alginate has a total viable bacterial count (TVC) of less than 100 colony-forming units (CFU) per gram.

[0411] 45. The alginate is 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, Pronova UP LG 20, Pronova LG 100, and Pronova A polysaccharide polymer according to one embodiment 21 or any one of embodiments 24-44, selected from one of SLG100.

[0412] 46. ​​The polysaccharide polymer according to Embodiment 21 or any one of Embodiments 24-45, wherein the alginate is selected from one of 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.

[0413] 47. The polysaccharide polymer according to Embodiment 21 or any one of Embodiments 24-46, wherein the alginate is Pronova UP VLVG.

[0414] 48. The polysaccharide polymer according to Embodiment 21 or any one of Embodiments 24-46, wherein the alginate is Pronova SLG100.

[0415] 49. The polysaccharide polymer according to Embodiment 21 or any one of Embodiments 24 to 46, wherein the alginate is Pronova SLG20.

[0416] 50. The polysaccharide polymer according to Embodiment 21 or any one of Embodiments 24-46, wherein the alginate is Pronova LG20.

[0417] 51. The photoactive crosslinked portion has the structure of formula (IV): [ka] or having a pharmaceutically acceptable salt or tautomer thereof, in the formula, X 1 However, non-existence, O, NR 33 or C(R 34a )(R 34b ) and R 30a , R 30b , R 31 , R 32 , R 33 , R 34a and R 34bEach of these can independently be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, or -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 R A1 , R B1 , R C1 , R D1 and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl has 1 to 6 R 7 It is optionally replaced by, Each R 7 The polysaccharide polymer according to any one of Embodiments 1 to 50, wherein the polymer is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0418] 52. X 1 NR 33 The polysaccharide polymer according to Embodiment 51, which is (for example, NH).

[0419] 53. R 30a , R 30b , R 31 and R 32 A polysaccharide polymer according to any one of embodiments 51 to 52, wherein each of the atoms is hydrogen.

[0420] 54. X 1 NR 33 And R 30a , R 30b , R31 and R 33 Each of them is hydrogen, R 32 The polysaccharide polymer according to any one of embodiments 51 to 53, wherein is a heteroalkyl (for example, a nitrogen-containing heteroalkyl).

[0421] 55. X 1 NR 33 And R 30a , R 30b and R 33 Each of them is hydrogen, R 31 is alkyl, R 32 The polysaccharide polymer according to Embodiment 51, wherein is a heteroalkyl (for example, a nitrogen-containing heteroalkyl).

[0422] 56. X 1 NR 33 And R 30a , R 30b , R 33 Each of them is hydrogen, R 31 C1~C 12 It is alkyl, R 32 The polysaccharide polymer according to Embodiment 51, wherein is a 2- to 12-membered heteroalkyl (for example, a 2- to 12-membered ring nitrogen-containing heteroalkyl).

[0423] 57. X 1 O is R 30a , R 30b , R 31 and R 33 Each of them is hydrogen, R 32 The polysaccharide polymer according to Embodiment 48, wherein is a heteroalkyl (for example, a nitrogen-containing heteroalkyl).

[0424] 58. X 1 O is R 30a and R 30b Each of them is hydrogen, R 31 is alkyl, R 32 The polysaccharide polymer according to Embodiment 51, wherein is a heteroalkyl (for example, a nitrogen-containing heteroalkyl).

[0425] 59. X 1O is R 30a and R 30b Each of them is hydrogen, R 31 C1~C 12 It is alkyl, R 32 The polysaccharide polymer according to Embodiment 51, wherein is a 2- to 12-membered heteroalkyl (for example, a 2- to 12-membered nitrogen-containing heteroalkyl).

[0426] 60. X 1 is C(R 34a )(R 34b ) and R 30a , R 30b , R 31 , R 33 , R 34a and R 34b Each of them is hydrogen, R 32 The polysaccharide polymer according to Embodiment 51, wherein is a heteroalkyl (for example, a nitrogen-containing heteroalkyl).

[0427] 61. X 1 is C(R 34a )(R 34b ) and R 30a , R 30b , R 31 , R 33 , R 34a and R 34b Each of them is hydrogen, R 31 is alkyl, R 32 The polysaccharide polymer according to Embodiment 51, wherein is a heteroalkyl (for example, a nitrogen-containing heteroalkyl).

[0428] 62. X 1 is C(R 34a )(R 34b ) and R 30a , R 30b , R 31 , R 33 , R 34a and R 34b Each of them is hydrogen, R 31 C1~C 12 It is alkyl, R 32 The polysaccharide polymer according to Embodiment 51, wherein is a 2- to 12-membered heteroalkyl (for example, a 2- to 12-membered ring nitrogen-containing heteroalkyl).

[0429] 63. X 1 A polysaccharide polymer according to Embodiment 51, wherein the oxygen is not O.

[0430] 64. X 1 O is R 32 The polysaccharide polymer according to Embodiment 51, wherein the polysaccharide polymer is a 2, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered heteroalkyl group.

[0431] 65. X 1 NR 33 And R 32 The polysaccharide polymer according to Embodiment 51, wherein the polysaccharide polymer is a 2, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered heteroalkyl group.

[0432] 66. X 1 O is R 32 The polysaccharide polymer according to Embodiment 48, wherein the polysaccharide polymer is not a three-membered heteroalkyl group.

[0433] 67. The photoactive crosslinked portion is [ka] A polysaccharide polymer according to any of embodiments 48 to 66, selected from a pharmaceutically acceptable salt thereof.

[0434] 68. The photoactive crosslinked portion is [ka] A polysaccharide polymer according to any of embodiments 48 to 66, selected from a pharmaceutically acceptable salt thereof.

[0435] 69. The photoactive crosslinked portion is [ka] A polysaccharide polymer according to any of embodiments 48 to 66, selected from a pharmaceutically acceptable salt thereof.

[0436] 70. The photoactive crosslinked portion has the structure of formula (IV-a): [ka] or having a pharmaceutically acceptable salt or tautomer thereof, wherein the formula, R 30a , R 30b , R 31 , R 32 and R 35 Each of these can independently be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, or -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 R A1 , R B1 , R C1 , R D1 and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl has 1 to 6 R 7 It is optionally replaced by, Each R 7 The polysaccharide polymer according to any one of Embodiments 1 to 69, wherein the polymer is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0437] 71. R 30a , R 30b , R 31 , R 32 and R 35 The polysaccharide polymer according to Embodiment 70, wherein each of the atoms is hydrogen.

[0438] 72. R 30a , R 30b , R 31 and R 35 Each of them is hydrogen, R 32 The polysaccharide polymer according to embodiment 70 or 71, wherein is a heteroalkyl (e.g., nitrogen-containing heteroalkyl).

[0439] 73. R 30a , R 30b , R 31 and R 35 Each of them is hydrogen, R 32 The polysaccharide polymer according to any one of embodiments 70 to 72, wherein is a 2-4 member heteroalkyl (for example, a 2-4 member nitrogen-containing heteroalkyl).

[0440] 74. R 30a , R 30b and R 35 Each of them is hydrogen, R 31 The C1-C6 alkyl group is R 32 A polysaccharide polymer according to any one of embodiments 70 to 73, wherein is a 2-4 member heteroalkyl (for example, a 2-4 member nitrogen-containing heteroalkyl).

[0441] 75. The photoactive crosslinked portion is [ka] A polysaccharide polymer according to any one of embodiments 70 to 74, selected from a pharmaceutically acceptable salt thereof.

[0442] 76. The photoactive crosslinked portion has the structure of formula (IV-c): [ka] or having a pharmaceutically acceptable salt or tautomer thereof, wherein the formula, R 30a , R 30b and R 31 Each of these can independently be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, or -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, R 32 However, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR A1 , -C(O)R B1 , cycloalkyl, heterocyclyl, aryl or heteroaryl, Each R A1 , R B1 , R C1 , R D1 and R E1 However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl has 1 to 6 R 7 It is optionally replaced by, Each R 7 The polysaccharide polymer according to any one of Embodiments 1 to 69, wherein the polymer is independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.

[0443] 77. R 30a , R 30b , R 31 and R 32The polysaccharide polymer according to Embodiment 76, wherein each of the atoms is hydrogen.

[0444] 78. R 30a , R 30b and R 31 Each of them is hydrogen, R 32 The polysaccharide polymer according to Embodiment 76, wherein is a heteroalkyl (for example, a nitrogen-containing heteroalkyl).

[0445] 79. R 30a , R 30b and R 31 Each of them is hydrogen, R 32 The polysaccharide polymer according to Embodiment 76, wherein is a 2-4 member heteroalkyl (for example, a 2-4 member nitrogen-containing heteroalkyl).

[0446] 80. R 30a and R 30b Each of them is hydrogen, R 31 The C1-C6 alkyl group is R 32 The polysaccharide polymer according to any one of embodiments 76 to 79, wherein the polysaccharide polymer is a 2-4 member heteroalkyl (for example, a 2-4 member nitrogen-containing heteroalkyl).

[0447] 81. The polysaccharide polymer according to any one of Embodiments 1 to 70, wherein the photoactive crosslinked portion has a structure selected from Table 4, or a pharmaceutically acceptable salt thereof.

[0448] 82. The polysaccharide polymer according to any one of Embodiments 1 to 81, wherein the photoactive crosslinked portion is selected from acrylates, methacrylates, acrylamides, and methacrylamides, or the corresponding acid chlorides and their anhydrides.

[0449] 83. The polysaccharide polymer according to any one of Embodiments 1 to 82, wherein the photoactive crosslinked portion is an acrylate, or a corresponding acid chloride, and their anhydrides.

[0450] 84. The polysaccharide polymer according to any one of Embodiments 1 to 82, wherein the photoactive crosslinked portion is a methacrylate, or a corresponding acid chloride, and their anhydrides.

[0451] 85. The polysaccharide polymer according to any one of Embodiments 1 to 82, wherein the photoactive crosslinked portion is acrylamide, or the corresponding acid chloride, and their anhydrides.

[0452] 86. The polysaccharide polymer according to any one of Embodiments 1 to 82, wherein the photoactive crosslinked portion is a methacrylamide, or a corresponding acid chloride, and their anhydrides.

[0453] 87. The polysaccharide polymer according to any one of Embodiments 1 to 86, wherein the photoactive crosslinked portion is selected from compound 205, compound 217, or a pharmaceutically acceptable salt thereof.

[0454] 88. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (Ia).

[0455] 89. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (Ib).

[0456] 90. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (Ibi).

[0457] 91. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is a compound of formula (Ib-ii).

[0458] 92. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (Ic).

[0459] 93. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (Id).

[0460] 94. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (Ie).

[0461] 95. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (If).

[0462] 96. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (II).

[0463] 97. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (II-a).

[0464] 98. A polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (III).

[0465] 99. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (III-a).

[0466] 100. A polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (III-b).

[0467] 101. A polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (III-c).

[0468] 102. A polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is a compound of formula (III-d).

[0469] 103. A polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (III-e).

[0470] 104. A polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is a compound of formula (III-f).

[0471] 105. A polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (III-g).

[0472] 106. A polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (III-h).

[0473] 107. The polysaccharide polymer according to any one of Embodiments 1 to 87, wherein the compound of formula (I) is the compound of formula (III-i).

[0474] 108. A polysaccharide polymer according to any one of Embodiments 1 to 107, wherein the compound of formula (I) has a structure selected from Table 3, or a pharmaceutically acceptable salt thereof.

[0475] 109. The polysaccharide polymer according to any one of Embodiments 1 to 108, wherein the compound of formula (I) is selected from compound 100, compound 101, compound 110, compound 112, compound 113, compound 114, compound 122, and compound 123, or a pharmaceutically acceptable salt thereof.

[0476] 110. The polysaccharide polymer according to any one of Embodiments 1 to 109, wherein the compound of formula (I) is compound 101 or a pharmaceutically acceptable salt thereof.

[0477] 111. The polysaccharide polymer according to any one of Embodiments 1 to 109, wherein the compound of formula (I) is compound 111 or a pharmaceutically acceptable salt thereof.

[0478] 112. The polysaccharide polymer according to any one of Embodiments 1 to 111, wherein the polysaccharide polymer is an alginate, the photoactive crosslinked portion is selected from compound 205 and compound 217, or a pharmaceutically acceptable salt thereof, and the compound of formula (I) is compound 101, or a pharmaceutically acceptable salt thereof.

[0479] 113. The polysaccharide polymer according to any one of Embodiments 1 to 111, wherein the polysaccharide polymer is an alginate, the photoactive crosslinked portion is selected from compound 205 and compound 217, or a pharmaceutically acceptable salt thereof, and the compound of formula (I) is compound 111, or a pharmaceutically acceptable salt thereof.

[0480] 114. A composition comprising a polysaccharide polymer as described in any one of Embodiments 1 to 113.

[0481] 115. A hydrogel capsule comprising a polysaccharide polymer as described in any one of Embodiments 1 to 113.

[0482] 116. The hydrogel capsule according to Embodiment 115, wherein the hydrogel capsule comprises a single compartment containing the polysaccharide polymer (for example, the polysaccharide polymer described herein).

[0483] 117. The hydrogel capsule according to Embodiment 115, wherein the hydrogel capsule does not contain a single compartment containing the polysaccharide polymer.

[0484] 118. The hydrogel capsule according to Embodiment 115 or 117, wherein the hydrogel capsule comprises a plurality of compartments, one of which comprises the polysaccharide polymer (for example, the polysaccharide polymer described herein).

[0485] 119. The hydrogel capsule according to any one of Embodiments 115 or 117-118, wherein the hydrogel capsule comprises a plurality of compartments, and two or more of the compartments contain the polysaccharide polymer (for example, the polysaccharide polymer described herein).

[0486] 120. The hydrogel capsule according to any one of embodiments 115 to 119, wherein the hydrogel capsule includes an inner compartment and an outer compartment.

[0487] 121. The inner compartment comprises a first polysaccharide polymer including the photoactive crosslinked portion, A hydrogel capsule according to any one of embodiments 115 to 120, wherein the outer compartment contains a second polysaccharide polymer including the photoactive crosslinked portion.

[0488] 122. The inner compartment contains the first unmodified polysaccharide polymer, A hydrogel capsule according to any one of embodiments 115 to 121, wherein the outer compartment contains a second polysaccharide polymer including the photoactive crosslinked portion.

[0489] 123. The inner compartment contains a first polysaccharide polymer modified with a cell-binding substance, A hydrogel capsule according to any one of embodiments 115 to 122, wherein the outer compartment contains a second polysaccharide polymer including the photoactive crosslinked portion.

[0490] 124. Hydrogel capsule, (i) Compounds of formula (I): [ka] An inner compartment comprising a first polysaccharide polymer comprising 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(RC )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 bonding group (e.g., the bonding groups described herein) and one or more R 1 It is optionally replaced by; L 1 and L 3 Each of them is independently bonded, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is one or more R 2 It is optionally replaced by; L 2 is a combination; M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of these is one or more R 3 It is arbitrarily replaced by; P is one or more R 4 A heteroaryl that is arbitrarily substituted by; Z is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of these is one or more R 5 It is arbitrarily replaced by; Each R A , R B , R C , R D , R E , R F , and R GThese are 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 arbitrarily replaced with; or R C and R D These, together with the nitrogen atom to which they are bonded, form one or more R 6 It forms an arbitrarily substituted ring (e.g., a 5- to 7-membered ring); Each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 These are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, oxo, and -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 These are cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 It is optionally replaced by; Each R A1 , R B1 , RC1 , 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 arbitrarily 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, with an inner compartment. (ii) A hydrogel capsule comprising an outer compartment containing a second polysaccharide polymer including a photoactive crosslinked portion.

[0491] 125. Hydrogel capsule, (i) an inner compartment containing a first unmodified polysaccharide polymer, (ii) A hydrogel capsule comprising a photoactive crosslinked moiety and an outer compartment comprising a second polysaccharide polymer containing the compound of formula (I).

[0492] 126. Hydrogel capsule, (i) an inner compartment containing a first polysaccharide polymer modified with a cell-binding substance, (ii) A hydrogel capsule comprising a photoactive crosslinked moiety and an outer compartment comprising a second polysaccharide polymer containing the compound of formula (I).

[0493] 127. Hydrogel capsule, (i) an inner compartment containing a first polysaccharide polymer modified with a photoactive crosslinked moiety, (ii) an outer compartment comprising a second polysaccharide polymer containing a photoactive crosslinked portion, A hydrogel capsule in which both the inner and outer compartments contain the compound of formula (I).

[0494] 128. Hydrogel capsule, (i) an inner compartment comprising a blend (e.g., a mixture) of a first unmodified polysaccharide polymer and a second unmodified polysaccharide polymer, (ii) A hydrogel capsule comprising an outer compartment comprising a blend of a third polysaccharide polymer and a fourth polysaccharide polymer, wherein the third polysaccharide polymer comprises a compound of formula (I) and the fourth polysaccharide polymer comprises a photoactive crosslinked portion.

[0495] 129. Hydrogel capsule, (i) an inner compartment comprising a blend (e.g., a mixture) of a first polysaccharide polymer and a second polysaccharide polymer, wherein the first polysaccharide polymer comprises a compound of formula (I) and the second polysaccharide polymer comprises a photoactive crosslinked portion, (ii) A hydrogel capsule comprising an outer compartment comprising a blend of a third polysaccharide polymer and a fourth polysaccharide polymer, wherein the third polysaccharide polymer comprises a compound of formula (I) and the fourth polysaccharide polymer comprises a photoactive crosslinked portion.

[0496] 130. Hydrogel capsule, (i) an inner compartment containing at least one unmodified polysaccharide polymer, (ii) A hydrogel capsule comprising an outer compartment comprising a blend of a second polysaccharide polymer and a third polysaccharide polymer, wherein the second polysaccharide polymer comprises a compound of formula (I) and the third polysaccharide polymer comprises a photoactive crosslinked portion.

[0497] 131. A hydrogel capsule according to any one of Embodiments 115 to 130, wherein the polysaccharide polymer (for example, the first polysaccharide polymer, the second polysaccharide polymer, the third polysaccharide polymer, and / or the fourth polysaccharide polymer) is selected from alginate, hyaluronate, and chitosan.

[0498] 132. A hydrogel capsule according to any one of embodiments 115 to 131, wherein the polysaccharide polymer (for example, the first polysaccharide polymer, the second polysaccharide polymer, the third polysaccharide polymer, and / or the fourth polysaccharide polymer) is an alginate.

[0499] 133. A hydrogel capsule according to any one of embodiments 115 to 132, wherein the first polysaccharide polymer is an alginate.

[0500] 134. A hydrogel capsule according to any one of embodiments 115 to 133, wherein the second polysaccharide polymer is an alginate.

[0501] 135. A hydrogel capsule according to any one of embodiments 115 to 134, wherein the third polysaccharide polymer is an alginate.

[0502] 136. A hydrogel capsule according to any one of Embodiments 115 to 135, wherein the fourth polysaccharide polymer is an alginate.

[0503] 137. A hydrogel capsule according to any one of embodiments 132 to 136, wherein the alginate is high guluronic acid (G) alginate or high mannuronic acid (M) alginate.

[0504] 138. A hydrogel capsule according to any one of embodiments 132 to 137, wherein the alginate is high guluronic acid (G) alginate.

[0505] 139. A hydrogel capsule according to any one of embodiments 132 to 138, wherein the alginate is high mannuronic acid (M) alginate.

[0506] 140. A hydrogel capsule according to any one of Embodiments 132 to 138, wherein the alginate is not high mannuronic acid (M) alginate.

[0507] 141. A hydrogel capsule according to any one of Embodiments 132 to 140, wherein the alginate is selected from low molecular weight alginate, medium molecular weight alginate, high molecular weight alginate, and ultra-high molecular weight alginate.

[0508] 142. A hydrogel capsule according to any one of embodiments 132 to 141, wherein the alginate is a low molecular weight alginate.

[0509] 143. A hydrogel capsule according to any one of Embodiments 132 to 141, wherein the alginate is a medium molecular weight alginate.

[0510] 144. A hydrogel capsule according to any one of embodiments 132 to 141, wherein the alginate is a high molecular weight alginate.

[0511] 145. A hydrogel capsule according to any one of Embodiments 132 to 141, wherein the alginate is an ultra-high molecular weight alginate.

[0512] 146. A hydrogel capsule according to any one of Embodiments 132 to 145, wherein the alginate is selected from low viscosity alginate, medium viscosity alginate, high viscosity alginate, and ultra-high viscosity alginate.

[0513] 147. A hydrogel capsule according to any one of embodiments 132 to 146, wherein the alginate is a low-viscosity alginate.

[0514] 148. A hydrogel capsule according to any one of embodiments 132 to 146, wherein the alginate is a medium viscosity alginate.

[0515] 149. A hydrogel capsule according to any one of embodiments 132 to 146, wherein the alginate is a high-viscosity alginate.

[0516] 150. A hydrogel capsule according to any one of embodiments 132 to 146, wherein the alginate is an ultra-high viscosity alginate.

[0517] 151. A hydrogel capsule according to any one of Embodiments 132 to 150, wherein the alginate has a purity of over 90%, for example, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or over 99.9%, as determined by high-performance liquid chromatography.

[0518] 152. A hydrogel capsule according to any one of embodiments 132 to 151, wherein the alginate has a purity of more than 95%.

[0519] 153. A hydrogel capsule according to any one of Embodiments 132 to 152, wherein the alginate has a purity of more than 98%.

[0520] 154. A hydrogel capsule according to any one of embodiments 132 to 153, wherein the alginate has a purity of more than 99%.

[0521] 155. A hydrogel capsule according to any one of Embodiments 132 to 154, wherein the alginate has a purity of more than 99.5%.

[0522] 156. A hydrogel capsule according to any one of embodiments 132 to 155, wherein the alginate has an endotoxin level of less than 50 EU / g.

[0523] 157. A hydrogel capsule according to any one of Embodiments 132 to 156, wherein the alginate has a total viable bacterial count (TVC) of less than 100 colony-forming units (CFU) per gram.

[0524] 158. The alginate is 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 158. The hydrogel capsule according to any one of embodiments 132-157, selected from one of SLG100.

[0525] 159. A hydrogel capsule according to any one of embodiments 132 to 159, wherein the alginate is selected from one of 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.

[0526] 160. A hydrogel capsule according to any one of embodiments 132 to 159, wherein the alginate is Pronova UP VLVG.

[0527] 161. A hydrogel capsule according to any one of embodiments 132 to 159, wherein the alginate is Pronova SLG100.

[0528] 162. A hydrogel capsule according to any one of embodiments 132 to 159, wherein the alginate is Pronova SLG20.

[0529] 163. The photoactive crosslinked portion has the structure of formula (IV): [ka] or having a pharmaceutically acceptable salt or tautomer thereof, in the formula, X 1 However, non-existence, O, NR 33 or C(R 34a )(R 34b ) and R 30a , R 30b , R 31 , R 32 , R 33 , ...

Claims

1. It is a hydrogel capsule, (i) (a) Structure of formula (IV): 【Chemistry 1】 or a pharmaceutically acceptable salt or tautomer thereof [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; 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 alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl has 1 to 6 R as appropriate. ７ It has been replaced with; Each R ７ [These are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.] A photoactive crosslinked portion having, (b) Compound of formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof [In the formula, A is -N(R) appropriately linked to a bonding group. Ｃ ) - and; L １ and L ３ Each of them is independently bonded, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is optionally one or more R ２ It has been replaced with; L ２ is a combination; M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may optionally contain one or more R ３ It has been replaced with; P may include one or more R as appropriate. ４ It is a triazolyl or imidazolyl substituted with; Z is an alkyl, heteroalkyl, heterocyclyl, aryl, or heteroaryl, each of which may optionally contain one or more R ５ It has been replaced with; R Ｃ is hydrogen or alkyl; Each R ２ , R ３ , R ４ and R ５ These 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 ) (Caution 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 ) (Caution Ｄ１ ), -P(R Ｆ１ ) ｙ These are cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R ７ It has been replaced with; Each R Ａ１ , R Ｂ１ , R Ｃ１ , R Ｄ１ , R Ｅ１ , and R Ｆ１ Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally one or more R ７ It has been replaced with; 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. and alginates containing, (ii) Island cells and, The hydrogel capsule containing the above.

2. The aforementioned photoactive crosslinked portion is (a) Covalently bonded to the sugar monomer in the alginate, and optionally bonded to the carboxylate portion in the alginate; and / or (b) comprising alkyl, alkenyl, alkynyl, ester, ketone, amine or amide groups; and / or (c) When activated by light, and optionally when activated by ultraviolet light, it can react with the second photoactive crosslinking portion; and / or (d) Present on the alginate at a density of at least about 1%, optionally at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or higher, as determined by LC-UV assay; and / or (e) Present on the alginate at a density of 1% to 10%, optionally 1% to 8%, 1% to 6%, or 1% to 4%, as determined by LC-UV assay, A hydrogel capsule according to claim 1.

3. (a) The compounds of formula (I) are shown in the following table: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Having a structure selected from or a pharmaceutically acceptable salt thereof; and / or (b) The compound of formula (I) has the following structure: 【Transformation 3】 Alternatively, a compound of formula (I) may be selected from a pharmaceutically acceptable salt thereof, and the compound of formula (I) may have the following structure: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof; and / or (c) The photoactive crosslinked portion has the following structure: 【Transformation 5】 Alternatively, a compound of formula (I) may be selected from a pharmaceutically acceptable salt thereof, and the compound of formula (I) may have the following structure: 【Transformation 6】 or a pharmaceutically acceptable salt thereof A hydrogel capsule according to claim 1.

4. (a) The hydrogel capsule comprises a single compartment containing the alginate; or (b) The hydrogel capsule comprises a plurality of compartments, one of which comprises the alginate; or (c) The hydrogel capsule comprises an inner compartment and an outer compartment, The inner compartment may optionally contain the first alginate including the photoactive crosslinked portion. The outer compartment may optionally contain a second alginate including the photoactive crosslinked portion. A hydrogel capsule according to claim 1.

5. It is a hydrogel capsule, (i) Compounds of formula (I): 【Transformation 7】 [In the formula, A is -N(R) appropriately linked to a bonding group. Ｃ ) - and; L １ and L ３ Each of them is independently bonded, alkyl, or heteroalkyl, and each alkyl and heteroalkyl is optionally one or more R ２ It has been replaced with; L ２ is a combination; M is absent, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may optionally contain one or more R ３ It has been replaced with; P may include one or more R as appropriate. ４ It is a triazolyl or imidazolyl substituted with; Z is an alkyl, heteroalkyl, heterocyclyl, aryl, or heteroaryl, each of which may optionally contain one or more R ５ It has been replaced with; R Ｃ is hydrogen or alkyl; Each R ２ 、R ３ 、R ４ and R ５ 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 )(O)S ｘ R Ｅ１ , -S(O) ｘ N(R Ｃ１ )(R Ｄ１ ), -P(R Ｆ１ ｙ is cycloalkyl, heterocyclyl, aryl, heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R ７ ;​ Each R Ａ１ , R Ｂ１ , R Ｃ１ , R Ｄ１ , R Ｅ１ , and R Ｆ１ Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally one or more R ７ It has been replaced with; 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. An inner compartment containing a first alginate, or a pharmaceutically acceptable salt thereof, Structure of equation (iv): 【Transformation 8】 [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 of these can independently be 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 ) (Caution Ｄ１ ), -N(R Ｃ１ ) C(O)R Ｂ１ , -C(O)N(R Ｃ１ ), SR Ｅ１ , cycloalkyl, heterocyclyl, aryl or heteroaryl; 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 alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl has 1 to 6 R as appropriate. ７ It has been replaced with; Each R ７ [These are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl.] An outer compartment comprising a second alginate, which includes a photoactive crosslinked moiety having a pharmaceutically acceptable salt or tautomer thereof, (iii) Island cells and, The hydrogel capsule containing the above.

6. The hydrogel capsule according to claim 1, wherein the alginate is high guluronic acid (G) alginate or high mannuronic acid (M) alginate.

7. X １ However, NR ３３ And, as appropriate, X １ However, it is NH, and further R as appropriate ３０ａ , R ３０ｂ , R ３１ and R ３２ The hydrogel capsule according to claim 1, wherein each of the elements is hydrogen.

8. The aforementioned photoactive crosslinked portion has the structure of formula (IV-a): 【Chemistry 9】 [In the formula, R ３０ａ , R ３０ｂ , R ３１ , R ３２ and R ３５ Each of these can independently be 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 ) (Caution Ｄ１ ), -N(R Ｃ１ ) C(O)R Ｂ１ , -C(O)N(R Ｃ１ ), SR Ｅ１ , cycloalkyl, heterocyclyl, aryl or heteroaryl; Each R Ａ１ , R Ｂ１ , R Ｃ１ , R Ｄ１ and R Ｅ１ However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl appropriately has 1 to 6 R ７ It has been replaced with; Each R ７ However, they are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; R as appropriate ３０ａ , R ３０ｂ , R ３１ , R ３２ and R ３５ Each of them is hydrogen. or having a pharmaceutically acceptable salt or tautomer thereof; or The aforementioned photoactive crosslinked portion has the structure of formula (IV-c): 【Chemistry 10】 [In the formula, R ３０ａ , R ３０ｂ and R ３１ Each of these can independently be 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 ) (Caution Ｄ１ ), -N(R Ｃ１ ) C(O)R Ｂ１ , -C(O)N(R Ｃ１ ), SR Ｅ１ , cycloalkyl, heterocyclyl, aryl or heteroaryl; R ３２ However, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, -C(O)OR Ａ１ , -C(O)R Ｂ１ , cycloalkyl, heterocyclyl, aryl or heteroaryl; Each R Ａ１ , R Ｂ１ , R Ｃ１ , R Ｄ１ and R Ｅ１ However, independently, they are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl appropriately has 1 to 6 R ７ It has been replaced with; Each R ７ However, they are independently alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, oxo, hydroxyl, cycloalkyl, or heterocyclyl; R as appropriate ３０ａ , R ３０ｂ , R ３１ and R ３２ Each of them is hydrogen. or having a pharmaceutically acceptable salt or tautomer thereof, A hydrogel capsule according to claim 1.

9. (a) The photoactive crosslinked portion is as shown in the following table: Table 8 Table 9 Having a structure selected from or a pharmaceutically acceptable salt thereof; and / or (b) The photoactive crosslinked portion is selected from acrylates, methacrylates, acrylamides, and methacrylamides, or their corresponding acid chlorides and anhydrides; and / or (c) The photoactive crosslinked portion has the following structure: 【Chemistry 11】 or selected from a pharmaceutically acceptable salt thereof, A hydrogel capsule according to claim 1.

10. (a) The compound of formula (I) is as shown in the following table: Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Having a structure selected from or a pharmaceutically acceptable salt thereof; and / or (b) The compound of formula (I) has the following structure: 【Chemistry 12】 Alternatively, a compound of formula (I) may be selected from a pharmaceutically acceptable salt thereof, and the compound of formula (I) may be as follows: 【Chemistry 13】 or a pharmaceutically acceptable salt thereof The hydrogel capsule according to claim 5.

11. (a) The hydrogel capsule encapsulates the island cells, the island cells optionally produce a therapeutic agent, and optionally the therapeutic agent is insulin; and / or (b) The hydrogel capsule is formulated for implantation into a target, and the hydrogel capsule is formulated for implantation within the IP space of the target, The hydrogel capsule according to claim 5.

12. A composition comprising a hydrogel capsule according to any one of claims 1 to 11.

13. A method for producing a hydrogel capsule containing alginate according to any one of claims 1 to 11.

14. A method for improving the stability of a hydrogel capsule containing multiple alginates, the method comprising providing means for both ionically crosslinking the alginates and covalently crosslinking the alginates, (a) The means for ion crosslinking the alginate as appropriate includes the use of divalent cations; and / or (b) A method wherein the means for covalently crosslinking the alginate optionally includes the use of a photoactive crosslinked portion, wherein the photoactive crosslinked portion optionally includes a vinyl crosslinked linker, wherein the vinyl crosslinked linker optionally is a methacrylate, a methacrylamide, or a pharmaceutically acceptable salt thereof.

15. A composition for use in the treatment of a subject having a disease, disorder or condition, comprising a hydrogel capsule according to any one of claims 1 to 11, (a) The disease, disorder or condition is, as appropriate, diabetes mellitus, and the disease, disorder or condition is, as appropriate, type 1 diabetes mellitus; and / or (b) A composition in which the subject is, as appropriate, a human.

Images