Modified polymer and use thereof

Abstract

The present disclosure relates to a modified polymer and a use thereof. Specifically, the present disclosure provides a modified monomer as shown in formula I, a polymer containing same, a hydrogel, a capsule, and a corresponding use. An alginate of the present disclosure is used for cell encapsulation, and can provide an anti-fibrotic effect and reduce foreign body reaction.

Description

A modified polymer and its uses Technical Field

[0001] This disclosure relates to a modified polymer and its use in cell encapsulation to reduce foreign body reactions. Background Technology

[0002] After biomaterials are implanted in the human body, they trigger a series of cellular and cytokine-related responses known as foreign body response (FBR). During the progression of FBR, macrophages regulate inflammation and healing by polarizing into pro-inflammatory or pro-healing phenotypes and recruit fibroblasts by secreting cytokines. Stimulation by the biomaterial eventually leads to the formation of fibrotic capsules. The implant and its newly formed capsules introduce various mechanosensory signals that influence cellular function. Mechanosensory proteins, such as integrins or ion channels, convert extracellular mechanosensory signals into cytoplasmic biochemical signals in response to mechanostimulation. Therefore, cell morphology, migration patterns, function, and polarization states are affected. Under the regulation of different intracellular signaling pathways and their crosstalk, the expression of fibrosis genes increases with fibroblast activation and the transformation of fibroblasts into myofibroblasts under rigid or external stimuli.

[0003] Currently, various materials are widely used in cell encapsulation research, such as inorganic nanoparticles, metal-organic frameworks, and hydrogels. In comparison, hydrogels are hydrophilic networks composed of cross-linked polymer chains, with a water content of approximately 90% and stiffness similar to the cell matrix. Encapsulating cells with hydrogels provides a physical microenvironment similar to the cell matrix, and can be modified through biological, chemical, or physical methods to achieve additional functions or provide a more balanced biochemical environment. Furthermore, hydrogels can protect encapsulated cells from immune rejection, while their porous framework allows for the diffusion of oxygen, nutrients, secretions, and metabolic waste, enabling cells to survive and perform their functions.

[0004] However, alginates induce a fibrosis reaction, which worsens with encapsulation of cells or xenogeneic donor tissue. Fibrosis on the alginate surface blocks the diffusion of nutrients and oxygen to the encapsulated cells, leading to cell necrosis. Therefore, there is a need in the art for polymeric materials that do not induce fibrosis and promote the health of the encapsulated cells or tissues. Summary of the Invention

[0005] The modified monomers disclosed herein, polymers containing them, hydrogels, and capsules can be used to encapsulate cells, exert anti-fibrotic effects, and reduce foreign body reactions.

[0006] This disclosure provides a modified monomer as shown in Formula I.

[0007] Where A is selected from units containing sugar;

[0008] R 1 R 2 Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, alkyl, or alkoxy, wherein the alkyl or alkoxy group is optionally converted by one or more R groups. 1a Replaced;

[0009] R 1a Each is independently selected from halogen, oxo, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, optionally substituted with one or more halogens, hydroxyl groups, amino groups, oxo groups, cyano groups, or C groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0010] X is selected from -O-, -S-, or -NR. 3 -;

[0011] R 3 Selected from hydrogen or C 1-4 Alkyl, the C 1-4 The alkyl group may be optionally divided by one or more halogens, oxo groups, hydroxyl groups, amino groups, cyano groups, or C groups. 1-6 Alkyl groups are substituted;

[0012] L1 and L3 are each independently selected from C 1-30 Alkylene, C 1-30 Heteroalkyl or The C 1-30 Alkylene, C 1-30 Heteroalkyl groups are optionally substituted with one or more R L Replaced;

[0013] R L Each is independently selected from halogen, oxo, hydroxyl, amino, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy;

[0014] R a R b R c and R d Each is independently selected from hydrogen, halogen, oxo, hydroxyl, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy;

[0015] M is selected from 3-8-membered cycloalkylene, 3-8-membered heterocycloalkylene, 6-10-membered arylene, or 5-10-membered heteroarylene, wherein the 3-8-membered cycloalkylene, 3-8-membered heterocycloalkylene, 6-10-membered arylene, and 5-10-membered heteroarylene are optionally converted by one or more halogens, oxo groups, hydroxyl groups, amino groups, cyano groups, or C groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituted with haloalkoxy groups;

[0016] m1 and m2 are each independently selected from integers between 0 and 30;

[0017] L2 is selected from

[0018] n1, n2, n3, n4, n5, n6, n7, n8 and n9 are each independently selected from integers between 0 and 6 (e.g., 0, 1, 2, 3, 4, 5 or 6);

[0019] p is selected from 2, 3, or 4.

[0020] In some embodiments, in the modifying monomers represented by Formula I, A is selected from units containing monosaccharides, units containing disaccharides, or units containing oligosaccharides.

[0021] In some embodiments, in the modified monomers represented by Formula I, A is selected from the group consisting of monosaccharides such as substituted or unsubstituted hexoses, hexuloses, hexuronic acids, pentoses, pentuloses, and penturonic acids.

[0022] In some embodiments, in the modifying monomer shown in Formula I, A is selected from units containing mannuronic acid and units containing guluronic acid.

[0023] In some implementations, A in the modified monomer shown in Formula I is The a-terminus is connected to X; Y1 and Y2 are each independently hydrogen or -PO (OR) 6 )2;R 6 It is hydrogen or C 1-6 alkyl.

[0024] In some implementations, A in the modified monomer shown in Formula I is End a is connected to X.

[0025] In some implementations, A in the modified monomer shown in Formula I is The a-terminus is connected to X; Y1 and Y2 are each independently hydrogen or -PO (OR) 6 )2;R 6 It is hydrogen or C 1-6 alkyl.

[0026] In some implementations, A in the modified monomer shown in Formula I is End a is connected to X.

[0027] In some implementations, A in the modified monomer shown in Formula I is End a is connected to X.

[0028] In some embodiments, the modifying monomer shown in Formula I is the modifying monomer shown in Formula II.

[0029] Among them, X, L1, L2, L3, R 1 R 2 And p is defined as in any scheme of Equation I; Y1 and Y2 are each independently selected from hydrogen or -PO (OR 6 )2;R 6 Selected from hydrogen or C 1-6 alkyl.

[0030] In some embodiments, Y1 and Y2 in the modified monomers shown in Formula II are hydrogen.

[0031] In some embodiments, the modifying monomer represented by Formula II is the modifying monomer represented by Formula II-1.

[0032] Y1, Y2, X, L1, L2, L3, R 1 R 2 And p is defined as in any scheme of Equation II.

[0033] In some embodiments, X is -NR in the modified monomers represented by Formula I, II, or II-1. 3 -

[0034] In some embodiments, X is -NH- in the modified monomers represented by Formula I, II, or II-1.

[0035] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 1 Selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 1a Replaced by, R 1a As defined in Equation I.

[0036] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 1It is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0037] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 1 It is hydrogen.

[0038] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 2 Selected from hydrogen or C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R 1a Replaced by, R 1a As defined in Equation I.

[0039] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 2 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R 1a Replaced by, R 1a As defined in Equation I.

[0040] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 2 The group is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl group is optionally mixed with one or more R groups. 1a Replaced by, R 1a As defined in Equation I.

[0041] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 2 The group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl group is optionally mixed with one or more R groups. 1a Replaced by, R 1a As defined in Equation I.

[0042] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 2 Selected from methyl, said methyl group optionally being converted by one or more R 1a Replaced by, R 1a As defined in Equation I.

[0043] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 1aSelected from 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, wherein the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally converted by one or more halogens, oxo groups, hydroxyl groups, amino groups, cyano groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituted with haloalkoxy groups.

[0044] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 1a Selected from 3-8 membered heterocyclic alkyl groups, wherein the 3-8 membered heterocyclic alkyl group is optionally converted by one or more halogens, oxo groups, hydroxyl groups, amino groups, cyano groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituted with haloalkoxy groups.

[0045] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 1a Selected from 3-8 membered heterocyclic alkyl groups containing one or two N, O, or S atoms, wherein the 3-8 membered heterocyclic alkyl group is optionally prefixed with one or more halogens, oxo groups, hydroxyl groups, amino groups, cyano groups, or C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituted with haloalkoxy groups.

[0046] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 1a Selected from one or more halogens, oxo, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups substituted

[0047] In some embodiments, in the modified monomers represented by Formula I, II, or II-1, R 1a Selected from

[0048] In some embodiments, the modifying monomer shown in Formula I is the modifying monomer shown in Formula III.

[0049] Among them, A, X, L1, L2, L3, R 1 p is defined as in any of the schemes in Equation I; R 2a and R 2b Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6Alkyl or C 1-6 Alkoxy group; r is an integer selected from 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6).

[0050] In some implementations, in the modified monomer shown in Formula III, R 2a and R 2b It is hydrogen.

[0051] In some implementations, r is 1 in the modified monomer shown in Formula III.

[0052] In some embodiments, the modifying monomer shown in Formula I is the modifying monomer shown in Formula IV.

[0053] Among them, X, L1, L2, L3, R 1 And p is defined as in any scheme of Equation I; Y1 and Y2 are each independently hydrogen or -PO (OR) 6 )2;R 6 It is hydrogen or C 1-6 Alkyl; R 2a and R 2b Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy group; r is an integer between 1 and 6.

[0054] In some implementations, Y1 and Y2 in the modified monomers shown in Formula IV are hydrogen.

[0055] In some implementations, in the modified monomer shown in Formula IV, R 2a and R 2b It is hydrogen.

[0056] In some implementations, r is 1 in the modified monomer shown in Formula IV.

[0057] In some embodiments, the modifying monomer shown in Formula IV is the modifying monomer shown in Formula IV-1.

[0058] Among them, Y1, Y2, X, L1, L2, L3, R 1 R 2a R 2b p and r are defined as in any of the schemes in Equation IV.

[0059] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from C 1-30 Alkylene or C 1-30 Heteroalkyl groups.

[0060] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from C 1-30 Alkylene, -(CH2CH2O) m3 -、-(OCH2CH2) m4 -,-alkylene-(OCH2CH2) m5 -, the C 1-30 Alkylene, -(CH2CH2O) m3 -、-(OCH2CH2) m4 -,-alkylene-(OCH2CH2) m5 -Optionally controlled by one or more R L Replaced by, R L As defined in Equation I, m3, m4 and m5 are each independently selected from integers between 1 and 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15), and are connected to X on the left.

[0061] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from C 1-30 Alkylene, the C 1-30 Alkylenes are optionally subjected to one or more R L Replaced by, R L As defined in Equation I.

[0062] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from C 1-10 Alkylene, the C 1-10 Alkylenes are optionally subjected to one or more R L Replaced by, R L As defined in Equation I.

[0063] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylenes are optionally subjected to one or more R L Replaced by, R L As defined in Formula I. In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from C 1-30 Heteroalkyl groups.

[0064] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from C having 1 to 5 heteroatoms selected from N, O, or S. 1-30 Heteroalkyl groups, which are optionally subjected to one or more RL Replaced by, R L As defined in Equation I.

[0065] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from C having 1 to 5 heteroatoms selected from N, O, or S. 1-10 Heteroalkyl groups, which are optionally subjected to one or more R L Replaced by, R L As defined in Equation I.

[0066] In some embodiments, in the modified monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from -(CH2CH2O). m3 -、-(OCH2CH2) m4 -,-alkylene-(OCH2CH2) m5 -, the -(CH2CH2O) m3 -、-(OCH2CH2) m4 -,-alkylene-(OCH2CH2) m5 -Optionally controlled by one or more R L Replaced by, R L As defined in Equation I, m3, m4, and m5 are each independently selected from integers between 1 and 15, and are connected to X on the left.

[0067] In some embodiments, in the modified monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from -(CH2CH2O). m3 -、-(OCH2CH2) m4 -,-alkylene-(OCH2CH2) m5 -, m3, m4 and m5 are each independently selected from integers between 1 and 15, and are connected to X on the left.

[0068] In some embodiments, in the modified monomers shown in Formula I, II, II-1, III, IV, or IV-1, L1 is selected from -(CH2CH2O). m3 -、-(OCH2CH2) m4 -,-alkylene-(OCH2CH2) m5 -, m3, m4 and m5 are each independently selected from integers between 1 and 6 (e.g., 1, 2, 3, 4, 5, 6), and are connected to X on the left.

[0069] In some embodiments, in the modified monomers shown in Formula I, II, II-1, III, IV or IV-1, L1 is selected from -(CH2)2-(OCH2CH2)-, -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, -(CH2CH2O)-, -(CH2CH2O)2- or -(CH2CH2O)3-, and is connected to X on the left side.

[0070] In some embodiments, L1 in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1 is selected from...

[0071] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from C 1-30 Alkylene or C 1-30 Heteroalkyl groups.

[0072] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from C 1-30 Alkylene, -(CH2CH2O) m6 -、-(OCH2CH2) m7 -,-alkylene-(OCH2CH2) m8 -, the C 1-30 Alkylene, -(CH2CH2O) m6 -、-(OCH2CH2) m7 -,-alkylene-(OCH2CH2) m8 -Optionally controlled by one or more R L Replaced by, R L As defined in Equation I, m6, m7 and m8 are each independently selected from integers between 1 and 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15), and are connected to L2 on the left.

[0073] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from C 1-30 Alkylene, the C 1-30 Alkylenes are optionally subjected to one or more R L Replaced by, R L As defined in Equation I.

[0074] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from C 1-10 Alkylene, the C 1-10 Alkylenes are optionally subjected to one or more R LReplaced by, R L As defined in Equation I.

[0075] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from C 1-6 Alkylene, the C 1-6 Alkylenes are optionally subjected to one or more R L Replaced by, R L As defined in Equation I.

[0076] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from C 1-30 Heteroalkyl groups.

[0077] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from C having 1 to 5 heteroatoms selected from N, O, or S. 1-30 Heteroalkyl groups, which are optionally subjected to one or more R L Replaced by, R L As defined in Equation I.

[0078] In some embodiments, in the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from C having 1 to 5 heteroatoms selected from N, O, or S. 1-10 Heteroalkyl groups, which are optionally subjected to one or more R L Replaced by, R L As defined in Equation I.

[0079] In some embodiments, in the modified monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from -(CH2CH2O). m6 -、-(OCH2CH2) m7 -,-alkylene-(OCH2CH2) m8 -, the C 1-30 Alkylene, -(CH2CH2O) m6 -、-(OCH2CH2) m7 -,-alkylene-(OCH2CH2) m8 -Optionally controlled by one or more R L Replaced by, R L As defined in Equation I, m6, m7 and m8 are each independently selected from integers between 1 and 15, and are connected to L2 on the left.

[0080] In some embodiments, in the modified monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from -(CH2CH2O). m6-、-(OCH2CH2) m7 -,-alkylene-(OCH2CH2) m8 -, m6, m7 and m8 are each independently selected from integers between 1 and 15, and are connected to L2 on the left.

[0081] In some embodiments, in the modified monomers shown in Formula I, II, II-1, III, IV, or IV-1, L3 is selected from -(CH2CH2O). m6 -、-(OCH2CH2) m7 -,-alkylene-(OCH2CH2) m8 - m6, m7, and m8 are each independently selected from integers between 1 and 6 (e.g., 1, 2, 3, 4, 5, 6). In some implementations, L3 is selected from -(OCH2CH2)-, -(OCH2CH2)2-, -(OCH2CH2)3-, -(CH2)2-(OCH2CH2)-, -(CH2)2-(OCH2CH2)2-, or -(CH2)2-(OCH2CH2)3-, and is connected to L2 on the left.

[0082] In some embodiments, L3 is selected from the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1.

[0083] In some embodiments, L2 is selected from the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1. The b end is connected to L1.

[0084] In some embodiments, L2 is selected from the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1.

[0085] In some embodiments, L2 is selected from the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1. The b end is connected to L1.

[0086] In some embodiments, L2 is selected from the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1. The b end is connected to L1.

[0087] In some embodiments, L2 is selected from the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1.

[0088] In some embodiments, L2 is selected from the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1. The b end is connected to L1.

[0089] In some embodiments, L2 is selected from the modifying monomers shown in Formula I, II, II-1, III, IV, or IV-1.

[0090] In some embodiments, the modifying monomer shown in Formula I is the modifying monomer shown in Formula V, Formula VI, or Formula VII.

[0091] Among them, X, L1, L3, R 1 As defined by any scheme in Equation I;

[0092] Y1 and Y2 are each independently selected from hydrogen or -PO (OR) 6 )2;R 6 Selected from hydrogen or C 1-6 alkyl;

[0093] R 2a and R 2b Each is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy group; r is an integer between 1 and 6.

[0094] In some embodiments, Y1 and Y2 are hydrogen in the modified monomers shown in Formula V, Formula VI or Formula VII.

[0095] In some embodiments, in the modifying monomers shown in Formula V, Formula VI, or Formula VII, R 2a and R 2b It is hydrogen.

[0096] In some implementations, r is 1 in the modifying monomers shown in Formula V, Formula VI, or Formula VII.

[0097] In some embodiments, the modifying monomer shown in Formula I is the modifying monomer shown in Formula VIII.

[0098] L2 is selected from Terminal b is connected to L1;

[0099] X, L1, L3, R 1 As defined in Equation I;

[0100] Y1 and Y2 are each independently selected from hydrogen or -PO (OR) 6 )2;R 6 Selected from hydrogen or C 1-6 alkyl;

[0101] R 2a and R 2bEach is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy group; r is an integer between 1 and 6.

[0102] In some embodiments, Y1 and Y2 in the modified monomers shown in Formula VIII are hydrogen.

[0103] In some implementations, in the modified monomer shown in Formula VIII, R 2a and R 2b It is hydrogen.

[0104] In some implementations, r is 1 in the modified monomer shown in Formula VIII.

[0105] In some embodiments, the modifying monomer shown in Formula V is the modifying monomer shown in Formula V-1.

[0106] Among them, Y1, Y2, X, L1, L3, R 1 R 2a R 2b And r is defined as in any scheme of equation V.

[0107] In some embodiments, the modifying monomer shown in Formula VI is the modifying monomer shown in Formula VI-1.

[0108] Among them, Y1, Y2, X, L1, L3, R1, R 2a R 2b And r is defined as in any scheme of equation VI.

[0109] In some embodiments, the modifying monomer shown in Formula VII is the modifying monomer shown in Formula VII-1.

[0110] Among them, Y1, Y2, X, L1, L3, R 1 R 2a R 2b And r is defined as in any of the schemes in equation VII.

[0111] In some embodiments, the modifying monomer shown in Formula VIII is the modifying monomer shown in Formula VIII-1.

[0112] L2 is selected from Terminal b is connected to L1; Y1, Y2, X, L1, L3, R 1 R 2a R 2b And r is defined as in any scheme of equation VIII.

[0113] In some embodiments, the modified monomers shown in Formula I, II, II-1, III, IV, or IV-1 contain -L1-L2-(L3-) p For any of the following structures, the c-end is connected to the X-end.

[0114] In some implementations, the modifying monomer is any of the following structures:

[0115] A is The a-terminus is connected to -NH-.

[0116] In some implementations, the modified monomer has the following structure:

[0117] A is The a-terminus is connected to -NH-.

[0118] This disclosure provides a polymer comprising the above-described modified monomers.

[0119] In some embodiments, at least 0.5% (e.g., 0.5%, 1%, 2.5%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, and any value between thereon) of the polymer, by molar percentage, are the aforementioned modifying monomers. In some embodiments, 0.5%-50%, 10%-90%, 10%-50%, or 25%-75% of the polymer, by molar percentage, are the aforementioned modifying monomers. In some embodiments, 5%-50% of the polymer, by molar percentage, are the aforementioned modifying monomers. In some embodiments, 10%-30% of the polymer, by molar percentage, are the aforementioned modifying monomers.

[0120] In some embodiments, the polymer uses Ca 2+ Ba 2+ or Sr 2+ Crosslinking is performed to form a hydrogel. In some embodiments, the polymer uses Ca... 2+ Cross-linking is performed to form a hydrogel.

[0121] In some embodiments, the polymer is a polymer of alginate or a salt thereof, the alginate or salt thereof being a polysaccharide composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G). In some embodiments, the alginate or salt thereof is homoguluronic acid (G) alginate or a salt thereof, and contains greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of guluronic acid (G). In some embodiments, the alginate or salt thereof is homomannuronic acid (M) alginate or a salt thereof, and contains greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of mannouronic acid (M). In some embodiments, the G:M ratio is about 1.5. In some embodiments, the G:M ratio is less than 1.5. In some embodiments, the G:M ratio is greater than or equal to 1.5.

[0122] In some implementation schemes, the compound (X, L1, L2, L3, R) 1 R 2 The conjugated density of p (as defined in any of the schemes of Formula I) is 2.0%-12.0% N. The conjugated density is the density of the polymer containing the aforementioned modified monomers, present in the chemically modified polymer (e.g., a polymer of alginate or its salts) with a conjugated density of at least 2.0% and less than 12.0% nitrogen (N) (e.g., 3.0% to 11.0%, 4.0% to 10.0%, 5.0% to 9.0%, or 7.0% to 9.0%) as determined by combustion analysis for nitrogen percentage. In some embodiments, the compound... The conjugate density is approximately 7.3% N.

[0123] This disclosure provides a polymer of formula IX,

[0124] Where B is

[0125] A, X, L1, L2, L3, R 1 R 2 p is defined as any scheme in Equation I;

[0126] k1 is selected from integers greater than or equal to 1;

[0127] k2 is independently selected from 0 or 1, and at least one k2 is 1.

[0128] In some embodiments, in the polymer represented by Formula IX, B is... X, L1, L2, L3, R 1 R 2a R 2b And p is defined as in any scheme of Equation III.

[0129] In some embodiments, in the polymer represented by Formula IX, k1 is selected from any integer from 5 to 10000. In some embodiments, k1 is selected from any integer from 10 to 5000. In some embodiments, in the polymer represented by Formula IX, k1 is selected from any integer from 10 to 500. In some embodiments, in the polymer represented by Formula IX, k1 is selected from any integer from 500 to 1000. In some embodiments, in the polymer represented by Formula IX, k1 is selected from any integer from 1000 to 5000.

[0130] In some embodiments, the number or quantity of "k2 = 1" is Q, where Q is at least 1. In some embodiments, Q represents at least 0.5% of k1 (e.g., 0.5%, 1%, 2.5%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, and any value between these values). In some embodiments, Q represents 0.5%-50%, 10%-90%, 10%-50%, or 25%-75% of k1. In some embodiments, Q represents 5%-50% of k1. In some embodiments, Q represents 10%-30% of k1.

[0131] This disclosure provides a hydrogel comprising the polymer described above.

[0132] In some embodiments, the polymer uses Ca 2+ Ba 2+ or Sr 2+ Crosslinking is performed to form a hydrogel. In some embodiments, the polymer uses Ca... 2+ Cross-linking is performed to form a hydrogel.

[0133] This disclosure also provides a capsule comprising the above-described hydrogel.

[0134] In some embodiments, the hydrogel encapsulates the therapeutic agent.

[0135] In some embodiments, the therapeutic agent is a cell. In some embodiments, the cell includes xenogeneic tissues or cells, heterologous tissues or cells, tissues or cells from cadavers, stem cells, stem cell-derived cells, cells from cell lines, primary cells, reprogrammed cells, reprogrammed stem cells, cells derived from reprogrammed stem cells, genetically engineered cells, or combinations thereof. In some embodiments, the cell is a human cell. In some embodiments, the cell is an insulin-producing cell. In some embodiments, the cell is an islet cell. In some embodiments, the cell includes, but is not limited to, embryonic stem cells, mesenchymal stem cells, and pancreatic β cells. In some embodiments, the cell is an islet β cell.

[0136] In some embodiments, the hydrogel encapsulates a single cell or multiple cells within the capsule.

[0137] In some embodiments, the capsule is spherical. In some embodiments, the average diameter of the capsule is 0.01 mm to 10 mm (e.g., any value between 0.01 mm, 0.05 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm, 5.5 mm, 6.0 mm, 6.5 mm, 7.0 mm, 7.5 mm, 8.0 mm, 8.5 mm, 9.0 mm, 9.5 mm, 10.0 mm). In some embodiments, the average diameter of the capsule is 0.1 mm to 10 mm. In some embodiments, the average diameter of the capsule is 1 mm to 8 mm. In some embodiments, the average diameter of the capsule is 1 mm to 5 mm. In some embodiments, the average diameter of the capsule is 1 mm to 3 mm. In some embodiments, the average diameter of the capsule is 1 mm to 2 mm. In some embodiments, the average diameter of the capsule is approximately 2 mm. In some embodiments, the average diameter of the capsule is approximately 1.5 mm.

[0138] In some embodiments, in capsules containing alginate or its salts, the amount of alginate or its salts (e.g., based on the actual weight of the alginate as a percentage of the capsule's weight) may be at least 5%, for example, at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, for example, w / w; less than 20%, for example, less than 20%, 15%, 10%, 5%, 1%, 0.5%, 0.1% or less.

[0139] This disclosure also provides a pharmaceutical composition comprising the modified monomer as shown in Formula I, the polymer or hydrogel described above, and one or more pharmaceutically acceptable excipients.

[0140] This disclosure also provides a pharmaceutical composition comprising the capsules described above and one or more pharmaceutically acceptable excipients.

[0141] In some embodiments, the capsule (e.g., the therapeutic agent therein) may be a therapeutically effective amount.

[0142] In some embodiments, the unit dose of the pharmaceutical composition may be 0.001 mg to 1000 mg.

[0143] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned capsules based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned capsules. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the capsules. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned capsules. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned capsules.

[0144] This disclosure further provides the use of the above-described modified monomer as shown in Formula I, the above-described polymer, the above-described hydrogel, the above-described capsule, or the above-described pharmaceutical composition in the preparation of a medicament for treating diseases, including but not limited to diabetes, hemophilia, skin lesions, spinal cord injuries, heart injuries, and osteoarthritis.

[0145] In some implementations, the disease is diabetes.

[0146] This disclosure also provides a method of treating a disease, comprising administering the above-described capsule or pharmaceutical composition to a subject. In some embodiments, the disease includes, but is not limited to, diabetes, hemophilia, skin lesions, spinal cord injuries, heart injuries, and osteoarthritis. In some embodiments, the disease is diabetes.

[0147] This disclosure also provides a method of treating a disease, comprising implanting the above-described capsule or pharmaceutical composition into a subject. In some embodiments, the disease includes, but is not limited to, diabetes, hemophilia, skin lesions, spinal cord injuries, heart injuries, and osteoarthritis. In some embodiments, the disease is diabetes.

[0148] This disclosure also provides a method for delivering a therapeutic agent to a subject, comprising administering the above-described capsule or pharmaceutical composition to the subject.

[0149] This disclosure also provides an apparatus comprising the capsule or the pharmaceutical composition described above.

[0150] This disclosure also provides a package comprising the capsules or the pharmaceutical composition described above.

[0151] This disclosure also provides an apparatus comprising the capsule or the pharmaceutical composition described above.

[0152] This disclosure also provides a compound of formula X or a salt thereof.

[0153] Where Z represents halogen, -OR 7 or -NR 8 R 9 ;

[0154] R 7 It is hydrogen or a protecting group;

[0155] R 8 and R 9 Each is independently hydrogen or alkyl;

[0156] L1, L2, L3, R 1 R 2 And p is defined as in any scheme of Equation I.

[0157] In some implementation schemes, R 7 In this context, the protecting group is a commonly used protecting group in the art, including but not limited to: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), benzyl (Bn), p-methoxybenzyl (PMB), triphenylmethyl (Tr, DMT), methyl (Me), tert-butyl (t-Bu), methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), 2-tetrahydropyranyl (THP), p-toluenesulfonyl (Ts), methanesulfonyl (Ms), nitrobenzenesulfonyl (Ns), trifluoromethanesulfonyl (Tf), etc.

[0158] In some embodiments, in the compound of formula X or a salt thereof, R 8 and R 9 Each is independently hydrogen or C 1-10 alkyl.

[0159] In some embodiments, in the compound of formula X or a salt thereof, R 8 and R 9 Each is independently hydrogen or C 1-6 alkyl.

[0160] In some embodiments, in the compound of formula X or a salt thereof, R8 and R 9 Each can be independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0161] In some embodiments, in the compound of formula X or a salt thereof, R 7 It can be hydrogen, benzyl (Bn) or p-toluenesulfonyl (Ts).

[0162] In some embodiments, in the compound of formula X or a salt thereof, R 8 and R 9 It is hydrogen.

[0163] In some embodiments, the compound represented by formula X has any of the following structures:

[0164] This disclosure provides a method for preparing the aforementioned polymer, comprising reacting alginate or its salt with... Or the step of linking the compound or its salt as shown in formula X, X, L1, L2, L3, R 1 R 2 And p is defined as in any scheme of Equation I.

[0165] Terminology Definition

[0166] Where no specific configuration is defined in this disclosure, the compounds disclosed herein may exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, rotationally hindered isomers (i.e., rotationally hindered stereoisomers), and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0167] Furthermore, the compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization.

[0168] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0169] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0170] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0171] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes various deuterated forms of Formula I compounds. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of Formula I compounds with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula I, or conventional techniques can be used to synthesize it using deuterated reagents. Deuterated reagents include, but are not limited to, deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. In the chemical structure of the compounds described in this disclosure, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. If an inhibited transisomer exists in the chemical structure, the bond... It can be This indicates that the direction is outward from the paper. Although all the above structural formulas are drawn in certain isomer forms for simplicity, this disclosure can include all isomers, such as tautomers, rotational isomers, rotor-blocked isomers, geometric isomers, diastereomers, racemates, and enantiomers. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration was specified, i.e., key The configuration can be E-type or Z-type, or both E-type and Z-type. Unless otherwise specified, the symbols used herein are... This indicates that it can be connected with one or more groups according to the scope of disclosure described herein.

[0172] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 30 carbon atoms (C16-C26). 1-30 Alkyl groups, preferably alkyl groups containing 1 to 12 carbon atoms (C 1-12 Alkyl groups, more preferably alkyl groups with 1 to 10 carbon atoms (C 1-10 Alkyl groups, more preferably alkyl groups with 1 to 6 carbon atoms (C 1-6 Alkyl groups, more preferably alkyl groups with 1 to 4 carbon atoms (C46-24 ... 1-4 Alkyl). Wherein, C 1-4Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0173] The term "alkylene" refers to the portion remaining after removing one hydrogen atom from an "alkyl" group, as defined above. Alkylenes can be substituted or unsubstituted, and the definition of substituents is the same as that of "alkyl".

[0174] The term "heteroalkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 30 carbon atoms and containing one or more heteroatoms selected from N, O, and S. Preferably, it is a heteroalkyl group containing 1 to 30 carbon atoms and 1 to 5 heteroatoms selected from N, O, and S; more preferably, it is a heteroalkyl group containing 1 to 20 carbon atoms and 1 to 5 heteroatoms selected from N, O, and S; even more preferably, it is a heteroalkyl group containing 1 to 10 carbon atoms and 1 to 5 heteroatoms selected from N, O, and S. The heteroalkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogen, hydroxyl, oxo, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0175] The term "heteroalkylene" refers to the portion remaining after removing one hydrogen atom from "heteroalkylene," as defined above. In this disclosure, heteroalkylene can be -(CH2CH2O). m -、-(OCH2CH2) m ,-alkylene-(OCH2CH2) m - m is any integer (e.g., an integer from 1 to 15). Heteroalkyl groups can be substituted or unsubstituted, and the definition of substituent is the same as that of "heteroalkyl".

[0176] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy. Alkenyl groups used in any context herein may optionally be substituted in the same manner as alkyl groups.

[0177] The term "alkenyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C10, C2-C8, C2-C7, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl groups. These include, but are not limited to, vinyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotonyl), etc. Alkenyl groups used in any context herein may optionally be substituted in the same manner as alkyl groups.

[0178] The term "alkynyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon triple bonds. Exemplary alkynyl groups include C2-C10, C2-C8, C2-C7, C2-C6, C2-C4, C3-C12, and C3-C6 alkynyl groups. This includes, but is not limited to, ethynyl, propynyl, butynyl, pentynyl, pentynyl-4-alkynyl, and pentynyl-1,4-diynyl. In any context herein, alkynyl groups may optionally be substituted in the same manner as alkyl groups.

[0179] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0180] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, where the definitions of "halogen" and "alkyl" are as above. The haloalkyl group is preferably formed by 1-5 C-termins substituted with fluorine, chlorine, or bromine. 1-6 Alkyl (C) 1-6 Halogenated alkyl groups, more preferably C substituted with 1-3 fluorine, chlorine or bromine atoms. 1-4 Alkyl (C) 1-4 (Halogenated alkyl groups). Examples of halogenated alkyl groups include, but are not limited to, -CF3, -CHF2, and -CH2F.

[0181] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where the definitions of "halogen" and "alkoxy" are as above. The haloalkoxy group is preferably substituted with 1-5 C atoms of fluorine, chlorine, or bromine. 1-6 Alkoxy (C 1-6 (haloalkoxy), more preferably C substituted with 1-3 fluorine, chlorine or bromine atoms. 1-4 Alkoxy (C 1-4 (Haloalkoxy groups). Examples of haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2, and -OCH2F.

[0182] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms (also referred to as 3 to 20-membered rings), preferably monocyclic cycloalkyl containing 3 to 6 carbon atoms (also referred to as 3 to 6-membered rings). Non-limiting examples of 3 to 6-membered cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, and C6 groups. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0183] The term "heterocyclic alkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms (also called 3 to 20 members), wherein one or more ring atoms are selected from N, O, S, P, C (=O) or S (=O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms (also referred to as 3 to 12-membered), of which 1 to 4 are heteroatoms; preferably, it contains 3 to 8 ring atoms (also referred to as 3 to 8-membered), of which 1 to 3 are heteroatoms; more preferably, it contains 3 to 6 ring atoms (also referred to as 4 to 6-membered) monocyclic heterocyclic alkyl groups.

[0184] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0185] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0186] The aryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, nitro, cyano, amino, C... 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0187] The term "heteroaromatic ring" or "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5 to 10-membered, and even more preferably 5- or 6-membered. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrole, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazole, benzimidazolyl, etc. wait.

[0188] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, nitro, cyano, amino, C... 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0189] The terms "cycloalkylene", "heterocycloalkylene", "arylene", and "heteroarylene" are the portions remaining after removing one hydrogen atom from "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl", respectively. The definitions of "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl" are as above. Cycloalkylene, heterocycloalkylene, arylene, and heteroarylene can be substituted or unsubstituted; the definitions of substituents are the same as for "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl".

[0190] The term "hydroxyl group" refers to -OH.

[0191] The term "cyano" refers to -CN.

[0192] The term "amino" refers to -NH2.

[0193] The term "nitro" refers to -NO2.

[0194] The term "oxo" refers to the =O substituent.

[0195] "Optional" or "optional" means that the event or environment described below may, but does not have to, occur; the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0196] The term "substitution" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, being independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions without much effort (through experiment or theory).

[0197] "Being replaced by one or more..." means that it can be replaced by a single or multiple substituents. When replaced by multiple substituents, it can be a plurality of identical substituents or a combination of one or a plurality of different substituents.

[0198] The term "connection," when referring to the link between two molecules, means that the two molecules are connected by a covalent bond or by a non-covalent bond (e.g., a hydrogen bond or an ionic bond), including direct and indirect connections.

[0199] The term "direct link" refers to the connection between a first compound or group and a second compound or group without any intercalating atoms or groups. The term "indirect link" refers to the connection between a first compound or group and a second compound or group via an intermediate group, compound, or molecule (e.g., a linking group).

[0200] Unless otherwise specified, the “modified monomers” and “polymers” of this disclosure may exist in the form of salts, including acid addition salts and base addition salts (e.g., sodium salts). These salts may be prepared by methods known in the art.

[0201] The term "alginic acid or its salts" refers to a collective term for polysaccharides and their salts and derivatives composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G) in any M / G ratio. The β-D-mannuronic acid (M) monomer and the α-L-guluronic acid (G) monomer in this disclosure have the following structures:

[0202] As used in this disclosure, the term "alginic acid or its salt" includes any polymer or its salt having the structure shown below.

[0203] In this disclosure express

[0204] In this disclosure express

[0205] The term "pharmaceutical composition" refers to a composition containing one or more entities described herein (e.g., capsules encapsulating therapeutic agents), as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0206] The terms “pharmaceutical-grade excipient” or “pharmaceutical-acceptable excipient” include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0207] The term "capsule" or "hydrogel capsule" refers to a particle formed from a cross-linked hydrogel, having a cross-linked hydrogel core surrounded by one or more polymer shells, having one or more cross-linked hydrogel layers, having a cross-linked hydrogel coating, or a combination thereof. Capsules can have any shape suitable for encapsulating therapeutic agents (e.g., cells), such as spherical shapes. Capsules can contain one or more cells dispersed in a cross-linked hydrogel, thereby "encapsulating" the cells. The term "capsule" as used herein refers to and includes microcapsules unless the context clearly indicates otherwise. In some embodiments, the average diameter of the capsule is selected from 0.01mm to 10mm (e.g., 0.01mm, 0.05mm, 0.1mm, 0.2mm, 0.3mm, 0.4mm, 0.5mm, 0.6mm, 0.7mm, 0.8mm, 0.9mm, 1.0mm, 1.5mm, 2.0mm, 2.5mm, 3.0mm, 3.5mm, 4.0mm, 4.5mm, 5.0mm, 5.5mm, 6.0mm, 6.5mm, 7.0mm, 7.5mm, 8.0mm, 8.5mm, 9.0mm, 9.5mm, 10.0mm and any value between these).

[0208] The term "islet cell" refers to any naturally occurring or synthetically produced or modified cell designed to partially or wholly reproduce, mimic, or otherwise express some or all of the functions of Langerhans islets of Langerhans cells. The term "islet cell" includes glucose-responsive insulin-producing cells derived from stem cells, such as those from induced pluripotent stem cell lines.

[0209] The term "spherical" refers to particles having curved surfaces that form a spherical shape (e.g., a perfectly round sphere) or a spherical shape. Spheres and spherical objects can be mathematically defined by circular, elliptical, or combined rotations about each of three vertical axes a, b, and c. For a sphere, the three axes a, b, and c are of equal length. Typically, a spherical shape is an ellipsoid (for its average surface) with semi-principal axes a, b, and c within 10%, 5%, or 2.5% of each other. The diameter of a sphere or spherical shape is the average diameter, such as the average of the semi-principal axes.

[0210] The term “administration” means implantation, absorption, ingestion, injection, or other introduction of the entity described herein (e.g., a capsule containing an encapsulated therapeutic agent, or a pharmaceutical composition containing a capsule), or delivery of it to a subject.

[0211] The term "subject" refers to a human or a non-human animal. In some embodiments, the subject is a human (i.e., male or female, e.g., any age group, pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or elderly adult)). In some embodiments, the subject is a non-human animal, such as a mammal (e.g., a primate (e.g., a cynomolgus monkey or rhesus monkey)). In some embodiments, the subject is a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog) or bird (e.g., commercially relevant poultry, such as a chicken, duck, goose, or turkey). In some embodiments, the animal is a mammal. The animal can be male or female and at any developmental stage. The non-human animal can be a genetically modified animal.

[0212] The terms “effective amount,” “effective dose,” “effective therapeutic amount,” or “therapeutic effective amount” refer to the amount of a drug, compound, or pharmaceutical composition necessary to achieve any one or more beneficial or desired therapeutic outcome. For preventative use, beneficial or desired outcomes include eliminating or reducing risk, mitigating severity, or delaying the onset of a condition, including the condition, its complications, and the biochemical, histological, and / or behavioral symptoms of intermediate pathological phenotypes that occur during the development of the condition.

[0213] The term “treatment” refers to reducing, reversing, alleviating, delaying the onset of or inhibiting the progression of one or more symptoms, manifestations or underlying causes of a disease, disorder or condition.

[0214] The term “inhibition” may be used interchangeably with “reduction,” “silence,” “downregulation,” “blockage,” and other similar terms, and includes any level of inhibition. Inhibition can be assessed by a reduction in the absolute or relative level of one or more of these variables compared to a control level. This control level can be any type of control level used in the art, such as a baseline level before administration or a level determined from similar untreated or controlled (e.g., buffer-only control or inert agent control) subjects, cells, or samples.

[0215] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated data and inevitably contain a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%. Attached Figure Description

[0216] Figure 1 shows the effect of alginate on the viability of HeLa cell lines.

[0217] Figure 2 compares the number of macrophages recruited in the peritoneal cavity of mice by the capsule of Example 2, v / s, and the capsule of Control Example 1.

[0218] Figure 3 compares the number of neutrophils recruited in the peritoneal cavity of mice by the capsule of Example 2, v / s, and the capsule of Control Example 1.

[0219] Figure 4 shows the encapsulation performance of the capsules in Example 2, v / s, and the capsules in Control Example 1.

[0220] Figure 5 shows the number of A26F cells after 5 days of in vitro culture, encapsulating the same number of A26F cell clusters in the capsules of Example 2, v / s, and Control Example 1.

[0221] Figure 6 compares the effects of the capsules of Example 2, v / s, and Control Example 1 on the secretory function of human pancreatic β cells, with unencapsulated β cells as a control. From left to right, the capsules represent v / s, Control Example 1, Example 2, and unencapsulated β cells.

[0222] Figure 7 compares the effects of the capsules from Example 2, v / s, and Control Example 1 on the viability of human pancreatic β cells, with unencapsulated β cells as a control. From left to right, the capsules represent v / s, Control Example 1, Example 2, and unencapsulated β cells.

[0223] Figure 8 shows the changes in blood glucose levels in mice over 66 days after encapsulating human pancreatic β cells in capsules and transplanting them into the peritoneal cavity of a type 1 diabetic model mouse, as a control group. Detailed Implementation Plan

[0224] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the disclosure. Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose source is not specified can be obtained from any supplier of molecular biology reagents at the quality / purity required for molecular biology applications.

[0225] Unless otherwise specified, all reagents used in the following examples are commercially available products.

[0226] Reagent and consumable information:

[0227] In the following examples, statistical significance is marked as: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0228] Example 1: Preparation of Compound 1

[0229] Step 1) Preparation of compound 1b

[0230] Compound 1a (100 g, 407 mmol, purchased from Leyan) was dissolved in N,N-dimethylformamide (1500 mL), and sodium tert-butoxide (59.93 g, 612 mmol) was added. The mixture was stirred at room temperature for 1 hour. Tetrabromoneopentane (242 g, 612 mmol) was rapidly added under an ice-water bath, purged with nitrogen three times, and reacted overnight at 25 °C with stirring. The mixture was cooled to 0 °C, and 3000 mL of water was added with stirring. The product was extracted with ethyl acetate (1500 mL x 4), dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, and purified by column chromatography (ethyl acetate / petroleum ether = 0-20%) to give 166 g of product, yield 74.4%.

[0231] MS(ESI): m / z 547.1 [M+1] + .

[0232] 1 H NMR (400MHz, DMSO-d6) δ7.37-7.28(m,5H),4.49(s,2H),3.59-3.56(m,8H),3.54(s,4H),3.50(s,6H),3.44(s,2H).

[0233] Step 2) Preparation of compound 1c

[0234] Sodium hydroxide (29.4 g, 60%, 1.22 mol) was dissolved in ultra-dry N,N-dimethylformamide (1000 mL) in a 3000 mL dry single-necked flask under ice-water bath conditions. The mixture was stirred for 10 minutes, and tetrahydropyran ether-polyethylene glycol (268 g, 1.14 mol, purchased from Amart) was added dropwise. The mixture was stirred at room temperature for 1 hour. The temperature was lowered to 5 °C, and compound 1b (89.3 g, 163 mmol) was added to the flask. The mixture was purged with nitrogen three times, heated to 90 °C, and stirred overnight. The temperature was lowered to 0 °C, and 2000 mL of water was added with stirring. The mixture was extracted with ethyl acetate (1000 mL x 4), dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, and purified by column chromatography (ethyl acetate / petroleum ether = 20-100%) to give 183 g of product, with a yield of 111%.

[0235] MS(ESI): m / z 1024.8 [M+18] + .

[0236] Step 3) Preparation of compound 1d

[0237] Compound 1c (180 g, 179 mmol) was dissolved in ethanol (500 mL), and a hydrogen chloride / ethanol solution (800 mL, 4 mol / L) was added under ice-water bath. The mixture was stirred at room temperature for 4 hours. The crude product was concentrated under reduced pressure and purified by column chromatography (methanol / dichloromethane = 0-10%) to give 123 g of product, with a yield of 91%.

[0238] MS(ESI): m / z 755.6 [M+1] + .

[0239] Step 4) Preparation of compound 1e

[0240] Compound 1d (112 g, 148 mmol), triethylamine (127 g, 1.26 mol), 4-dimethylaminopyridine (3.63 g, 29.7 mmol), and p-toluenesulfonyl chloride (164 g, 860 mmol) were dissolved in dichloromethane (1000 mL), purged three times with nitrogen, and stirred overnight at room temperature. The solution was cooled to 0 °C, and 1500 mL of water was added with stirring. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (500 mL x 4), dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, and purified by column chromatography (ethyl acetate / petroleum ether = 0-100%) to give 133 g of product, yield 73.9%.

[0241] MS(ESI): m / z 1234.7 [M+18] + .

[0242] Step 5) Preparation of compound 1f

[0243] Compound 1e (131 g, 107 mmol), azide trimethylsilane (61.98 g, 538 mmol, purchased from Adamas), and tetrabutylammonium difluorotriphenylsilicate (290.45 g, 538 mmol, purchased from Leyan) were dissolved in tetrahydrofuran (1000 mL), purged with nitrogen three times, heated to 70 °C, and stirred under reflux overnight. The tetrahydrofuran was removed by concentration under reduced pressure, 1500 mL of water was added, and the mixture was extracted with dichloromethane (500 mL x 4). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0.6%) to give 84 g of product, with a yield of 94%.

[0244] MS(ESI): m / z 830.6 [M+1] + .

[0245] 1H NMR (400MHz, DMSO-d6) δ7.37-7.28(m,5H),4.49(s,2H),3.61-3.59(m,6H),3.57-3.49(m,28H),3.47-3.45(m,8H),3.40-3.36(m,6H),3.31(s,8H).

[0246] Step 6) Preparation of 1g of compound

[0247] Compound 1f (84 g, 101 mmol), 4-prop-2-ynyl-thiomorpholine-1,1-dioxide (80 g, 461 mmol, purchased from Leyan), copper sulfate pentahydrate (2.53 g, 10.1 mmol), and sodium vitamin C (200 g, 1.01 mol) were dissolved in tetrahydrofuran (1000 mL) and water (300 mL). The mixture was purged with nitrogen three times, heated to 70 °C, and stirred under reflux overnight. The tetrahydrofuran was removed by concentration under reduced pressure. 1000 mL of water was added, and the aqueous phase was extracted with dichloromethane (500 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0-6%) to give 128 g of product, with a yield of 93%.

[0248] MS(ESI): m / z 1349.9 [M+1] + .

[0249] 1H NMR (400MHz, DMSO-d6) δ7.98 (s, 3H), 7.37-7.25 (m, 5H), 4.51-4.48 (m, 8H), 3.80 (t, J = 5.2Hz ,6H),3.75(s,6H),3.55-3.44(m,36H),3.29(s,8H),3.10-3.08(m,12H),2.90-2.84(m,12H).

[0250] Step 7) Preparation of compound 1h

[0251] 1 g (81 g, 60.0 mmol) of the compound was dissolved in methanol (700 mL), and palladium on carbon (32 g, 10%) was added. The mixture was purged with hydrogen three times, and the reaction was stirred at 69 °C for 24 hours under a hydrogen balloon. The product was concentrated to 72 g by diatomaceous earth filtration, yielding 95%.

[0252] MS(ESI): m / z 1349.9 [M+1] + .

[0253] 1H NMR(400MHz,DMSO-d6)δ7.99(s,3H),4.58(s,1H),4.51(t,6H),3.81(t,6H) ,3.76(s,6H),3.51-3.40(m,36H),3.10-3.08(m,12H),2.93-2.89(m,12H).

[0254] Step 8) Preparation of compound 1i

[0255] Compound 1h (66 g, 52.40 mmol) was dissolved in 1,2-dichloroethane (1000 mL), and p-toluenesulfonyl chloride (18.1 g, 209 mmol), 4-dimethylaminopyridine (3.20 g, 26.2 mmol), and triethylamine (31.8 g, 314 mmol) were added. The mixture was heated to 88 °C and stirred overnight. The solution was cooled to 0 °C, and 1500 mL of water was added. The aqueous phase was extracted with dichloromethane (500 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to column chromatography (methanol / dichloromethane = 0-6%) to give 48 g of product, with a yield of 71%.

[0256] MS(ESI): m / z 1277.7 [M+1] + .

[0257] 1H NMR (400MHz, DMSO-d6) δ7.99 (s, 3H), 4.51 (t, J = 5.2Hz, 6H), 3.83-3.80 (m, 6H), 3.76 (s, 6H), 3.71-3.66(m,4H),3.55-3.45(m,31H),3.30(s,8H),3.11-3.08(m,12H),2.90-2.88(m,12H).

[0258] Step 9) Preparation of Compound 1

[0259] Compound 1i (48 g, 37.6 mmol) was dissolved in ammonia water (180 mL), heated to 80 °C, and stirred overnight at an internal pressure of 75 psi. The solution was cooled to 0 °C, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL x 4). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0-25%) to give 32.5 g of product, with a yield of 69%.

[0260] MS(ESI): m / z 1258.8 [M+1] + .

[0261] 1H NMR (400MHz, DMSO-d6) δ7.99 (s, 3H), 4.52-4.49 (m, 6H), 3.81 (t, J = 5.2Hz, 6H), 3.76 (s, 6H), 3.5 2-3.45(m,35H),3.41-3.35(m,9H),3.11-3.05(m,12H),2.90-2.88(m,12H),2.65-2.62(m,2H).

[0262] Example 2: Chemical modification of sodium alginate

[0263] Low molecular weight sodium alginate (1.0 g, 5.05 mmol, purchased from Qingdao Mingyue, viscosity 13 mPa·s, G:M ratio ≥ 1.5) was dissolved in water (30 mL), and an aqueous solution (40 mL) of 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (1.05 g, 3.79 mmol, purchased from Adamas) and compound 1 obtained in Example 1 (4.77 g, 3.79 mmol) was added. The mixture was heated to 55 °C and stirred overnight. After cooling to room temperature, ethanol (560 mL) was added to precipitate the product. The product was filtered, and the filter cake was dissolved in physiological saline (50 mL). Ethanol (400 mL) was added to precipitate the product. The product was filtered, and the filter cake was dissolved in water (30 mL). The product was freeze-dried to obtain 1.7 g of product.

[0264] The conjugated density of the chemically modified sodium alginate was measured by combustion analysis against nitrogen, and the conjugated density of compound 1 was 7.3%N.

[0265] Comparative Example 1: The following control compound was synthesized according to Example 2 of CN112203646A, with a conjugated density of 5.5%N.

[0266] Test Example 1: In vitro biocompatibility evaluation

[0267] To test the in vitro biocompatibility of chemically modified alginate, its cytotoxicity to HeLa cells was evaluated. Example 2 (dissolved in 0.8% physiological saline at a 2% weight / volume ratio) was loaded into 96-well tissue culture plates. As controls, low molecular weight sodium alginate (dissolved in 0.8% physiological saline at a 2% weight / volume ratio), Control Example 1 (dissolved in 0.8% physiological saline at a 2% weight / volume ratio), and physiological saline were also loaded into the wells of the 96-well plates and treated with 100 mM CaCl2 crosslinking solution. After removing excess crosslinking agent, 200 μL of cell culture medium was added, and the plates were incubated at 37°C and humidity-controlled for 24 hours. Subsequently, the culture medium was added to the wells pre-seeded with HeLa cells, and the plates were incubated at 37°C and humidity-controlled for 3 days.

[0268] Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol bromide (MTT). After aspirating the culture medium from all wells, 100 μL of phenol red-free DMEM medium and 10 μL of 5 mg / mL MTT solution were added to each well. The plates were incubated at 37°C in a humidity-controlled incubator for 4 hours. After incubation, 85 μL of the solution was aspirated and 10 μL of DMSO was added. Before measurement, the purple formazan crystals in the wells were dissolved using a pipette. After incubating the plates at 37°C for 10 minutes, air bubbles generated by stirring were removed, and cells seeded in the alginate-free wells were normalized.

[0269] The cell viability results are shown in Figure 1, which illustrates the effect of alginate on the viability of HeLa cell lines. Compared to the negative control (physiological saline), the cell viability of low molecular weight alginate was 97%, that of control example 1 alginate was 80%, and that of example 2 was 120%. The cell viability of example 2 was significantly better than that of control example 1, demonstrating a promoting effect on cell survival. This assay identified a modified alginate polymer that showed lower cytotoxicity compared to control example 1, and the alginate from example 2 was selected for further analysis.

[0270] Test Example 2: Preparation of Alginate Hydrogel Capsules

[0271] All buffer solutions were sterilized using an autoclave, while the alginate solution was sterilized by filtration through a 0.2-micron membrane. The sterilized solutions were then aseptically processed in a Class I A2 biosafety cabinet to ensure the sterility of the prepared capsules / spheres. The preparation steps for the hydrogel capsules are as follows:

[0272] (1) Low molecular weight sodium alginate (VLVG): 5.05 mmol, purchased from Qingdao Mingyue, viscosity 13 mPa.s, G:M ratio ≥1.5, dissolved in 0.8% physiological saline at a weight / volume ratio of 5%;

[0273] (2) High molecular weight sodium alginate: purchased from Qingdao Mingyue, viscosity 143 mPa.s, G:M ratio ≥1.5, dissolved in 0.8% physiological saline at a weight / volume ratio of 3%;

[0274] (3) Preparation of v / s hydrogel capsules: v / s hydrogel capsules were prepared by mixing 70% low molecular weight sodium alginate and 30% high molecular weight sodium alginate by volume.

[0275] (4) Preparation of hydrogel capsules for control example 1: control example 1 was first dissolved in 0.8% physiological saline at a weight / volume ratio of 5%, and then mixed at a volume ratio of 50% control example 1 and 50% high molecular weight sodium alginate to prepare control example 1 hydrogel capsules.

[0276] (5) Preparation of hydrogel capsules in Example 2: Example 2 was first dissolved in 0.8% physiological saline at a weight / volume ratio of 5%, and then mixed at a volume ratio of 50% of Example 2 and 50% of high molecular weight sodium alginate to prepare hydrogel capsules of Example 2.

[0277] Test Example 3: Verification of Anti-fibrotic Activity

[0278] (1) Capsule preparation: Refer to Test Example 2 above;

[0279] (2) Transplantation of hydrogel capsules

[0280] This section used immunocompetent male C57BL / 6 mice provided by Vital River as experimental subjects. All procedures were conducted in accordance with animal ethics guidelines. Preoperatively, mice were subcutaneously injected with 0.05 mg / kg butorphanol as a preoperative analgesic, and simultaneously injected with 0.3 mL of 0.9% saline to prevent dehydration. Mice were anesthetized in a mixture of 3% isoflurane and oxygen, and their abdomens were shaved and disinfected with povidone-iodine and isopropanol. A 0.5 cm incision was made along the midline of the abdomen, and the peritoneum was exposed using blunt dissection. The peritoneal wall was then held with forceps, and a 0.5–1 cm incision was made at the linea alba. The required volume of capsule was loaded into a sterile pipette and transplanted into the peritoneal cavity through the incision. The incision was then sutured with 5-0 conical polydioxanone (PDS II) absorbable sutures, and the skin was closed with wound clips and tissue glue.

[0281] (3) Material recycling

[0282] On day 14 post-transplantation, mice were euthanized via CO inhalation, followed by cervical dislocation. Using forceps and scissors, an incision was made along the abdominal skin and peritoneal wall. The tip of a wash bottle was inserted into the peritoneal cavity, and all material capsules within the cavity were flushed with Krebs buffer (Solepro, catalog #G0430) and collected into a culture dish. After ensuring all capsules were flushed out or manually removed, any capsules directly adhered to the peritoneal tissue by fibrosis were transferred to a 50 mL conical tube for further processing and imaging.

[0283] (4) Cell recovery and flow cytometry (FACS) analysis

[0284] The recovered material capsules were first gently washed with Krebs buffer (Solepro, catalog #G0430) and then transferred to 15 mL conical tubes. Excess buffer was then aspirated, and 5 mL of 0.25% trypsin (Thermo Fisher Scientific, catalog #25200056) was added. The mixture was incubated at 37°C for 5 minutes, and the reaction was terminated by adding 5 mL of sterile 1x PBS. The remaining cells were centrifuged at 300–400 g at 4°C and resuspended in a small amount (approximately 65 μL) of eBioscience staining buffer (Thermo Fisher Scientific, catalog #00-4222). 15 μL of this buffer was then aspirated for cell counting using a Countstar cell counter (catalog #IN030101), and the remaining 50 μL was used for antibody incubation.

[0285] All samples were co-stained with two fluorescently labeled monoclonal antibodies for 25 minutes at 4°C in the dark. The specific antibodies were: CD68 (1 μL, 0.5 μg per sample; CD68-Alexa647, Clone FA-11, catalog number #11-5931, BioLegend), Ly-6G(Gr-1) (1 μL, 0.5 μg per sample; Ly-6G-Alexa-647, Clone RB6-8C5, catalog number #108418, BioLegend), and CD11b (0.4 μL, 0.2 μg per sample; CD11b-Alexa-488, Clone M1 / 70, catalog number #101217, BioLegend). Then, 2 mL of eBioscience flow cytometry staining buffer (Thermo Fisher Scientific, catalog number #00-4222) was added, and the samples were centrifuged at 400-500g for 5 minutes at 4°C. Aspirate the supernatant and repeat the washing step twice with staining buffer. After the third wash, each sample is resuspended in 500 μL of flow cytometry staining buffer and filtered through a 40 μm filter (Thermo Fisher Scientific, catalog number #22363547). Finally, flow cytometry analysis is performed using an Attune flow cytometer (Thermo Fisher Scientific, catalog number #A24863).

[0286] Fourteen days post-transplantation, the recovered capsules were analyzed by flow cytometry (FACS) to characterize the different immune cell populations recruited intraperitoneally by the capsules of Example 2, v / s, and Control Example 1 (see Figures 2 and 3). The results showed that the number of macrophages per 350 μL v / s capsule was 26.38 x 10⁻⁶. 4 The number of neutrophils was 18.00 x 10⁻⁶. 4 The number of macrophages per 350 μL of control capsule 1 was 5.75 x 10^6. 4 The number of neutrophils was 3.46 x 10⁻⁶. 4The number of macrophages in each 350 μL capsule of Example 2 was 2.03 x 10⁻⁶. 4 The number of neutrophils was 1.23 x 10⁻⁶. 4 The number of macrophages and neutrophils in the capsule of Example 2 was significantly lower than that in v / s and the control capsule of Example 1, indicating its advantage in reducing inflammatory response.

[0287] (5) Statistical Analysis

[0288] Data are presented as mean ± standard error (mean ± SEM). In HeLa cell line viability assays, N = 12 biological replicates were performed per treatment group. In in vivo biocompatibility assays, N = 7 mice were performed per treatment group. All animals were included in the analysis unless unforeseen disease or death occurred. Animal populations were randomly selected. Researchers were not misled during the experiments. Statistical significance analysis of FACS data was performed using unpaired two-tailed t-tests or one-way ANOVA with Bonferroni multiple comparison correction, unless otherwise specified, and these analyses were performed in GraphPad Prism 5.

[0289] Statistical significance was marked as: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0290] Test Example 4: Encapsulating A26F cell clusters

[0291] (1) Preparation of sodium alginate solution: Prepare sodium alginate solution V / S, control example 1 and example 2 according to test example 2.

[0292] (2) Cell culture: Human induced embryonic stem cell line A26F (iXCell, 30HU-002) was used. A26F cells were cultured at 3 × 10⁻⁶ cells / year. 5 The cells were seeded at a density of / wells into a low-adsorption 6-well plate, 2 mL of StemScale PSC medium (Thermo Fisher Scientific, A4965001) was added, and the plate was incubated overnight on a shaker (70 rpm). Cells were observed to form spheroids the next day.

[0293] (3) Cell encapsulation

[0294] Aspirate the culture medium from the well plate, add 500 μL of fresh culture medium, mix well, and distribute into five 24-well plates. Manually count the cells. Take 500 cell clusters into a 1.5 mL centrifuge tube, let stand for 30 seconds until the cell clusters settle, discard the culture medium, and add 500 μL of sodium alginate solution from Example 2. Mix well by pipetting, transfer the mixture of cells and sodium alginate solution to a 1 mL screw-top syringe, remove air bubbles, attach a 30G needle, and manually squeeze dropwise into 109 mM CaCl2 from a height of about 20 cm above the liquid surface. Crosslink and harden for 20 min, discard the CaCl2 crosslinking solution, and wash four times with physiological saline for 1 min each time. After cleaning, obtain the capsules of Example 2. Mix equal amounts of cell clusters with Control Example 1 and V / S sodium alginate solutions respectively, and prepare Control Example 1 and V / S capsules using the same method.

[0295] The encapsulated capsules were then cultured in StemScale PSC medium, with the medium changed every other day. Bright-field photography was performed on days 1, 2, and 3 post-encapsulation to record the cell state. The results (see Figure 4) showed that Example 2 could support a cell cluster encapsulation density of 2000 cells / mL, and the cells maintained their encapsulation integrity without rupture during in vitro culture. A significant amount of space remained inside the capsules, indicating that the upper limit of the encapsulation density exceeded 2000 cells / mL.

[0296] (4) Live and dead staining

[0297] Cells from Example 2, Control Example 1, and V / S were encapsulated at a density of 1000 cell clusters / mL. The initial cell count and capsule volume were the same for all groups (500 μL). After 5 days of culture, five capsules from each group were placed in new wells and stained using a live / dead cell staining kit (Solepro, CA1630). Calcein AM was used as the live cell dye, producing green fluorescence upon excitation, and PI was used as the dead cell dye, producing red fluorescence upon excitation. Specific procedures were followed according to the kit instructions. After staining, imaging was performed using a fluorescence microscope (Thermo Fisher Scientific, EVOS M5000). The results showed that the cells in Example 2 had the highest viability and the least fluorescence signal from dead cells.

[0298] (5) Dissociate the capsule and release the cells.

[0299] Cells from Example 2, Control Example 1, and V / S were encapsulated at a density of 1000 cell clusters / mL. The initial cell count and capsule volume were the same for all groups (500 μL). After 5 days of in vitro culture, the culture medium was aspirated, and 2 mL of 2 mg / mL sodium alginate enzyme (Sigma A1603) was added. The cells were incubated at 37°C for 10 min, with the contents being pipetted several times during incubation until the sodium alginate capsules were degraded, releasing the A26F cell clusters. The cell clusters were collected in centrifuge tubes, and 2 mL of Accutase was added. TM The digestion solution (Thermo Fisher Scientific, A1110501) was used for 15 min at 37°C, with gentle pipetting at 10 min. Then, 5 mL of DMEM medium (Thermo, 11965092) was added to terminate the process. The mixture was centrifuged at 300 g for 5 min, the supernatant was discarded, and the mixture was resuspended in 1 mL of PBS. Counting was performed using AO / PI (see Figure 5).

[0300] Cell counting results inside the capsules showed that, with the same initial cell number, the cell number in Example 2 was the highest after 5 days of culture, reaching 5.06 × 10⁶. 6 The cell count in the capsules of V / S and Control Example 1 was only 3.54 × 10⁻⁶. 6 and 4.46×10 4 This suggests that it can support cell growth and proliferation for a long time and has optimal biocompatibility.

[0301] Test Example 5: Encapsulated Mesenchymal Stem Cells

[0302] (1) Preparation of sodium alginate solution: Prepare sodium alginate solution as described in Test Example 2.

[0303] (2) Cell culture: Human bone marrow-derived mesenchymal stem cells (ATCC, PCS-500-012) were used. TM As a model, the encapsulation ability and biocompatibility of the molecule from Example 2 on single cells were tested. The amplification medium was DMEM / F12 (Thermometer, C11330500BT) + 10% serum (Pronos, 164210) + 10 ng / mL FGF2 (R&D System, 3718-FB-100). When the cells reached 80% confluence, the medium was discarded, and 10 mL of StemPro was added. TM Accutase TM Cell Dissociation Reagent (Thermo, A1110501) was used to treat the cells at 37°C for 3 min. An equal volume of proliferation medium was added, and the cells were centrifuged at 300g for 5 min. The supernatant was discarded, and the cells were resuspended in 1 mL of PBS. Cell counts were performed using AO / PI. Based on the count results, 4.5 × 10⁴ cells were extracted.6 After centrifugation again, the supernatant was discarded, and the cells were resuspended in 0.5 mL of the molecular solution from Example 2, resulting in an encapsulation density of 9 × 10⁻⁶ cells / mL. 6 / mL. Crosslinking was then performed using CaCl2, following the same method as in Test Example 4.

[0304] The washed capsules were placed on a shaker for in vitro culture at 70 rpm and the culture conditions were 37°C and 5% CO2. The amplification medium was changed every other day.

[0305] (3) Live and dead staining

[0306] At different time points during in vitro culture, the cells were stained using a live-death staining kit, and the survival of the encapsulated cells was observed using a fluorescence microscope, following the same method as in test case 4.

[0307] The results showed that the molecular encapsulation of Example 2 could support the survival of mesenchymal stem cells in vitro for up to 30 days. No dead cell signals were observed during the in vitro culture period, indicating that the molecular encapsulation of Example 2 can support the long-term survival of single cells in vitro and has good biocompatibility.

[0308] Test Example 6: Encapsulation of pancreatic islet cells

[0309] (1) Preparation of sodium alginate solution: Prepare sodium alginate solution V / S, control example 1 and example 2 according to test example 2.

[0310] (2) Cell culture: Human pancreatic β cells were obtained by differentiating embryonic stem cells (hPSCs) according to the method described in the literature (Hogrebe NJ.Et al, Generation of insulin-producing pancreatic β cells from multiple human stem cell lines.Nat Protoc.2021,16(9):4109-4143.doi:10.1038 / s41596-021-00560-y.). The specific steps are as follows:

[0311] Embryonic stem cell culture (Phase 0): Human H9 embryonic stem cell lines were expanded in Matrigel (Corning, 354277) coated culture dishes and cultured in mTeSR1 (stemcell, 1000276) medium until the cells reached 90% confluence. Cells were digested into single-cell suspensions using TrypLE and cultured at an appropriate density (typically 0.8 × 10⁵ cells / cm²). 2 The cells are inoculated into new culture dishes and prepared to begin differentiation.

[0312] Endoderm shaping induction (Phase 1): After differentiation began, cells were cultured for 24 hours in BE1 basal medium containing Activin A (RD, 338-AC-CF-050, 100 ng / mL) and CHIR99021 (MCE, HY-10182G, 3 μM), followed by 3 days of culturing with Activin A alone. This phase aimed to induce endoderm shaping, and cells should express the endoderm markers FOXA2 and SOX17.

[0313] Primitive intestinal formation (stage 2): The shaped endoderm cells were cultured for 2 days in BE2 medium containing KGF (RD, 251-KG-CF-050, 50 ng / mL) to further differentiate into primitive intestinal cells.

[0314] Pancreatic progenitor cell generation (stages 3 and 4): Cells were cultured in BE3 medium containing KGF, SANT1 (sigma, S4572), TPPB (santa cruz, SC-204424), LDN193189 (MCE, HY-12071G), and Retinoic Acid (sigma, R2625). PDX1+ pancreatic progenitor cells were first induced (stage 3), followed by promotion of NKX6-1 expression by reducing RA concentration (stage 4). The key to this stage was the generation of PDX1+ / NKX6-1+ double-positive cells, which are precursors to functional pancreatic β-cells.

[0315] Endocrine induction (Phase 5): Pancreatic progenitor cells were cultured for 7 days in S5 medium containing SANT1, RA, XXI (Millipore, 565790), ALK5i II (Enzo, ALX-270-445), T3 (RD, 133.32), and latrunculin A (Cayman Chemical, 10010630) to induce NEUROG3 expression and promote endocrine cell differentiation. Latrunculin A was administered within the first 24 hours to relieve the inhibition of endocrine differentiation by the cytoskeleton.

[0316] Pancreatic β-cell maturation (stage 6): Endocrine cells are cultured in serum-rich medium (ESFM) for more than 14 days to further mature into functional pancreatic β-cells.

[0317] (3) Differentiated mature pancreatic β cells were encapsulated in the molecule of Example 2 at a density of 1000 islet cell clusters per milliliter to prepare the capsule of Example 2. Control Example 1 and V / S capsules were used as controls. The encapsulation method was the same as that in Test Example 4.

[0318] (4) Detecting insulin secretion

[0319] On the day of testing, KRB buffer solution was prepared and then placed at 37°C for temperature equilibration.

[0320] Table 1 Preparation method of KRB buffer

[0321] On the day of testing, 10 capsules (30 cell clusters for the unencapsulated group) were placed in one well (24-well plate) from each group and washed three times with KRB buffer. 1 mL of 30 mM KCl (prepared using KRB buffer) was added to each well, and the cells were incubated at 37°C for 1 hour. The supernatant was then collected. The insulin content in the supernatant was measured using a human insulin ELISA kit (ALPCO, 80-INSHU-E01.1), following the kit instructions.

[0322] The capsules were dissociated using sodium alginate enzyme to release β-cell clusters, following the procedure outlined in Test Example 4. The cell clusters were collected into centrifuge tubes, and 2 mL of Accutase was added. TM Digestion solution (Thermo Fisher Scientific, A1110501) was used for treatment at 37°C for 15 min, with gentle pipetting at 10 min. Then, 5 mL of DMEM culture medium was added to terminate the treatment. The cells were centrifuged at 300 g for 5 min, the supernatant was discarded, and the cells were resuspended in 1 mL of PBS and counted. The insulin content in the supernatant was read according to the ELISA results, and the insulin release per 1000 cells was calculated based on the count results. The results showed that, one day after encapsulation, the insulin secretion of cells encapsulated with the molecule from Example 2 and unencapsulated cells was 9.96 μIU / 1000 cells and 8.92 μIU / 1000 cells, respectively; eight days after encapsulation, the insulin secretion of cells encapsulated with the molecule from Example 2 and unencapsulated cells was 10.76 μIU / 1000 cells and 11.70 μIU / 1000 cells, respectively. These two levels are comparable, indicating that the encapsulation in Example 2 does not affect the cell's secretory function (see Figure 6).

[0323] (5) Detecting cell viability

[0324] At 1, 3, and 8 days post-encapsulation, the cells in the capsules were stained using a live / dead staining kit, following the procedure described in Test Example 4. Subsequently, the capsules were dissociated to release the pancreatic β-cell clumps, which were then digested into single cells, following the procedure described in Test Example 5. After obtaining single cells, cell viability was analyzed by flow cytometry using an Attune flow cytometer (Thermo Fisher Scientific, catalog number #A24863). At 1, 3, and 8 days post-encapsulation, the viability of pancreatic β-cells encapsulated with the molecule from Example 2 was 89.2%, 89.9%, and 92.2%, respectively, while the viability of unencapsulated pancreatic β-cells was 90.2%, 91.4%, and 86.3%, respectively. The viability of β-cells encapsulated in Example 2 was high at all time points and comparable to that of unencapsulated cells, indicating that encapsulation with the molecule from Example 2 does not affect long-term cell survival (see Figure 7).

[0325] Test Example 7: Encapsulation for xenotransplantation

[0326] Transplantation of pancreatic β-cells is a promising therapeutic strategy with the potential for a functional cure of type 1 diabetes. In this system, we used the molecules from Example 2 for cell encapsulation, leveraging their anti-fibrotic activity to prolong the survival time of exogenous cells.

[0327] (1) Preparation of sodium alginate solution: The sodium alginate solution of control example 1 and example 2 was prepared with reference to test example 2.

[0328] (2) Cell culture: The method is the same as in test example 6.

[0329] (3) Differentiated mature pancreatic β cells were divided into 2×10 6 The cells were encapsulated in the molecules of Example 2 at a density of / mL to prepare the capsules of Example 2. The encapsulation method was largely the same as that of Test Example 4, except that 20mM BaCl2 was used as a cross-linking agent.

[0330] (4) Establishment of a type 1 diabetes model in C57 / 6J mice

[0331] Male C57BL / 6J mice (Vitolliwa), 23-25g, 8-9 weeks old, were purchased and acclimatized for one week prior to modeling. The mice were fasted overnight (12-16 hours) the day before modeling. On the day of modeling, citrate buffer solution was prepared. Specifically: 2.1g of citric acid (Mw: 210.14) was dissolved in 100mL of double-distilled water to prepare solution A; 2.94g of sodium citrate (Mw: 294.10) was dissolved in 100mL of double-distilled water to prepare solution B; solutions A and B were mixed in a 1:1 ratio, and the pH was measured and adjusted to 4.2-4.5. STZ was dissolved in buffer solution to a concentration of 15mg / mL, and the initial injection dose was 150mg / kg. A second injection was given three days later, prepared using the same method, at a dose of 100mg / kg.

[0332] (5) Peritoneal transplantation of capsules: The method is the same as in test case 3.

[0333] (6) Blood glucose monitoring: Blood was collected from the tail tip of mice weekly, and random blood glucose was measured using a Roche blood glucose meter (Superior Gold).

[0334] (7) Sample collection and analysis: 66 days post-transplantation, mice were sacrificed for sample collection. Peritoneal capsules were recovered using the same method as in Test Case 3. Bright-field imaging was performed on the recovered capsules to observe the FBR effect on their surface. The recovered capsules were stained for viability and dead cells, and fluorescence microscopy was used to analyze the survival of β cells, using the same method as in Test Case 4.

[0335] (8) Statistical Analysis

[0336] Data are presented as mean ± standard error (mean ± SEM), with N = 2 mice in each treatment group. All animals were included in the analysis. Animal populations were randomly selected.

[0337] The results showed that β cells encapsulated with the molecule from Example 2 could effectively control blood glucose at around 10 mM over a 66-day testing period, while the average blood glucose in the model group was around 25 mM (see Figure 8). Analysis of the recovered capsules showed that the vast majority of the transplanted pancreatic β cells remained viable, indicating that the molecule from Example 2 effectively provides anti-fibrotic activity and prolongs the survival of exogenous transplanted cells after cell encapsulation.

Claims

1. A modified monomer of the formula I ###0001### I wherein A is selected from a unit comprising a sugar; R 1 , R 2 each independently is selected from hydrogen, halogen, hydroxyl, amino, cyano, alkyl or alkoxy, said alkyl or alkoxy optionally being substituted with one or more R 1a ; R 1a each independently is selected from halogen, oxo, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, said C 1-6 alkyl, or C 1-6 alkoxy is optionally substituted with one or more halogen, hydroxyl, amino, oxo, cyano, C X is selected from -0-, -S- or -NR 3 -; R 3 selected from hydrogen or C 1-4 alkyl, said C 1-4 alkyl is optionally substituted with one or more halogen, oxo, hydroxy, amino, cyano or C 1-6 alkoxy; L1and L3are each independently selected from C 1-30 alkylene, C 1-30 heteroalkylene, or The C 1-30 alkylene, C 1-30 heteroalkylene is optionally substituted with one or more R L substituted; R L each independently is selected from halogen, oxo, hydroxyl, amino, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy; R a , R b , R c and R d are each independently selected from hydrogen, halogen, oxo, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy; M is selected from 3-8 membered cycloalkylene, 3-8 membered heterocycloalkylene, 6-10 membered arylene, or 5-10 membered heteroarylene, said 3-8 membered cycloalkylene, 3-8 membered heterocycloalkylene, 6-10 membered arylene, and 5-10 membered heteroarylene being optionally substituted with one or more halogen, oxo, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; m1 and m2 are each independently selected from an integer between 0-30; L2is selected from n1, n2, n3, n4, n5, n6, n7, n8 and n9 are each independently selected from an integer between 0-6; p is selected from 2, 3 or 4.

2. The modification monomer of claim 1, wherein, A is selected from a unit comprising a monosaccharide, a unit comprising a disaccharide or a unit comprising an oligosaccharide; preferably, A is selected from the group consisting of a substituted or unsubstituted hexose, hexulose, hexuronic acid, pentose, pentulose and penturonic acid; further preferably, A is selected from a unit comprising a mannuronic acid and a unit comprising a guluronic acid.

3. The modification monomer according to claim 1 or 2, wherein, the modified monomer of Formula I is a modified monomer of Formula II, Among them, X, L1, L2, L3, R 1 R 2 And p as defined in claim 1; Y1 and Y2 are each independently selected from hydrogen or -PO (OR) 6 )2;R 6 Selected from hydrogen or C 1-6 alkyl.

4. The modification monomer according to any one of claims 1-3, wherein, X is -NR 3 - 5. The modified monomer according to any one of claims 1-4, wherein R 1 Selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy groups are optionally surrounded by one or more R groups. 1a Replaced by, R 1a As defined in claim 1; further, R 1 The preferred compounds are hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

6. The modified monomer according to any one of claims 1 to 5, wherein R 2 is selected from hydrogen or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by one or more R 1a , R 1a is as defined in claim 1 ; further, R 2 is preferably hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl, said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl is optionally substituted by one or more R 1a , R 1a is as defined in claim 1.

7. The modified monomer according to any one of claims 1 to 6, wherein R 1a is selected from a 3-8 membered cycloalkyl or a 3-8 membered heterocycloalkyl, said 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl being optionally substituted with one or more halogen, oxo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; further, R 1a is preferably a 3-8 membered heterocycloalkyl containing 1 or 2 N, O, S atoms, said 3-8 membered heterocycloalkyl being optionally substituted with one or more halogen, oxo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.

8. The modification monomer according to claim 7, wherein R 1a is selected from the group consisting of optionally substituted 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy. Further, R 1a is preferably 9. The modified monomer of any one of claims 1-8, wherein the modified monomer of Formula I is a modified monomer of Formula III, wherein A, X, L1, L2, L3, R 1 , p are as defined in claim 1 ; R 2a and R 2b are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl or C 1-6 alkoxy; r is selected from an integer between 1 and 6.

10. The modified monomer of any one of claims 1-9, wherein the modified monomer of Formula I is a modified monomer of Formula IV, wherein X, L1, L2, L3, R 1 and p is as defined in claim 1 ; Y1and Y2are each independently hydrogen or -PO(OR 6 )2; R 6 is hydrogen or C 1-6 alkyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 alkyl or C 1-6 alkoxy; r is selected from an integer between 1-6.

11. The modified monomer according to any one of claims 1 to 10, wherein L1 is selected from the group consisting of C 1-30 alkylene, -(CH2CH20) m3 - -(OCH2CH2) m4 - -alkylene-(OCH2CH2) m5 -, said C 1-30 alkylene, -(CH2CH20) m3 - -(OCH2CH2) m4 - -alkylene-(OCH2CH2) m5 - is optionally substituted with one or more R L , R L m3, m4 and m5 are each independently selected from an integer between 1 and 15 as defined in claim 1 ; L1 is preferably -(CH2CH20) m3 - -(OCH2CH2) m4 - -alkylene-(OCH2CH2) m5 - ; further, L1 is preferably -(CH2)2-(OCH2CH2)-, -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, -(CH2CH20)-, -(CH2CH20)2- or -(CH2CH20)3-.

12. The modified monomer according to any one of claims 1 to 11, wherein L3 is selected from C 1-30 alkylene, -(CH2CH20) m6 - -(OCH2CH2) m7 - -alkylene-(OCH2CH2) m8 -, said C 1-30 alkylene, -(CH2CH20) m6 - -(OCH2CH2) m7 - -alkylene-(OCH2CH2) m8 - is optionally substituted by one or more R L , R L m6, m7 and m8 are each independently selected from an integer between 1 and 15 as defined in claim 1; L3 is preferably -(CH2CH20) m6 - -(OCH2CH2) m7 - -alkylene-(OCH2CH2) m8 - ; further, L3 is preferably -(OCH2CH2)-, -(OCH2CH2)2-, -(OCH2CH2)3-, -(CH2)2-(OCH2CH2)-, -(CH2)2-(OCH2CH2)2- or -(CH2)2-(OCH2CH2)3-.

13. The modification monomer of any one of claims 1-12, wherein, L2is selected from 14. The modification monomer of any one of claims 1-12, wherein, L2 is selected from preferably from 15. The modification monomer of any one of claims 1-14, wherein, The modified monomer of Formula I is any of the following structures, A is a end is attached to -NH-.

16. A polymer comprising one or more modified monomers according to any one of claims 1-15.

17. A hydrogel comprising the polymer of claim 16; the polymer is preferably crosslinked by Ca 2+ , Ba 2+ or Sr 2+ ions to form the hydrogel.

18. A capsule comprising the hydrogel according to claim 17; preferably, the hydrogel encapsulates a therapeutic agent, preferably a cell, preferably an islet cell.

19. The capsule according to claim 18, which is spherical; The average diameter of the capsule is preferably between 0.01 mm and 10 mm, more preferably between 0.1 mm and 10 mm, further preferably between 1 mm and 8 mm, more further preferably between 1 mm and 2 mm.

20. A pharmaceutical composition comprising the capsule according to claim 18 or 19 and one or more pharmaceutically acceptable excipients.

21. Use of a modified monomer according to any one of claims 1-15, a polymer according to claim 16, a hydrogel according to claim 17, a capsule according to claim 18 or 19 or a pharmaceutical composition according to claim 20 for the manufacture of a medicament for the treatment of a disease selected from the group consisting of diabetes, haemophilia, skin damage, spinal cord injury, heart damage, osteoarthritic inflammation, preferably diabetes.

22. A device comprising the capsule according to claim 18 or 19 or the pharmaceutical composition according to claim 20.

23. A compound of Formula X: ###0009### or a salt thereof. wherein, Z is halogen, -OR 7 or -NR 8 R 9 ; R 7 is hydrogen or a protecting group; R 8 and R 9 each independently is hydrogen or alkyl; L1, L2, L3, R 1 , R 2 and p are defined according to any one of claims 1 to 14.

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