Modified polysaccharide polymers and related compositions and methods

Abstract

This specification describes polymers containing specific hydroxyl group modifications, as well as related compositions and methods thereof. [Solution] This specification describes polysaccharide polymers comprising sugar moieties (e.g., sugar monomers of formula (I)) modified with hydroxyl modifiers, as well as related compositions, hydrogels, implantable elements, and methods of use thereof.

Description

[Technical Field]

[0001] Claim of priority This application claims priority to U.S. Patent Application No. 63 / 295,297, filed on 30 December 2022, and its entire contents are incorporated herein by reference. [Background technology]

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

[0003] This specification describes polymers comprising a predetermined hydroxyl group modification, as well as related compositions and methods thereof. In one embodiment, the disclosure features a polysaccharide polymer comprising a sugar monomer having a hydroxyl moiety, wherein the sugar monomer comprises a hydroxyl modifier covalently bonded to the hydroxyl moiety. In one embodiment, the sugar monomer has a plurality of hydroxyl moieties, and the sugar monomer comprises a hydroxyl modifier covalently bonded to the hydroxyl moiety. In another embodiment, the disclosure features a polysaccharide polymer comprising a sugar monomer having a hydroxyl moiety, wherein the sugar monomer comprises a hydroxyl modifier at the location of the hydroxyl moiety. In some embodiments, the sugar monomer is selected from glucose, galactose, mannose, allose, altrose, talose, idose, gros, fructose, ribose, arabinose, lyxose, xylose, rhamnose, glucuronic acid, galacturonic acid, mannuronic acid, and guluronic acid. In one embodiment, the polysaccharide polymer is selected from hyaluronate, alginate, cellulose, chitosan, chitin, amylose, dextran, starch, glycogen, chondroitin, and pectin. In one embodiment, the hydroxyl modifier is a nitrogen-containing hydroxyl modifier. In one embodiment, the hydroxyl modifier includes an amine or an amide.

[0004] In one embodiment, the present disclosure relates to a polysaccharide polymer comprising a sugar monomer, wherein the sugar monomer is of formula (I): [ka] The present invention features a polysaccharide polymer having the structure of a pharmaceutically acceptable salt thereof, wherein the formula comprises variable elements X and R 1 , R 2 , R 3 , R 4 , R 5a , R 5band their secondary variable elements are defined herein. In some embodiments, the sugar monomer of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f) described herein. In some embodiments, the sugar monomer of formula (I) or a pharmaceutically acceptable salt thereof is shown in Table 1 herein.

[0005] In another aspect, the disclosure is a polysaccharide polymer comprising a sugar monomer, wherein the sugar monomer is of formula (I-a):

Chemical formula

[0006] In another aspect, the disclosure is an alginate comprising a sugar monomer, wherein the sugar monomer is of formula (I-a):

Chemical formula

[0007] In other embodiments, the disclosure features hydrogels comprising polysaccharide polymers (e.g., alginates) described herein, and implantable elements (e.g., devices or materials) comprising the same. In some embodiments, the hydrogel or implantable element comprises cells. Exemplary cell types include epithelial cells, endothelial cells, fibroblasts, keratinocytes, and stem cells (e.g., iPSCs or MSCs). In some embodiments, the hydrogel or implantable element comprises epithelial cells, e.g., retinal pigment epithelial cells (RPE cells). In some embodiments, the hydrogel or implantable element comprises engineered cells (e.g., engineered epithelial cells, e.g., engineered RPE cells).

[0008] In some embodiments, cells (e.g., engineered cells) produce substances, such as therapeutic agents. Exemplary therapeutic agents include nucleic acids (e.g., RNA or DNA), proteins (e.g., hormones, enzymes, antibodies, antibody fragments, antigens, or epitopes), small molecules, lipids, drugs, vaccines, or derivatives thereof. For example, a transplantable element may include engineered cells capable of producing proteins (e.g., blood clotting factors (e.g., factor VIII protein)) or hormones (e.g., insulin)).

[0009] In another aspect, the present disclosure features a method of providing a substance (e.g., a therapeutic agent) to a subject, the method comprising administering to the subject a hydrogel or implantable element comprising (i) a polysaccharide polymer (e.g., alginate) comprising a sugar monomer of formula (I) described herein, and (ii) cells capable of producing the substance (e.g., a therapeutic agent). In some embodiments, the substance is a therapeutic agent such as a protein (e.g., a blood clotting factor (e.g., Factor VIII protein) or a hormone (e.g., insulin)).

[0010] In another aspect, the present disclosure features a method of treating a disease, disorder, or condition of a subject with a therapeutic agent capable of treating the disease, disorder, or condition of the subject, the method comprising administering to the subject a hydrogel or implantable element comprising (i) a polysaccharide polymer (e.g., alginate) comprising a sugar monomer of formula (I) described herein, and (ii) cells capable of producing the therapeutic agent. In some embodiments, the disorder is a blood clotting disorder (e.g., hemophilia A), a lysosomal storage disorder (e.g., Fabry disease, MPS I), an endocrine disorder, diabetes, or a neurodegenerative disease.

[0011] In some embodiments, the method of providing or treating the substance comprises reducing a foreign body reaction to the administered implantable element (e.g., minimizing the formation of pericapsular fibrotic overgrowth (PFO) in the implantable element).

[0012] In all aspects of this disclosure, in some embodiments, the polysaccharide polymers described herein, for example, those comprising a sugar monomer of formula (I), or their hydrogels or implantable elements (e.g., devices or materials) are not the polysaccharide polymers, hydrogels, or implantable elements described in any one of WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 187225, WO2016 / 019391, WO2017 / 075630, WO2017 / 075631, WO2018 / 067615, WO2019 / 169333, and US2016-0030359.

[0013] Details of one or more embodiments of the present invention are described herein. Other features, purposes, and advantages of the present invention will become apparent from the modes for carrying out the invention, drawings, examples, and claims. [Modes for carrying out the invention]

[0014] This disclosure provides polysaccharide polymers comprising sugar monomers having hydroxyl moieties modified with hydroxyl modifiers, as well as related compositions thereof, methods for their preparation, and uses. In one embodiment, the sugar monomer comprises a hydroxyl modifier covalently bonded to the hydroxyl moiety. In one embodiment, for example, a polysaccharide polymer comprising a sugar monomer of formula (I), as well as hydrogels and implantable elements (e.g., devices and materials) comprising the same, as well as related compositions and methods for their use. In particular, the polysaccharide polymers, hydrogels, and implantable elements described herein may be used in methods for the prevention and treatment of diseases, disorders, or pathological conditions of interest. In some embodiments, polysaccharide polymers comprising a sugar monomer of formula (I), as well as hydrogels and implantable elements comprising the same, and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotope-labeled derivatives thereof may be used to mitigate immune responses in subjects.

[0015] definition To make the present invention more easily understandable, certain technical and scientific terms are specifically defined below. Unless otherwise specifically defined elsewhere in this document, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which the present invention pertains.

[0016] As used herein, including in the attached claims, the singular forms of terms such as "a," "an," and "the" include the corresponding plural references unless the context otherwise clearly indicates.

[0017] When used herein to modify a numerically defined parameter (e.g., the physical description of a polymer or implantable element described herein, e.g., diameter, sphericity, number of cells in a particle (e.g., hydrogel), number of particles in a preparation), it means that the parameter may vary by up to 15% above or below the numerical value described for that parameter. For example, an implantable element defined as having an average diameter of up to 1.5 millimeters (mm) and encapsulating up to 5 million (M) cells may have an average diameter of 1.275 to 1.725 mm and may encapsulate up to 4.25 M to 5.75 M cells. In some embodiments, the term "up to" means that the parameter may vary by up to 10% or 5% above or below the numerical value described for that parameter.

[0018] "To obtain" or "to acquire," as used herein, means to obtain a value or physical entity by "directly obtaining" or "indirectly obtaining" the possession of a value, e.g., a numerical value, or an image, or a physical entity (e.g., a sample). "Directly obtaining" means performing a process (e.g., performing an analytical method or protocol) to obtain a value or physical entity. "Indirectly obtaining" means receiving a value or physical entity from another entity or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a value or physical entity includes performing a process or using a machine or device that involves a physical change of a physical substance. An example of directly obtaining a value includes obtaining a sample from a human subject. Directly obtaining a value includes performing a process using a machine or device such as a fluorescence microscope to obtain fluorescence microscopy data.

[0019] "Administer," "administer," or "dosage" as used herein means implanting, absorbing, ingesting, injecting, positioning, or otherwise introducing, an entity described herein (e.g., a polysaccharide polymer described herein, or a hydrogel or implantable element containing thereof, e.g., a hydrogel or implantable element containing cells), or a composition containing such particles) into a subject, or providing such entity to a subject for administration.

[0020] When used herein, "afibrotic" means a compound or material that mitigates at least one aspect of foreign body reaction (FBR) to an implant, for example, by minimizing the formation of pericapsular fibrous overgrowth (PFO) in the implant. For example, FBR in biological tissue or tissue fluid induced by implanting a polysaccharide polymer or device containing a afibrotic compound (e.g., a hydrogel or implantable element) (e.g., a hydrogel containing a polysaccharide polymer covalently modified with the compounds listed in Table 1) into biological tissue or tissue fluid occurs at a lower amount or at a later time than FBR induced by implanting a afibrotic null reference polymer or device (i.e., having substantially the same composition except lacking any afibrotic compounds) (e.g., a hydrogel capsule formed from the same unmodified polymer and having substantially the same shape and size). In one embodiment, the degree of FBR can be measured, for example, using assays known in the art, such as those described in WO2017 / 075630, or by Vegas, A., et al., Nature The immunological response in tissue or tissue fluid containing the implanted device (e.g., hydrogel capsule) may include, for example, protein adsorption, macrophages, multinucleated foreign body giant cells, eosinophils, neutrophils, T cells, B cells, fibroblasts, and angiogenesis, and may be evaluated by using one or more of the assays / methods described in Biotechnol (above) (e.g., subcutaneous cathepsin measurement of the implanted capsule, Masson trichrome (MT), hematoxylin or eosin staining of tissue sections, quantification of collagen density, cytostaining and confocal microscopy of macrophages (CD68 or F4 / 80), granulocytes (Siglec-F, Ly-6G), myofibroblasts (alpha muscle actin, SMA) or general cell deposition, quantification of 79 RNA sequences of known inflammatory factors and immune cell markers, or FACS analysis of macrophages and neutrophils in the device (e.g., capsule) retrieved after being placed in the peritoneal cavity of a suitable test subject such as an immunocompetent mouse for 14 days.In one embodiment, FBR is evaluated by measuring the levels of one or more immunoreactive biomarkers, such as cathepsin, TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-1, IL-4, IL-5, CCL2, CCL4, and TIMP-1, in the tissue or tissue fluid containing the implant. In some embodiments, FBR is evaluated by examining the amount of PFO in the implant (e.g., a hydrogel capsule) at one or more time points after administration to a suitable test subject (e.g., an immunocompetent mouse). This evaluation can be carried out using assays known in the art, e.g., any of the assays described in this definition. In some embodiments, one aspect of FBR (e.g., PFO) induced by the modified polymer or device of the present invention (e.g., a hydrogel capsule containing a non-fibrous compound described herein placed on an external surface) is at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% lower, or at least about 10%, about 20%, about 40%, or about 50% later than an aspect of the same FBR induced by a non-fibrous null reference polymer or device. In some embodiments, the FBR (e.g., the level of a biomarker(s)) is measured at about 30 minutes, about 1 hour, about 6 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 1 week, about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, or later.

[0021] As used herein, “cells” refers to manipulated or unmanipulated cells.

[0022] As used herein, “effective amount” means an amount of the compounds, modified polymers, or implantable elements described herein (including, for example, cells such as engineered cells, or agents such as therapeutic agents produced by cells such as engineered cells) sufficient to reduce or induce a biological response, for example, to minimize an immune response, or to treat a disease, disorder, or condition. As will be understood by those skilled in the art, the effective amount may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the therapeutic agent, composition, or implantable element, the condition being treated, the mode of administration, and the age and health of the subject. The effective amount encompasses therapeutic and prophylactic treatments. For example, to reduce a foreign body reaction (e.g., PFO) induced by an implantable element, the compounds described herein may be placed on the surface of the implantable element in an amount effective to reduce PFO, or in an amount effective to stop the growth or diffusion of fibrous tissue on or near the implantable element.

[0023] When used herein, "endogenous nucleic acid" refers to nucleic acids that are naturally present in the cells of interest.

[0024] When used herein, "endogenous polypeptide" refers to a polypeptide that is naturally present in the cells of interest.

[0025] "Engineered cell," as used herein, is a cell having modifications not present in nature and typically includes nucleic acid sequences (e.g., DNA or RNA) (e.g., exogenous nucleic acid sequences) or polypeptides that are not present (or present at different levels) in otherwise similar cells under similar conditions. In one embodiment, the engineered cell includes an exogenous nucleic acid (e.g., a vector or a modified chromosomal sequence). In one embodiment, the engineered cell includes an exogenous polypeptide. In one embodiment, the engineered cell includes an exogenous nucleic acid sequence, e.g., a sequence not present in similar unengineered cells, e.g., DNA or RNA. In one embodiment, the exogenous nucleic acid sequence is chromosomal, e.g., an exogenous nucleic acid sequence is an exogenous sequence located within an endogenous chromosomal sequence. In one embodiment, the exogenous nucleic acid sequence is chromosomal or extrachromosomal, e.g., a non-integrated vector. In one embodiment, the exogenous nucleic acid sequence includes an RNA sequence, e.g., mRNA. In one embodiment, the exogenous nucleic acid sequence includes a chromosomal or extrachromosomal exogenous nucleic acid sequence containing a sequence expressed as RNA, e.g., mRNA or regulatory RNA. In one embodiment, the exogenous nucleic acid sequence includes a chromosomal or extrachromosomal exogenous nucleic acid sequence containing a sequence encoding or expressed as a polypeptide. In one embodiment, the exogenous nucleic acid sequence includes a first chromosomal or extrachromosomal exogenous nucleic acid sequence that modulates the conformation or expression of a second nucleic acid sequence, the second amino acid sequence may be exogenous or endogenous. For example, the engineered cell may contain an exogenous nucleic acid that controls the expression of an endogenous sequence. In one embodiment, the engineered cell contains a polypeptide that is present at a different level or distribution than that found in similar unengineered cells. In one embodiment, the engineered cell includes a cell engineered to yield RNA or polypeptide. For example, the engineered cell may contain an exogenous nucleic acid sequence containing a chromosomal or extrachromosomal exogenous nucleic acid sequence containing a sequence expressed as RNA, e.g., mRNA or regulatory RNA. In one embodiment, the manipulated cells include exogenous nucleic acid sequences, which include chromosomal or extrachromosomal nucleic acid sequences that encode or are expressed as polypeptides.In one embodiment, the manipulated cells contain an exogenous nucleic acid sequence that modulates the conformation or expression of an endogenous sequence. In one embodiment, the manipulated cells (e.g., RPE cells) are cultured from a population of stably transfected cells or from a monoclonal cell line.

[0026] As used herein, "exogenous nucleic acid" refers to a nucleic acid that is not naturally present in the target cells, such as manipulated cells.

[0027] When used herein, "exogenous polypeptide" refers to a polypeptide that does not exist naturally in the target cells, such as manipulated cells.

[0028] As used herein, “implantable element” includes cells, for example, multiple cells, for example, cell clusters, where the cells or cell population are arranged whole or partially within a containment component (the containment component is non-cellular), for example, the containment component includes non-cellular components. The term “implantable element” includes devices or materials described herein. In one embodiment, the implantable element inhibits an immune attack or the effects of an immune attack on a contained cell or cell population. In one embodiment, the implantable element includes a semipermeable membrane or a semipermeable polymer matrix or coating. The implantable element described herein includes a polysaccharide polymer (e.g., alginate) having the structure of formula (I) or a pharmaceutically acceptable salt thereof. The implantable element described herein may optionally include a polymer (e.g., polysaccharide polymer, e.g., alginate) or other material modified with another compound (e.g., a non-fibrous compound or peptide).

[0029] As used herein, “pericapsular fibrous overgrowth” or “PFO” refers to a layer of fibrous cells that occurs in part or in whole of a hydrogel or transplantable element as a result of a foreign body reaction to the transplantable element.

[0030] As used herein, "polypeptide" refers to a polymer comprising amino acid residues linked via peptide bonds, and having at least two, and in some embodiments at least 10, 100, or 200, amino acid residues.

[0031] When used herein, “prevention,” “prevention,” and “prevention” refer to administering or applying a therapy, for example, a treatment including administering a composition of cell-encapsulated transplantable elements (e.g., as described herein) before the onset of a disease, disorder, or pathological condition in order to prevent physical signs of said disease, disorder, or pathological condition. In some embodiments, “prevention,” “prevention,” and “prevention” require that no signs or symptoms of the disease, disorder, or pathological condition have developed or been observed.

[0032] "Replacement therapy" or "replacement protein" refers to a therapeutic protein or functional fragment thereof that replenishes or enhances a protein that is reduced, present in insufficient amounts, altered (e.g., mutated), or deficient in a subject having a disease or condition associated with a reduced, altered, or deficient protein. Examples include a specific blood coagulation factor in a specific blood coagulation disorder, or a specific lysosomal enzyme in a specific lysosomal storage disorder. In one embodiment, the replacement therapy or replacement protein provides the function of an endogenous protein. In one embodiment, the replacement therapy or replacement protein has the same amino acid sequence as a naturally occurring variant of the protein being replaced, e.g., a wild-type allele or an allele not associated with the disorder. In one embodiment, the replacement therapy or replacement protein differs in amino acid sequence from a naturally occurring variant, e.g., a wild-type allele or an allele not associated with the disorder, e.g., an allele possessed by the subject, by approximately 1, 2, 3, 4, 5, 10, 15, or 20% or less of amino acid residues.

[0033] As used herein, “Subject” refers to a human or a non-human animal. In one embodiment, the subject is a human (i.e., a male or female of any age group, a child subject (e.g., infancy, childhood, adolescence) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)). In one embodiment, the subject is a non-human animal, e.g., a mammal (e.g., a primate (e.g., a crab-eating macaque or rhesus macaque)). In one embodiment, the subject is a commercially relevant mammal (e.g., a cattle, pig, horse, sheep, goat, cat, or dog) or a bird (e.g., a commercially relevant bird, e.g., a chicken, duck, goose, or turkey). In a given embodiment, the animal is a mammal. The animal may be male or female and may be at any stage of development. The non-human animal may be a transgenic animal.

[0034] When used herein, “treatment,” “to treat,” and “doing treatment” refer to reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of one or more symptoms, signs, or underlying causes of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of symptoms of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of signs of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, reducing, or delaying the onset of underlying causes of a disease, disorder, or condition. In some embodiments, “treatment,” “to treat,” and “doing treatment” require that signs or symptoms of a disease, disorder, or condition have developed or been observed. In other embodiments, treatment may be administered, for example, in the absence of signs or symptoms of a disease or condition, such as in prophylactic treatment. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., in consideration of symptom history and / or in terms of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. In some embodiments, treatment includes prevention, while in other embodiments it does not.

[0035] Selected chemical definitions Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in Handbook of Chemistry and Physics, 75. thThe specific functional groups are identified according to the Ed. (inside cover), and are usually defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional sites and reactivity, are as follows: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0036] The abbreviations used herein have their conventional meanings within the chemical and biological fields. The chemical structures and formulas shown herein are constructed according to standard rules of chemical valency known in the chemical field.

[0037] When a range of values ​​is enumerated, it is intended to include each value within the range and its sub-ranges. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0038] As used herein, "alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C24"). 24 "Alkyl" refers to 1 to 12 carbon atoms ("C1-C1"). In some embodiments, an alkyl group is a group of 1 to 12 carbon atoms ("C1-C1"). 12The alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"), 1 to 6 carbon atoms ("C1-C6 alkyl"), 1 to 5 carbon atoms ("C1-C5 alkyl"), 1 to 4 carbon atoms ("C1-C4 alkyl"), 1 to 3 carbon atoms ("C1-C3 alkyl"), 1 to 2 carbon atoms ("C1-C2 alkyl"), or 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Each example of an alkyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl").

[0039] As used herein, "alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2- 24 The term "alkenyl" refers to an alkenyl group consisting of 2 to 10 carbon atoms ("C2-C2"). In some embodiments, the alkenyl group consists of 2 to 10 carbon atoms ("C2-C2"). 10C2-C4 alkenyl groups have 2-8 carbon atoms ("C2-C8 alkenyl"), 2-6 carbon atoms ("C2-C6 alkenyl"), 2-5 carbon atoms ("C2-C5 alkenyl"), 2-4 carbon atoms ("C2-C4 alkenyl"), 2-3 carbon atoms ("C2-C3 alkenyl"), or 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl groups include the aforementioned C 2-4 This includes alkenyl groups and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Each example of an alkenyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl").

[0040] As used herein, the term “alkynyl” refers to a radical of a linear or branched hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2- 24 The term "alkenyl" refers to an alkenyl group. In some embodiments, the alkynyl group consists of 2 to 10 carbon atoms ("C2-C2"). 10C2-C4 alkynyl groups have 2-8 carbon atoms ("C2-C8 alkynyl"), 2-6 carbon atoms ("C2-C6 alkynyl"), 2-5 carbon atoms ("C2-C5 alkynyl"), 2-4 carbon atoms ("C2-C4 alkynyl"), 2-3 carbon atoms ("C2-C3 alkynyl"), or 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. Each example of an alkynyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl").

[0041] As used herein, the term “heteroalkyl” refers to an acyclic stable linear or branched chain, or a combination thereof, comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen, phosphorus, silicon, or sulfur atom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S, and Si may be substituted at any position in the heteroalkyl group. Exemplary heteroalkyls include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. When "heteroalkyl" is described, it is followed by a specific heteroalkyl, e.g., -CH2O, -NR C RD When such descriptions are given, the terms heteroalkyl and -CH2O or -NR may be used. C R D It is understood that these terms are neither redundant nor mutually exclusive. Rather, specific heteroalkyl groups are described to provide clarity. Therefore, the term "heteroalkyl" refers to specific heteroalkyl groups, e.g., -CH2O, -NR C R D This specification should not be interpreted as excluding such things.

[0042] The terms "alkylene," "alkenylene," "alkynylene," or "heteroalkylene," unless otherwise specified, refer to divalent radicals derived from alkyl, alkenyl, alkynyl, or heteroalkyl groups, either alone or as part of another substituent. Alkylene, alkenylene, alkynylene, or heteroalkylene groups may be written, for example, as C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, or C1-C6 heteroalkylene. In the case of heteroalkylene groups, heteroatoms may also occupy either or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not indicated by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- may represent both -C(O)2R'- and -R'C(O)2-.

[0043] As used herein, “aryl” refers to a radical ("C6- 14 This refers to an aryl group ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10"Aryl" (e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). The aryl group is, for example, C6-C 10 They may be described as member aryls, where the term "member" refers to a non-hydrogen ring atom within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example of an aryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").

[0044] As used herein, “heteroaryl” refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having a ring carbon atom and 1 to 4 ring heteroatoms provided in an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems in which the heteroaryl ring as defined above is fused with one or more aryl groups, and the bond site is in either an aryl or heteroaryl ring, in which case the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site can be on either ring, i.e., on a ring containing a heteroatom (e.g., 2-indolyl) or on a ring not containing a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryls, where the term "member" refers to a non-hydrogen ring atom within the moiety.

[0045] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Each example of the heteroaryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl").

[0046] Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolidinyl, and prinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0047] As used herein, the terms “arylene” and “heteroarylene” mean divalent radicals derived from aryl and heteroaryl, respectively, either alone or as part of another substituent.

[0048] As used herein, "cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C3-C 10 A cycloalkyl group refers to a radical of a non-aromatic cyclic hydrocarbon group that does not have a heteroatom. In some embodiments, a cycloalkyl group may have 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"), or 5 to 10 ring carbon atoms ("C5-C6 cycloalkyl"). 10 A cycloalkyl group has a cycloalkyl group. A cycloalkyl group may be described, for example, as a C4-C7 member cycloalkyl group, where the term "member" refers to a non-hydrogen ring atom within the group. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Examples of C3-C8 cycloalkyl groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), etc. 10 Cycloalkyl groups include, but are not limited to, the aforementioned C3-C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10) and the like are included. As the above examples show, in certain embodiments, the cycloalkyl group may be monocyclic ("monocyclic cycloalkyl") or may contain condensed, crosslinked, or spirocyclic systems, such as bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which the cycloalkyl ring defined above is condensed with one or more aryl groups and the bonding site is on the cycloalkyl ring, in which case the carbon number still refers to the carbon number in the cycloalkyl ring system. Each example of a cycloalkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl").

[0049] As used herein, "heterocyclyl" refers to a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, where the valence allows. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or condensed, bridging, or spirocyclic, for example, bicyclic ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. A “heterocyclyl” includes a ring system in which the heterocyclyl ring defined above is fused with one or more cycloalkyl groups, and the bond site is located on either the cycloalkyl ring or the heterocyclyl ring, or a ring system in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups, and the bond site is located on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, where the term “member” refers to the non-hydrogen ring atom in the site, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each example of a heterocyclyl may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In a given embodiment, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In a given embodiment, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0050] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0051] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azildinyl, oxyranyl, and thiorenyl. Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Exemplary five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianil, and dioxanil. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl or thiomorpholinyl-1,1-dioxide. Exemplary seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl, and thiokanyl. Examples of five-membered heterocyclyl groups condensed to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0052] When used herein, "amino" refers to radical-NR C R D (In the formula, R C and R D These are, independently, hydrogen and C1-C 12 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 10 Aryl, and C5-C 10 It refers to a heteroaryl compound. In some embodiments, amino refers to NH2.

[0053] As used herein, "cyano" refers to the radical-CN.

[0054] As used herein, "halo" or "halogen" means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, either independently or as part of another substituent, unless otherwise stated.

[0055] As used herein, "hydroxyl" or "hydroxy" refers to the radical -OH.

[0056] In this specification, "hydroxyl modifier" refers to a substance or compound that can be bonded to a material containing a hydroxyl moiety (i.e., -OH) at the position of the hydroxyl moiety. For example, a hydroxyl modifier can be bonded to a carbon atom covalently bonded to the hydroxyl moiety. Exemplary hydroxyl modifiers include amines, esters, and thiols. For example, to covalently bond a hydroxyl modifier to a material containing a hydroxyl moiety as described herein, the sugar moiety containing the hydroxyl moiety can be subjected to a predetermined reaction such as oxidation, reduction, or amination to activate the atoms surrounding the hydroxyl moiety.

[0057] Alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted, as defined herein (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). Typically, the term "substituted" means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, e.g., a substituent that results in a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reactions), whether or not the term "optionally" precedes it. Unless otherwise indicated, a “substituted” group has substituents at one or more substitutable positions of the group, and if multiple positions in any given structure are substituted, the substituents are either the same or different at each position. The term “substituted” is intended to include substitution at all acceptable substituents of an organic compound, such as any substituent described herein, resulting in the formation of a stable compound. The present invention intends any such combination to arrive at a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any preferred substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable site.

[0058] Two or more substituents may be optionally attached to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituent is attached to an adjacent member of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituent is attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituent is attached to a non-adjacent member of the base structure.

[0059] The compounds of formula (I) described herein may contain one or more chiral centers and thus may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture of concentrated stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0060] As used herein, a pure enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer-rich). In other words, the "S" form of a compound is enantiomer-rich with respect to the "R" form, as it substantially does not contain the "R" form of the compound. The terms "enantiomerically pure" or "pure enantiomer" indicate that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight of an enantiomer. In a given embodiment, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0061] The compounds of formula (I) described herein may also include one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium), and 3 It can be any isotopic form containing H (T or tritium); C is 12 C, 13 C, and 14 It can be any isotopic form containing C; O is 16 O and 18 It can be any isotopic form containing O; and so on.

[0062] The term “pharmaceutically acceptable salt” means a salt of an active compound prepared with a relatively non-toxic acid or base, depending on the specific substituents found in the compounds described herein. Where a compound used in this disclosure has a relatively acidic functionality, a base addition salt may be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either in its raw state or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. Where a compound used in this disclosure has a relatively basic functionality, an acid addition salt may be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either in its raw state or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids, such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds used in this disclosure possess both basic and acidic functionality, enabling the compound to be converted into either a base or an acid addition salt. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in this disclosure.

[0063] In addition to salt forms, the present disclosure may also use compounds of formula (I) in prodrug form. Prodrugs are compounds that readily undergo chemical changes under physiological conditions in order to provide compounds useful in the present invention. Furthermore, prodrugs can be converted to useful compounds of formula (I) by chemical or biochemical methods in an ex vivo environment.

[0064] Certain compounds of formula (I) described herein may exist in solvated forms, including non-solvated and hydrated forms. Typically, the solvated forms are equivalent to the non-solvated forms and are included within the scope of the present invention. Certain compounds of formula (I) described herein may exist in polycrystalline or amorphous forms. Typically, all physical forms are equivalent for the uses intended by this disclosure and are intended to be within the scope of this disclosure.

[0065] The term "solvate" usually refers to a form of compound associated with a solvent through solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form and then solvated. Preferred solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates.

[0066] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules in a compound hydrate is within a limited ratio to the number of compound molecules in the hydrate. Therefore, a compound hydrate can be represented, for example, by the general formula R·x H₂O (where R is the compound and x is a number greater than 0).

[0067] As used herein, the term “tautomer” refers to a compound whose structurally interchangeable form involves changes in the substitution of hydrogen atoms and electrons. Thus, the two structures may also be in equilibrium with the transfer of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with either an acid or a base. The tautomer form may be related to the realization of optimal chemical reactivity and biological effects of the compound in question.

[0068] symbol [ka] As used herein, "connection" refers to an entity such as a polysaccharide polymer (e.g., a hydrogel-forming polymer such as alginate) or an implantable element (e.g., a device or material). [ka] The connection represented by may refer to a direct bond to an entity such as a polymer or a transplantable element, or to a linkage to an entity via a bonding group. Where used herein, "bonding group" refers to a site for linking the compound of formula (I) to an entity (e.g., a polymer or transplantable element as described herein), and may include any bonding chemistry known in the art. A list of exemplary bonding groups can be found in Bioconjugate Techniques (3 rd This is outlined in (ed., Greg T. Hermanson, Waltham, MA: Elsevier, Inc., 2013). In some embodiments, the bonding groups are alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)-, -OC(O)-, -N(R C )-,-N(R C )C(O)-, -C(O)N(R C )-,-N(R C )N(R D )-, -NCN-, -C(=N(R C )(RD ))O-, -S-, -S(O) x -, -OS(O) x -, -N(R C )S(O) x -, -S(O) x N(R C )-,-P(R F ) y -, -Si(OR A )2-,-Si(R G )(OR A )-, -B(OR A )-, or containing metal, R A , R C , R D , R F , R G Each of x and y is independently as described herein. In some embodiments, the binding group comprises an amine, ketone, ester, amide, alkyl, alkenyl, alkynyl, or thiol. In some embodiments, the binding group is a crosslinking agent. In some embodiments, the binding group is -C(O)(C1-C6-alkylene)-, where alkylene is R 1 It is replaced with R 1 These are as described herein. In some embodiments, the bonding group is -C(O)(C1-C6-alkylene)-, and the alkylene is substituted with 1-2 alkyl groups (e.g., 1-2 methyl groups). In some embodiments, the bonding group is -C(O)C(CH3)2-. In some embodiments, the bonding group is -C(O)(methylene)-, and the alkylene is substituted with 1-2 alkyl groups (e.g., 1-2 methyl groups). In some embodiments, the bonding group is -C(O)CH(CH3)-. In some embodiments, the bonding group is -C(O)C(CH3)-.

[0069] Modified sugar monomers The present invention features a polysaccharide polymer comprising a sugar monomer, wherein the sugar monomer comprises a hydroxyl modifier covalently bonded to a hydroxyl site. In some embodiments, the hydroxyl modifier comprises an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amine, amide, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety. In some embodiments, the hydroxyl modifier comprises an amine.

[0070] The sugar monomer can be any sugar monomer, such as a naturally occurring sugar monomer or a non-naturally occurring sugar monomer. The sugar monomer can comprise 1, 2, 3, 4, 5, 6, 7, 8, or more hydroxyl sites. In one embodiment, the sugar monomer is a triose, tetrose, pentose, hexose, heptose, or octose. In one embodiment, the sugar monomer further comprises an additional functional group, such as a carboxylic acid or an amine. In one embodiment, the sugar monomer further comprises a plurality of additional functional groups. In one embodiment, the sugar monomer is selected from glucose, galactose, mannose, allose, altrose, talose, idose, gulose, fructose, ribose, arabinose, lyxose, xylose, rhamnose, glucuronic acid, galacturonic acid, mannuronic acid, and guluronic acid. In one embodiment, the sugar monomer is mannuronic acid or guluronic acid.

[0071] In one embodiment, the sugar monomer has the formula (I):

Chemical formula

[0072] In one embodiment, the sugar monomer is of formula (Ia): [ka] or having a pharmaceutically acceptable salt structure thereof, where X is O, NR 6 , or S; R 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C )C(O)-, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are one or more R 8 It is arbitrarily replaced by;R 2 and R 3 These are, independently, hydrogen and C 1-6 Alkilen-R 9 , C 1-6 Heteroalkylene-R 9 , C(O)-C 1-6 Alkilen-R 9 , C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R) 7a )-R 9 , or C 1-6 Heteroalkylene-N(R7a )-R 9 Here, each alkylene or alkenyl is one or more R 10 It is arbitrarily substituted by R 2 and R 3 Each of them cannot be both hydrogen; each R 4 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R 8 It is arbitrarily replaced by;R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, N(R) 7a )(R 7b ), OR A , C(O)R B , C(O)OR A , C(O)N(R C )(R D ), N(R C )C(O)R B , halogen, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are one or more R 8 It is arbitrarily replaced by;R 6 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, or C 1-6 It is a haloalkyl, where alkyl, heteroalkyl, and haloalkyl are one or more R10 It is arbitrarily replaced by;R 7a and R 7b These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is one or more R 10 It is arbitrarily substituted by; each R 8 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, oxo, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, OR A , N(R C )(R D ), C(O)OR A , C(O)R B , C(O)N(R C )(R D ), or N(R C )C(O)R B Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl has 0 to 12 R 11 It is replaced by;R A R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl has 0 to 12 R 11 It is replaced by;R B , R C , and R Dis a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is one or more R 11 It is arbitrarily replaced by; or R B and R C These, together with the atoms to which they are bonded, form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which contains one or more R 10 It is arbitrarily replaced with;R 9 is a peptide or non-fibrous compound; each R 10 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, oxo, OR A , N(R C )(R D ), C(O)OR A , C(O)R B , C(O)N(R C )(R D ), or N(R C )C(O)R B Here, each alkyl, heteroalkyl, and haloalkyl is one or more R 11 It is arbitrarily substituted by; each R 11 Independently, C 1-6 They are alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0073] In one embodiment, X is O. In one embodiment, R 1 is OR A In one embodiment, R 5 C(O)OR A or C(O)N(R C )(R D ) is. In one embodiment, R 5 C(O)OR A In one embodiment, R A is hydrogen. In one embodiment, R5 is C(O)N(R C )(R D ) is. In one embodiment, R C and R D Each of these is independently hydrogen, a non-fibrous compound (e.g., the non-fibrous compounds shown in Table 2), or a peptide. In one embodiment, R C and R D One of them is hydrogen, and R C and R D The other is independently a non-fibrous compound (e.g., the non-fibrous compounds shown in Table 2) or a peptide.

[0074] In one embodiment, R 2 C 1-6 Alkilen-R 9 , C 1-6 Heteroalkylene-R 9 , C(O)-C 1-6 Alkilen-R 9 , C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R) 7a )-R 9 , or C 1-6 Heteroalkylene-N(R 7a )-R 9 In one embodiment, R 3 C 1-6 Alkilen-R 9 , C 1-6 Heteroalkylene-R 9 , C(O)-C 1-6 Alkilen-R 9 , C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R) 7a )-R 9, or C 1-6 Heteroalkylene-N(R 7a )-R 9 In one embodiment, R 2 is hydrogen, R 3 C 1-6 Alkilen-R 9 , C 1-6 Heteroalkylene-R 9 , C(O)-C 1-6 Alkilen-R 9 , C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R) 7a )-R 9 , or C 1-6 Heteroalkylene-N(R 7a )-R 9 In one embodiment, R 2 C 1-6 Alkilen-R 9 , C 1-6 Heteroalkylene-R 9 , C(O)-C 1-6 Alkilen-R 9 , C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R) 7a )-R 9 , or C 1-6 Heteroalkylene-N(R 7a )-R 9 And R 3 It is hydrogen.

[0075] In some embodiments, R 1 is O. In some embodiments, R 5 C(O)OR A or C(O)N(R C)(R D ) is. In some embodiments, R 5 is C(O)N(R C )(R D ) and R C and R D These are, independently, hydrogen, a non-fibrous compound (e.g., the non-fibrous compounds shown in Table 2), or a peptide (e.g., RGD peptide). In some embodiments, R C and R D One of them is hydrogen, and R C and R D The other is independently a non-fibrous compound (e.g., the non-fibrous compounds shown in Table 2) or a peptide (e.g., RGD peptide). In some embodiments, R 9 These are non-fibrous compounds (for example, the non-fibrous compounds shown in Table 2).

[0076] In one embodiment, the sugar monomer is of formula (Ib): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 2 , R 3 , R 5 , and each of their sub-variable elements are as defined herein.

[0077] In one embodiment, the sugar monomer is of formula (Ic): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 3a , R 5 , R 9 Each of , n, and their sub-variable elements is as defined herein.

[0078] In one embodiment, the sugar monomer is of formula (Id): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 2 , R 3 , R C , and R D , and each of their sub-variable elements are as defined herein.

[0079] In one embodiment, the sugar monomer is given by formula (Ie): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 3a , R 9 , R C , R D Each of , n, and their sub-variable elements is as defined herein.

[0080] In one embodiment, R 9 It is a non-fibrous compound. In one embodiment, n is 2.

[0081] In one embodiment, the sugar monomer is given by formula (If): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 3 , R 5 , and each of their sub-variable elements are as defined herein; P 1 is an aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is one or more R 12 It is arbitrarily replaced by; L 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(RC )-, or -N(R C )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R 8 It is arbitrarily replaced by;Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 8 It is arbitrarily replaced by;R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 It is a haloalkyl or halo; each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a and R 8 This is defined herein.

[0082] In one embodiment, the sugar monomer is of formula (Ig): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 3 , R 12 , R C , R D , and each of their sub-variable elements are as defined herein; P 1 is an aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is one or more R 12 It is arbitrarily replaced by; L 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C)C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R 8 It is arbitrarily replaced by;Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 8 It is arbitrarily replaced by;R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 It is a haloalkyl or halo; each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a and R 8 This is defined herein. In one embodiment, P 1 and P 2 Each of these is independently a heteroaryl. In one embodiment, P 1 and P 2 Each of these is independently a monocyclic heteroaryl. In one embodiment, P 1 and P 2 Each of these is independently a nitrogen-containing heteroaryl. In one embodiment, P 1 and P 2 Each of these is independently a monocyclic nitrogen-containing heteroaryl. In one embodiment, P 1 and P 2 Each of these is independently a 5-membered heteroaryl. In some embodiments, P is a 5-membered nitrogen-containing heteroaryl.

[0083] In one embodiment, P 1 is a heteroaryl (e.g., triazolyl). In one embodiment, P 1 teeth [ka] And R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 It is a haloalkyl or halo.

[0084] In one embodiment, P 1 is one or more R 12 It is a triazolyl substituted with R. In one embodiment, R 12 Deuterium, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azide, -N(R) C1 )(R D1 ), -N(R C1 )C(O)R B1 ,-C(O)N(R C1 ), -S(O) x R E1 , -N(R C1 )S(O) x R E1 , -S(O) x N(R C1 )(R D1 ), -P(R F1 ) y These are cycloalkyl, heterocyclyl, aryl, and heteroaryl. In one embodiment, R 12 is deuterium, alkyl, heteroalkyl, halogen, cyano, or azide. In one embodiment, R 12 is chloro. In one embodiment, P 1 teeth [ka] And R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 It is a haloalkyl or halo. In one embodiment, P 1 teeth [ka] That is the case.

[0085] In one embodiment, L 1 is non-existent, or C 1-6It is an alkylene (e.g., -CH2-). In one embodiment, Z 1 is an aryl, heteroaryl, or heterocyclyl. In one embodiment, Z 1 is a heterocycline. In one embodiment, Z 1 teeth [ka] That is the case.

[0086] In one embodiment, the sugar moiety is selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0087] In one embodiment, the sugar moiety is selected from compounds 100 to 127. In one embodiment, the sugar moiety is compound 100. In one embodiment, the sugar moiety is compound 101. In one embodiment, the sugar moiety is compound 102. In one embodiment, the sugar moiety is compound 103. In one embodiment, the sugar moiety is compound 104. In one embodiment, the sugar moiety is compound 105. In one embodiment, the sugar moiety is compound 106. In one embodiment, the sugar moiety is compound 107. In one embodiment, the sugar moiety is compound 108. In one embodiment, the sugar moiety is compound 109. In one embodiment, the sugar moiety is compound 110. In one embodiment, the sugar moiety is compound 111. In one embodiment, the sugar moiety is compound 112. In one embodiment, the sugar moiety is compound 113. In one embodiment, the sugar moiety is compound 114. In one embodiment, the sugar moiety is compound 115. In one embodiment, the sugar moiety is compound 116. In one embodiment, the sugar moiety is compound 117. In one embodiment, the sugar moiety is compound 118. In one embodiment, the sugar moiety is compound 119. In one embodiment, the sugar moiety is compound 120. In one embodiment, the sugar moiety is compound 121. In one embodiment, the sugar moiety is compound 122. In one embodiment, the sugar moiety is compound 123. In one embodiment, the sugar moiety is compound 124. In one embodiment, the sugar moiety is compound 125. In one embodiment, the sugar moiety is compound 126. In one embodiment, the sugar moiety is compound 127. In one embodiment, the sugar moiety is compound 128. In one embodiment, the sugar moiety is compound 129. In one embodiment, the sugar moiety is compound 130. In one embodiment, the sugar moiety is compound 131. In one embodiment, the sugar moiety is compound 132. In one embodiment, the sugar moiety is compound 133. In one embodiment, the sugar moiety is compound 134. In one embodiment, the sugar moiety is compound 135.

[0088] In one embodiment, the sugar moiety further comprises a non-fibrous compound covalently bonded to another functional group on the sugar moiety, for example. In one embodiment, the non-fibrous compound is selected from the compounds shown in Table 2. [Table 2-1] Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7

[0089] In one embodiment, the non-fibrous compound is selected from compounds 200 to 254 or their salts. In one embodiment, the non-fibrous compound is compound 200. In one embodiment, the non-fibrous compound is compound 201. In one embodiment, the non-fibrous compound is compound 202. In one embodiment, the non-fibrous compound is compound 203. In one embodiment, the non-fibrous compound is compound 204. In one embodiment, the non-fibrous compound is compound 205. In one embodiment, the non-fibrous compound is compound 206. In one embodiment, the non-fibrous compound is compound 207. In one embodiment, the non-fibrous compound is compound 208. In one embodiment, the non-fibrous compound is compound 209. In one embodiment, the non-fibrous compound is compound 210. In one embodiment, the non-fibrous compound is compound 211. In one embodiment, the non-fibrous compound is compound 212. In one embodiment, the non-fibrous compound is compound 213. In one embodiment, the non-fibrous compound is compound 214. In one embodiment, the non-fibrous compound is compound 215. In one embodiment, the non-fibrous compound is compound 216. In one embodiment, the non-fibrous compound is compound 200. In one embodiment, the non-fibrous compound is compound 217. In one embodiment, the non-fibrous compound is compound 218. In one embodiment, the non-fibrous compound is compound 219. In one embodiment, the non-fibrous compound is compound 220. In one embodiment, the non-fibrous compound is compound 221. In one embodiment, the non-fibrous compound is compound 222. In one embodiment, the non-fibrous compound is compound 223. In one embodiment, the non-fibrous compound is compound 224. In one embodiment, the non-fibrous compound is compound 225. In one embodiment, the non-fibrous compound is compound 226. In one embodiment, the non-fibrous compound is compound 227. In one embodiment, the non-fibrous compound is compound 228. In one embodiment, the non-fibrous compound is compound 229. In one embodiment, the non-fibrous compound is compound 230. In one embodiment, the non-fibrous compound is compound 231. In one embodiment, the non-fibrous compound is compound 232. In one embodiment, the non-fibrous compound is compound 233. In one embodiment, the non-fibrous compound is compound 234.In one embodiment, the non-fibrous compound is compound 235. In one embodiment, the non-fibrous compound is compound 236. In one embodiment, the non-fibrous compound is compound 237. In one embodiment, the non-fibrous compound is compound 238. In one embodiment, the non-fibrous compound is compound 239. In one embodiment, the non-fibrous compound is compound 240. In one embodiment, the non-fibrous compound is compound 241. In one embodiment, the non-fibrous compound is compound 242. In one embodiment, the non-fibrous compound is compound 243. In one embodiment, the non-fibrous compound is compound 244. In one embodiment, the non-fibrous compound is compound 245. In one embodiment, the non-fibrous compound is compound 246. In one embodiment, the non-fibrous compound is compound 247. In one embodiment, the non-fibrous compound is compound 248. In one embodiment, the non-fibrous compound is compound 249. In one embodiment, the non-fibrous compound is compound 250. In one embodiment, the non-fibrous compound is compound 251. In one embodiment, the non-fibrous compound is compound 252. In one embodiment, the non-fibrous compound is compound 253. In one embodiment, the non-fibrous compound is compound 254. In one embodiment, the non-fibrous compound is compound 255. In one embodiment, the non-fibrous compound is compound 256.

[0090] In one embodiment, the sugar moiety further comprises a peptide covalently bonded to another functional group on the sugar moiety (e.g., the sugar moiety of formula (I)). In one embodiment, the peptide is a cell-binding peptide. As used herein, “cell-binding peptide (CBP)” means a linear or cyclic peptide comprising an amino acid sequence derived from the cell-binding domain of a ligand of a cell adhesion molecule (CAM) (e.g., mediating cell-matrix or cell-cell connections). CBPs are less than 50, 40, 30, 25, 20, 15, or 10 amino acids in length. In one embodiment, CBPs are 3–12 amino acids, 4–10 amino acids, or 3, 4, 5, 6, 7, 8, 9, or 10 amino acids in length. The CBP amino acid sequence may be identical to a naturally occurring binding domain sequence or a conserved variant thereof. In one embodiment, the CAM ligand is a mammalian protein. In one embodiment, the CAM ligand is a human protein selected from the group of proteins listed in Table 1 below. In one embodiment, CBP comprises a cell-binding sequence listed in Table 1 below or a conservedly substituted variant thereof. In one embodiment, CBP comprises at least one of the cell-binding sequences listed in Table 3 below. In one embodiment, CBP is essentially composed of the cell-binding sequences listed in Table 3 below. In one embodiment, CBP is an RGD peptide, meaning that the peptide comprises the amino acid sequence RGD (SEQ ID NO: 20) and optionally contains one or more additional amino acids located at either or both of the N-terminus and / or C-terminus. In one embodiment, the peptide is the peptide shown in Table 3. [Table 3]

[0091] In one embodiment, the peptide includes SEQ ID NO: 1. In one embodiment, the peptide includes SEQ ID NO: 2. In one embodiment, the peptide includes SEQ ID NO: 3. In one embodiment, the peptide includes SEQ ID NO: 4. In one embodiment, the peptide includes SEQ ID NO: 5. In one embodiment, the peptide includes SEQ ID NO: 6. In one embodiment, the peptide includes SEQ ID NO: 7. In one embodiment, the peptide includes SEQ ID NO: 8. In one embodiment, the peptide includes SEQ ID NO: 9. In one embodiment, the peptide includes SEQ ID NO: 10. In one embodiment, the peptide includes SEQ ID NO: 11. In one embodiment, the peptide includes SEQ ID NO: 12. In one embodiment, the peptide includes SEQ ID NO: 13. In one embodiment, the peptide includes SEQ ID NO: 14. In one embodiment, the peptide includes SEQ ID NO: 15. In one embodiment, the peptide includes SEQ ID NO: 16. In one embodiment, the peptide includes SEQ ID NO: 17. In one embodiment, the peptide includes SEQ ID NO: 18. In one embodiment, the peptide includes SEQ ID NO: 19. In one embodiment, the peptide includes SEQ ID NO: 20. In one embodiment, the peptide includes SEQ ID NO: 21. In one embodiment, the peptide includes SEQ ID NO: 22. In one embodiment, the peptide includes SEQ ID NO: 23. In one embodiment, the peptide includes SEQ ID NO: 24. In one embodiment, the peptide includes SEQ ID NO: 25. In one embodiment, the peptide includes SEQ ID NO: 26. In one embodiment, the peptide includes SEQ ID NO: 27. In one embodiment, the peptide includes SEQ ID NO: 28. In one embodiment, the peptide is the peptide disclosed in WO2020069429A1, which is incorporated herein by reference as a whole.

[0092] Modified polymers The polysaccharide polymers described herein include sugar moieties modified with hydroxyl modifiers. In one embodiment, the polysaccharide polymer may be linear, branched, or crosslinked polysaccharide polymers, or polysaccharide polymers of a selected molecular weight range, degree of polymerization, viscosity, or melt flow rate. Branched polysaccharide polymers may include one or more of the following types: star polymers, comb polymers, brush polymers, dendrimerized polymers, graftco(polymers), ladder polymers, and dendrimers. The polysaccharide polymer may be a thermoresponsive polymer, e.g., a gel (e.g., becoming solid or liquid upon exposure to heat or a given temperature) or a photocrosslinkable polymer. In some embodiments, the polysaccharide polymer consists of a single type of repeating monomer units. In other embodiments, the polysaccharide polymer consists of different types of repeating monomer units (e.g., two types of repeating monomer units, three types of repeating monomer units, e.g., polymer blends).

[0093] In one embodiment, the polysaccharide polymer is cellulose, for example, carboxymethylcellulose. In one embodiment, the polysaccharide polymer is polylactide, polyglycoside, or polycaprolactone. In one embodiment, the polysaccharide polymer is hyaluronate, for example, sodium hyaluronate. In one embodiment, the polymer is collagen, elastin, or gelatin.

[0094] In some embodiments, the polysaccharide polymer is a hydrogel-forming polymer. Hydrogel-forming polymers contain a hydrophilic structure and are therefore capable of holding large amounts of water within a three-dimensional network. Hydrogel-forming polymers may include polymers that form homopolymer hydrogels, copolymer hydrogels, or multipolymer interpenetrating polymer hydrogels, and may be essentially amorphous, semicrystalline, or crystalline, as described, for example, in Ahmed (2015) J Adv Res 6:105-121. Exemplary hydrogel-forming polymers include proteins (such as collagen), gelatin, polysaccharides (such as starch, alginates, hyaluronates, and agarose), and synthetic polysaccharides.

[0095] Examples of polysaccharides include alginates, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, amylose, chitin, chitosan, or derivatives or variants thereof (e.g., those described in Laurienzo (2010), Mar Drugs 9:2435-65). The polysaccharide polymer may include heparin, chondroitin sulfate, dermatan, dextran, or carboxymethylcellulose. In some embodiments, the polysaccharide polymer is a crosslinked polymer. In some embodiments, the polysaccharide polymer is a cell surface polysaccharide.

[0096] In some embodiments, the polysaccharide polymer is an alginate. The alginate is a polysaccharide composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G). In some embodiments, the alginate is a high-guluronic acid (G) alginate containing about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more guluronic acid (G). In some embodiments, the alginate is a high-mannuronic acid (M) alginate containing about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more mannuronic acid (M). In some embodiments, the M:G ratio is about 1. In some embodiments, the M:G ratio is less than 1. In some embodiments, the M:G ratio is greater than 1. In some embodiments, the alginate has an approximate molecular weight of <75 kDa and optionally a G:M ratio ≥1.5. In some embodiments, the alginate has an approximate molecular weight of 75 kDa to 150 kDa and optionally a G:M ratio ≥1.5. In some embodiments, the alginate has an approximate molecular weight of 150 to 250 kDa and optionally a G:M ratio ≥1.5.

[0097] A polysaccharide polymer (e.g., any of the polymers described herein, e.g., any of the alginates described herein) containing a sugar moiety having the structure of formula (I) or a pharmaceutically acceptable salt thereof may be modified in one or more monomer units. In some embodiments, at least 0.5 percent of the sugar monomers of the polysaccharide polymer have the structure of formula (I) (e.g., at least 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99 percent or more of the sugar monomers have the structure of formula (I)). In some embodiments, 0.5 to 50%, 10 to 90%, 10 to 50%, or 25 to 75% of the sugar monomers of the polysaccharide polymer have the structure of formula (I). In some embodiments, 1 to 20% of the sugar monomers of the polysaccharide polymer have the structure of formula (I). In some embodiments, 1-10% of the sugar monomers of the polysaccharide polymer have the structure of formula (I).

[0098] In some embodiments, the polysaccharide polymer (if it contains sugar monomers having the structure of formula I) includes an increase in %N of at least 0.1, 0.2, 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10%N by weight (compared to the unmodified polymer), where %N is determined by elemental analysis and corresponds to the amount of compound of formula (I) in the modified polymer.

[0099] In some embodiments, the polysaccharide polymer (if it contains a sugar monomer having the structure of formula (I)) includes an increase in %N of 0.1 to 10%N by weight (compared to the unmodified polymer), where %N is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0100] In some embodiments, the polysaccharide polymer (if it contains a sugar monomer having the structure of formula (I)) includes an increase in %N of 0.1 to 2%N by weight (compared to the unmodified polymer), where %N is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0101] In some embodiments, the polysaccharide polymer (if it contains a sugar monomer having the structure of formula (I)) includes an increase in %N of 2-4%N by weight (compared to the unmodified polymer), where %N is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0102] In some embodiments, the polysaccharide polymer (if it contains a sugar monomer having the structure of formula (I)) includes an increase in %N of 4-8%N by weight (compared to the unmodified polymer), where %N is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0103] In some embodiments, the polysaccharide polymers (e.g., alginates) described herein each comprise a sugar monomer having one or more of the formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), or a pharmaceutically acceptable salt thereof. In some embodiments, the polymer (e.g., alginate) is modified with the compounds shown in Table 2. In some embodiments, a polymer modified with a compound of formula (I) (e.g., an alginate) is not a modified polymer described in any one of WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 187225, WO2016 / 019391, WO2017 / 075630, WO2017 / 075631, WO2018 / 067615, WO2019 / 169333, and US2016-0030359.

[0104] portable elements This disclosure also features an implantable element (e.g., a device or material) comprising a polysaccharide polymer of formula (I) as described herein or a pharmaceutically acceptable salt thereof. The surface of the implantable element may further comprise a material modified with a non-fibrous compound, for example, as shown in Table 2. In one embodiment, the polysaccharide polymer of formula (I) is present on the surface of the implantable element (e.g., an external or internal surface). The implantable element comprising the polysaccharide polymer of formula (I) may have improved properties compared to a reference implantable element (e.g., an identical implantable element except lacking the polysaccharide polymer of formula (I)). In one embodiment, the improved property is a reduction in the foreign body reaction to the implantable element when administered to a subject (e.g., a reduction in the amount and / or delay in the occurrence of PFO).

[0105] In some embodiments, the transplantable element includes cells. In some embodiments, the cells are manipulated cells. In some embodiments, the cells are arranged whole or partially with the transplantable element. The transplantable element may include a containment element that partially or completely encapsulates or coats the cells. In one embodiment, the transplantable element includes a containment component which is formed or may be formed in situ on or around cells, such as a group of cells, such as a cell cluster, or on a matrix containing microcarriers, such as beads, or cells or groups of cells.

[0106] The implantable element may include any material, such as the polymers or other materials described herein. In some embodiments, the implantable element is composed of one material or many types of materials. The implantable element may include non-organic or metallic components or materials, such as steel (e.g., stainless steel), titanium, or other metals or alloys. The implantable element may also include non-metallic components or materials, such as ceramic or hydroxyapatite elements.

[0107] The implantable element may include components or materials made of conductive materials (such as gold, platinum, palladium, titanium, copper, aluminum, silver, metals, or any combination thereof).

[0108] The implantable element may include multiple components, for example, multiple components disclosed herein, such as metals, plastics, ceramics, composite materials, or hybrid materials.

[0109] Exemplary transplantable elements include materials such as metals, metal alloys, ceramics, polymers, fibers, inert materials, and combinations thereof. A transplantable element may consist entirely of one type of material, or it may only relate to a surface or the surface of the transplantable element (e.g., an outer or inner surface).

[0110] In some embodiments, the portable element (e.g., device or material) includes a metal or metallic alloy. Exemplary metals or metallic alloys include titanium and titanium group alloys (e.g., Nitinol, nickel-titanium alloy, thermal memory alloy materials), platinum, platinum group alloys, stainless steel, tantalum, palladium, zirconium, niobium, molybdenum, nickel-chromium, chromium-molybdenum alloy, or a given cobalt alloy (e.g., cobalt-chromium and cobalt-chromium-nickel alloy). For example, the metallic material may be stainless steel grade 316 (SS 316L) (composed of Fe, <0.3% C, 16-18.5% Cr, 10-14% Ni, 2-3% Mo, <2% Mn, <1% Si, <0.45% P, and <0.03% S). In metal-containing implantable elements, the amount of metal (e.g., by weight %, actual weight) may be at least 5 percent, e.g., at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99 percent, or more, e.g., w / w, less than 20 percent, e.g., less than 20, 15, 10, 5, 1, 0.5, 0.1 percent or less.

[0111] In some embodiments, the implantable element (e.g., device or material) is ceramic. Exemplary ceramic materials include oxides, carbides, or nitrides of transition elements such as titanium oxide, hafnium oxide, iridium oxide, chromium oxide, aluminum oxide, and zirconium oxide. Silicon-based materials such as silica may also be used. In ceramic-containing implantable elements, the amount of ceramic (e.g., wt%, actual weight) may be at least 5 percent, e.g., at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99 percent, or more, e.g., w / w, less than 20 percent, e.g., less than 20, 15, 10, 5, 1, 0.5, 0.1 percent or less.

[0112] In some embodiments, the implantable element comprises a polymer (e.g., hydrogel, plastic) component. Exemplary polymers include polyethylene, polypropylene, polystyrene, polyester (e.g., PLA, PLG, or PGA, polyhydroxyalkanoate (PHA), or other bioabsorbable plastics), polycarbonate, polyvinyl chloride (PVC), polyethersulfone (PES), polyacrylate (e.g., acrylic or PMMA), hydrogel (e.g., acrylic polymer or a blend of acrylic polymer and silicone polymer), polysulfone, polyetheretherketone, thermoplastic elastomer (TPE or TPU), thermosetting elastomer (e.g., silicone (e.g., silicone elastomer)), poly-p-xylylene (parylene), fluoropolymer (e.g., PTFE), and polyacrylics such as poly(acrylic acid) and / or poly(acrylamide), or mixtures thereof. In polymer-containing implantable elements, the amount of polymer (e.g., by weight %, actual weight) may be at least 5 percent, e.g., at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99 percent, or more, e.g., w / w, less than 20 percent, e.g., less than 20, 15, 10, 5, 1, 0.5, 0.1 percent, or less.

[0113] In some embodiments, the implantable element (e.g., a device or material) comprises a polymer, which is (i) modified with a compound of formula (I), and (ii) covalently or non-covalently associated with components of the implantable element (e.g., the surface of the implantable element). In some embodiments, the polymer is covalently associated with components of the implantable element (e.g., on the inner or outer surface of the implantable element). In some embodiments, the polymer is non-covalently associated with components of the implantable element (e.g., on the inner or outer surface of the implantable element). The polymer can be applied to the implantable element by various techniques in the art, including, but not limited to, spraying, wetting, immersion, dipping, e.g., dip coating (e.g., intraoperative dip coating), painting, or by other means of applying a hydrophobic polymer to the surface of the implantable element.

[0114] In one embodiment, the implantable element comprises a flexible polymer such as alginate (e.g., any of the chemically modified alginates described herein), PLA, PLG, PEG, CMC, or a mixture thereof (referred to herein as the “polymer-encapsulated implantable device”).

[0115] In some embodiments, the implantable element comprises a hydrogel-forming polymer. The hydrogel-forming polymer has a hydrophilic structure and is therefore capable of holding a large amount of water within a three-dimensional network. The hydrogel-forming polymer may include polymers that form homopolymer hydrogels, copolymer hydrogels, or multipolymer interpenetrating polymer hydrogels, and may be essentially amorphous, semicrystalline, or crystalline, as described, for example, Ahmed (2015) J Adv Res 6:105-121. Exemplary hydrogel-forming polymers include proteins (e.g., collagen), gelatin, polysaccharides (e.g., starch, alginate, hyaluronate, agarose), and synthetic polymers. In some embodiments, the hydrogel-forming polymer is a polysaccharide (e.g., alginate).

[0116] In some embodiments, the transplantable element comprises a polysaccharide. Exemplary polysaccharides include alginates, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, amylose, chitin, chitosan, or derivatives or variants thereof (e.g., those described in Laurienzo (2010), Mar Drugs 9:2435-65). The transplantable element may also comprise polysaccharides including heparin, chondroitin sulfate, dermatan, dextran, or carboxymethylcellulose. In some embodiments, the polysaccharide is a crosslinked polymer. In some embodiments, the polysaccharide is a cell surface polysaccharide.

[0117] In some embodiments, the transplantable element comprises an alginate. In some embodiments, the M:G ratio in the alginate is about 1. In some embodiments, the M:G ratio in the alginate is less than 1. In some embodiments, the M:G ratio in the alginate is greater than 1. In some embodiments, the alginate is one of the modified alginates described herein.

[0118] In one embodiment, the transplantable element is formed or can be formed in situ on or around cells, such as a group of cells, such as a cell cluster, or on a matrix containing microcarriers, such as beads, or cells or groups of cells.

[0119] In one embodiment, the transplantable element is formed before being combined with contained cells, such as a group of cells, such as a cell cluster, or on a matrix containing microcarriers, such as beads, or cells or cell groups. The transplantable element may include proteins or polypeptides such as antibodies, proteins, enzymes, or growth factors. The transplantable element may include active or inactive fragments of proteins or polypeptides such as glucose oxidase (e.g., for glucose sensors), kinases, phosphatases, oxygenases, hydrogenases, or reductases.

[0120] The implantable elements included herein include implantable elements configured with lumens, such as tubular devices, such as catheters, which have one, two, or more openings. A typical stent is an example of a device configured with lumens and having two openings. Other examples include shunts.

[0121] The implantable elements included in this specification include, for example, flexible implantable elements configured to conform to the shape of the body.

[0122] The transplantable elements included herein include components for stabilizing the position of the transplantable elements, such as adhesives, or fasteners, such as torque-based or friction-based fasteners, such as screws or pins.

[0123] The implantable elements included herein may be configured to monitor exogenous substances such as therapeutic agents or toxins, or endogenous endogenous products such as polypeptides such as insulin or glucose. In some embodiments, the implantable elements are diagnostic means.

[0124] The implantable elements included herein may be configured to release substances such as exogenous substances, for example, therapeutic agents described herein. In some embodiments, the therapeutic agent is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is a biological material. In some embodiments, the therapeutic agent is a nucleic acid (e.g., RNA or DNA), a protein (e.g., a hormone, enzyme, antibody, antibody fragment, antigen, or epitope), a small molecule, a lipid, a drug, a vaccine, or any derivative thereof.

[0125] The implantable elements described herein may be configured to change conformation in response to bodily signals or movements, such as artificial joints, e.g., knees, hips, or other artificial joints.

[0126] Examples of implantable elements include stents, shunts, dressings, ophthalmic devices, ports, sensors, orthopedic fixation devices, implants (e.g., dental implants, ophthalmic implants, silicone implants, corneal implants, dermal implants, gastric implants, facial implants, hip implants, bone implants, cochlear implants, penile implants, incontinence control implants), skin covering devices, dialysis media, drug delivery devices, artificial or manipulated organs (e.g., spleen, kidneys, liver, or heart), and drainage devices (e.g., bladder drainage devices). This includes vices, cell selection systems, adhesives (e.g., cement, clamps, clips), contraceptive devices, intrauterine devices, defibrillators, dosimeters, electrodes, pumps (e.g., infusion pumps), filters, embolization devices, fasteners, fillers, fixators, grafts, hearing aids, cardiac or cardiac-related devices (e.g., pacemakers, heart valves), batteries or power sources, hemostatic agents, incontinence devices, intervertebral fusion devices, intraoral devices, lenses, meshes, needles, nervous system stimulants, patches, peritoneal access devices, plates, plugs, pressure monitoring devices, rings, transponders, and valves. It also includes devices used in one or more of the following fields: anesthesiology, cardiology, clinical chemistry, otolaryngology, dentistry, gastroenterology, urology, hematology, immunology, microbiology, neurology, obstetrics / gynecology, ophthalmology, orthopedics, pathology, physical therapy, radiology, general surgery or plastic surgery, veterinary medicine, psychiatry, surgery, and / or clinical toxicology.

[0127] The portable elements included herein include FDA Class 1, 2, or 3 devices, such as unclassified, un-classified, or classified devices for humanitarian use (HUDs).

[0128] In some embodiments, the transplantable element includes encapsulated or captured cells or tissues. The cells or tissues may be encapsulated or captured in a polymer. In some embodiments, the transplantable element includes cells, such as cells, placed within a polymer containment component (e.g., alginate).

[0129] In some embodiments, the transplantable element targets or is designed for a predetermined system of the body, such as the nervous system (e.g., the peripheral nervous system (PNS) or the central nervous system (CNS)), the vascular system, the skeletal system, the respiratory system, the endocrine system, the lymphatic system, the reproductive system, or the gastrointestinal tract. In some embodiments, the transplantable element targets the CNS. In some embodiments, the transplantable element targets or is designed for a predetermined part of the body, such as the blood, eyes, brain, skin, lungs, stomach, mouth, ears, legs, feet, hands, liver, heart, kidneys, bones, pancreas, spleen, large intestine, small intestine, spinal cord, muscles, ovaries, uterus, vagina, or penis.

[0130] The components or materials used in the implantable element (or the entire implantable element) may be optimized for one or more of the following: biocompatibility (e.g., minimizing immune rejection or fibrosis); thermal resistance; elasticity; tensile strength; chemical resistance (e.g., resistance to oils, greases, disinfectants, bleaches, processing aids, or other chemicals used in the production, use, cleaning, sterilization, and disinfection of the device); electrical properties; surface and volume conductivity or resistivity, dielectric strength; comparative tracking index; mechanical properties; shelf life, long-term sterilization endurance (e.g., the ability to withstand sterilization processes such as steam, dry heat, ethylene oxide (EtO), electron beam, and / or gamma radiation while maintaining properties relevant to the intended use of the device), e.g., thermal resistance to autoclave / steam conditions, hydrolysis stability during steam sterilization, chemical resistance to EtO, resistance to high-energy radiation (e.g., electron beam, UV, and gamma); or crystalline structure.

[0131] Transplantable elements can be constructed in vivo (for example, injectable substances that form a structured shape in vivo, for example, at body temperature) or ex vivo.

[0132] The implantable elements may have nanoscale dimensions and may include nanoparticles such as nanoparticles made from polymers described herein, such as PLA. The nanoparticles may be chemically modified, for example, modified to prevent uptake by macrophages and Kupfer cells (e.g., a process called opsonization), or modified to alter the circulating half-life of the nanoparticles. The nanoparticles may include iron nanoparticles (injectable) (e.g., iron nanoparticles from Advanced Magnetics). Exemplary nanoparticles are described in Veiseh et al (2010) Adv Drug Deliv Rev 62:284-304.

[0133] The transplantable elements may be configured for transplantation or administration to any body part of the subject, or to be administered to, transplanted to, or otherwise positioned in or on such body part, including, but not limited to, the skin, mucous membrane surfaces, body cavities, intraperitoneal (IP) spaces, the central nervous system (CNS) (e.g., brain or spinal cord), the peripheral nervous system, organs (e.g., heart, liver, kidneys, bladder, pancreas, prostate, spleen, lungs), the lymphatic system, the vascular system, the oral cavity, the nasal cavity, teeth, gums, gastrointestinal tract, bones, hip joints, adipose tissue (e.g., subcutaneous fat), muscle tissue, breast tissue, circulating blood, eyes, breasts, vagina, uterus, joints (e.g., knees, hips, or spine), adjacent to nerves, and malignant or non-malignant tumors located on, in, or near any of the aforementioned.

[0134] In some embodiments, the implantable element is configured for implantation, administration, or placement within the IP space, such as the peritoneal cavity, retinoplasm, or omental bursa. The omental bursa, also known as the lesser omentum, refers to a cavity located in the abdomen formed by the retinoplasm, and is adjacent to, for example, the greater omentum, lesser omentum, stomach, small intestine, large intestine, liver, spleen, gastrosplenic ligament, adrenal gland, and pancreas. Typically, the omental bursa is connected to the bursa greatus via the greater omental foramen (i.e., Winslow's foramen). The implantable element may be implanted or administered into the IP space, peritoneal cavity (e.g., retinoplasm, e.g., omental bursa) via injection or catheter, or placed on a surface within the peritoneal cavity (e.g., retinoplasm, e.g., omental bursa). Additional considerations for implantation, administration, or placement of the implantable element into the retinoplasm (e.g., omental bursa) are provided in M. Pellicciaro et al. (2017) CellR4 5(3):e2410.

[0135] In some embodiments, the implantable element is configured for implantation, administration, or is implanted, administered, or otherwise positioned within the central nervous system (CNS) (e.g., brain or spinal cord) and its corresponding tissues and cavities (e.g., dorsal body cavities including the cranial cavity and spinal canal). In some embodiments, the implantable element is configured for implantation, administration, or is implanted, administered, or otherwise positioned within intracranial spaces (e.g., intraparenchymal spaces, intraventricular spaces, or subdural spaces). The implantable element may be implanted into the CNS through a hole drilled in the skull or positioned on a surface within the CNS and delivered by injection or catheter.

[0136] In some embodiments, the implantable element is configured for intraocular implantation, administration, or is implanted, administered, or otherwise positioned in one or more of any intraocular surfaces or cavities, such as the retina, cornea, epithelium, aqueous humor, or vitreous space. The implantable element may be implanted intraocularly or positioned on an intraocular surface by incision and / or injection.

[0137] The implantable element may include an electrochemical sensor, for example, an electrochemical sensor including a working electrode and a reference electrode. For example, the electrochemical sensor includes a working electrode and a reference electrode, the reference electrode reacting with an analyte to produce a sensor measurement related to the concentration of the analyte in a fluid to which an eye-wearable device is exposed. The implantable element may include, for example, a window of a transparent polymer material having concave and convex surfaces, for example, a substrate at least partially embedded in a transparent polymer material. The implantable element may also include an electronic module including an antenna and one or more controllers electrically connected to the electrochemical sensor and the antenna, the controller being configured to control the electrochemical sensor to obtain a sensor measurement related to the concentration of the analyte in a fluid to which the implantable element (e.g., an attachable implantable element) is exposed, and to use the antenna to indicate the sensor measurement.

[0138] The transplantable elements can take any suitable shape, such as a sphere, ellipsoid, ellipse, disk, cylinder, torus, cube, stadium-shaped, cone, pyramidal, triangular, rectangular, square, or rod-shaped, and may include curved or flat portions. Any curved or flat transplantable element of any shape may be coated with a non-fibrous compound (e.g., those shown in Table 2), a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharmaceutically acceptable salt thereof, or may be chemically derivatized.

[0139] In some embodiments, the transplantable element has a maximum linear dimension (LLD), average diameter, or size of 1 millimeter (mm) or less, or within the range of 0.2 mm to 1 mm, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mm. In some embodiments, the transplantable element has an LLD, average diameter, or size greater than 0.5 mm, 1 mm, or 1.5 mm. In some embodiments, the transplantable elements described herein are 1mm-8mm, 1mm-6mm, 1mm-5mm, 1mm-4mm, 1mm-3mm, 1mm-2mm, 1mm-1.5mm, 1.5mm-8mm, 1.5mm-6mm, 1.5mm-5mm, 1.5mm-4mm, 1.5mm-3mm, 1.5mm-2mm, 2mm-8mm, 2mm-7mm, 2mm-6mm, 2mm-5mm, 2mm-4mm, 2mm-3mm, 2.5mm-8mm, 2.5mm-7mm, 2.5mm-6mm, 2.5mm-5mm, 2.5mm-4mm, 2.5mm-3mm, 3mm-8mm, 3mm-7mm The sizes are within the following ranges: 3mm-6mm, 3mm-5mm, 3mm-4mm, 3.5mm-8mm, 3.5mm-7mm, 3.5mm-6mm, 3.5mm-5mm, 3.5mm-4mm, 4mm-8mm, 4mm-7mm, 4mm-6mm, 4mm-5mm, 4.5mm-8mm, 4.5mm-7mm, 4.5mm-6mm, 4.5mm-5mm, 5mm-8mm, 5mm-7mm, 5mm-6mm, 5.5mm-8mm, 5.5mm-7mm, 5.5mm-6mm, 6mm-8mm, 6mm-7mm, 6.5mm-8mm, 6.5mm-7mm, 7mm-8mm, or 7.5mm-8mm. In some embodiments, the transplantable elements have an LLD, average diameter, or size of 0.5mm-1mm or 1mm-4mm. In some embodiments, the transplantable element has an LLD of 1 mm to 2 mm, an average diameter, or size. In some embodiments, the transplantable element has a spherical shape and an average diameter within any of the aforementioned numerical ranges.

[0140] In some embodiments, the transplantable element includes at least one pore or opening, for example, to allow free flow of material. In some embodiments, the average pore size of the transplantable element is about 0.1 μm to about 10 μm. For example, the average pore size could be 0.1 μm to 10 μm, 0.1 μm to 5 μm, 0.1 μm to 2 μm, 0.15 μm to 10 μm, 0.15 μm to 5 μm, 0.15 μm to 2 μm, 0.2 μm to 10 μm, 0.2 μm to 5 μm, 0.25 μm to 10 μm, 0.25 μm to 5 μm, 0.5 μm to 10 μm, 0.75 μm to 10 μm, 1 μm to 10 μm, 1 μm to 5 μm, 1 μm to 2 μm, 2 μm to 10 μm, 2 μm to 5 μm, or 5 μm to 10 μm. In some embodiments, the average pore size of the transplantable elements is approximately 0.1 μm to 10 μm. In some embodiments, the average pore size of the transplantable elements is approximately 0.1 μm to 5 μm. In some embodiments, the average pore size of the transplantable elements is approximately 0.1 μm to 1 μm.

[0141] In some embodiments, the transplantable element can prevent material exceeding a predetermined size from passing through holes or openings. In some embodiments, the transplantable element can prevent the passage of material exceeding 50kD, 75kD, 100kD, 125kD, 150kD, 175kD, 200kD, 250kD, 300kD, 400kD, 500kD, 750kD, and 1,000kD.

[0142] The implantable elements (e.g., the implantable elements described herein) may be provided as preparations or compositions for implantation or administration to a subject. In some embodiments, at least 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the implantable elements in the preparation or composition have the properties described herein, such as average pore size.

[0143] In some embodiments, the transplantable element may be configured or used for a variety of periods ranging from a few minutes to several years. For example, the transplantable element may be configured or used for a period ranging from about one hour to about ten years. In some embodiments, the transplantable element may be configured or used for a period longer than any of the following: about one to 24 hours, about one to seven days, about one to four weeks, about one to 24 months, about two to ten years, or longer. The transplantable element may be configured to function over the expected transplantation period, for example, to be resistant to inactivation by PFO over all or part of the expected period.

[0144] In some embodiments, the transplantable elements can be easily recovered from the subject without causing injury to the subject or significant destruction of the surrounding tissue. In one embodiment, the transplantable elements can be recovered with minimal or no surgical separation from the surrounding tissue, for example, by minimally invasive surgical incision, excision, or resection.

[0145] In some embodiments, the portable element is not one of the portable elements disclosed in WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 187225, WO2016 / 019391, WO2017 / 075630, WO2017 / 075631, WO2018 / 067615, WO2019 / 169333, or US2016-0030359.

[0146] In some embodiments, the transplantable element is associated with a polysaccharide polymer of formula (I). In some embodiments, the transplantable element comprises a polysaccharide polymer of formula (I) and cells arranged entirely or partially within the transplantable element.

[0147] In some embodiments, the surface of a transplantable element containing cells (e.g., manipulated cells) is chemically modified with a non-fibrous compound (e.g., those shown in Table 2). In some embodiments, the surface includes the outer or inner surface of the transplantable element. In some embodiments, the surface (e.g., the outer surface) of a transplantable element containing cells (e.g., manipulated cells) is chemically modified with a non-fibrous compound (e.g., those shown in Table 2). In some embodiments, the surface (e.g., the outer surface) is covalently bonded to the non-fibrous compound (e.g., those shown in Table 2).

[0148] The implantable element may be coated with a non-fibrous compound (e.g., those shown in Table 2) or a pharmaceutically acceptable salt thereof, or with a polymer containing a non-fibrous compound (e.g., those shown in Table 2) or a pharmaceutically acceptable salt thereof. In one embodiment, the non-fibrous compound (e.g., those shown in Table 2) is placed on a surface such as the inner or outer surface of the implantable element. In some embodiments, the non-fibrous compound (e.g., those shown in Table 2) is placed on a surface such as the inner or outer surface of a containment component associated with the implantable element. In one embodiment, the non-fibrous compound (e.g., those shown in Table 2) is uniformly distributed across the entire surface. In one embodiment, the non-fibrous compound (e.g., those shown in Table 2) is non-uniformly distributed across the entire surface.

[0149] In some embodiments, the implantable element (or its containment component, etc.) is coated (e.g., partially or entirely) with a non-fibrous compound (e.g., those shown in Table 2), a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharmaceutically acceptable salt thereof. In some embodiments, the implantable element (or its containment component, etc.) is coated with a single layer of a non-fibrous compound (e.g., those shown in Table 2). In some embodiments, the implantable element is coated with multiple layers of a non-fibrous compound (e.g., those shown in Table 2), for example, at least two, three, four, five, ten, twenty, fifty, or more.

[0150] In one embodiment, a first portion of the surface of the transplantable element contains a non-fibrous compound (e.g., those shown in Table 2), and a second portion of the transplantable element does not contain the compound or has a substantially low density of the compound.

[0151] In some embodiments, the transplantable elements are symmetrically coated with a non-fibrous compound (e.g., those shown in Table 2), a material containing a non-fibrous compound (e.g., those shown in Table 2), or a pharmaceutically acceptable salt thereof, or are chemically derivatized. In some embodiments, the transplantable elements are asymmetrically coated with a non-fibrous compound (e.g., those shown in Table 2), a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharmaceutically acceptable salt thereof, or are chemically derivatized. For example, exemplary transplantable elements may be partially coated with a polymer modified with a compound of formula (I), or a non-fibrous compound (e.g., those shown in Table 2), or a pharmaceutically acceptable salt thereof (e.g., they may be coated with at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 99.9%).

[0152] Exemplary implantable elements coated or chemically derivatized with non-fibrous compounds (e.g., those shown in Table 2), polymers modified with non-fibrous compounds (e.g., those shown in Table 2), or pharmaceutically acceptable salts thereof, can be prepared using any method known in the art, such as self-assembly (e.g., by block copolymerization, adsorption (e.g., competitive adsorption), phase separation, microfabrication, or masking).

[0153] In some embodiments, the portable element includes a surface exhibiting two or more different physicochemical properties (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or more different physicochemical properties).

[0154] In some embodiments, the coating or chemical derivatization of the surface of an exemplary implantable element with a non-fibrous compound (e.g., those shown in Table 2), a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharmaceutically acceptable salt thereof is described as the average number of attached compounds per given area, for example, as density. For example, the density of the coating or chemical derivatization of an exemplary implantable element may be, for example, 0.01, 0.1, 0.5, 1, 5, 10, 15, 20, 50, 75, 100, 200, 400, 500, 750, 1,000, 2,500, or 5,000 compounds per square micrometer or square millimeter on the surface or inside the implantable element.

[0155] Transplantable elements containing non-fibrous compounds (e.g., those shown in Table 2) or pharmaceutically acceptable salts thereof may exhibit a reduced immune response (e.g., immunoassay markers) compared to identical transplantable elements that do not contain non-fibrous compounds (e.g., those shown in Table 2) or pharmaceutically acceptable salts thereof. Immunosynt markers are one or more of the following, measured by PFO, cathepsin levels, or immunoassay marker levels, such as TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-4, CCL2, or CCL4, for example by ELISA. In some embodiments, the immune response to transplantable elements containing non-fibrous compounds (e.g., those shown in Table 2) or pharmaceutically acceptable salts thereof is reduced by at least about 1 percent and up to about 100 percent, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99 percent. In some embodiments, the reduced immune response (e.g., an immune response marker) is measured at any of the following times: about 30 minutes, about 1 hour, about 6 hours, about 12 hours, about 1 day, about 2 days, about 3 days, or about 4 days, about 1 week or about 2 weeks, about 1 month, about 2 months, about 3 months, or about 6 months, or longer. In some embodiments, implantable elements containing a non-fibrous compound (e.g., those shown in Table 2) are coated with the non-fibrous compound (e.g., those shown in Table 2) or encapsulated within a layer (e.g., a polymer layer) containing the non-fibrous compound (e.g., those shown in Table 2).

[0156] The implantable elements may have a smooth surface, or they may have protrusions, depressions, wells, slits, or holes, or any combination thereof. The protrusions, depressions, wells, slits, or holes may be of any size, e.g., 10 μm to about 1 nm, about 5 μm to about 1 nm, about 2.5 μm to about 1 nm, 1 μm to about 1 nm, 500 nm to about 1 nm, or about 100 nm to about 1 nm. The smooth surface or the protrusions, depressions, wells, slits, or holes, or any combination thereof, may be coated with a non-fibrous compound (e.g., those shown in Table 2), a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharmaceutically acceptable salt thereof, or may be chemically derivatized.

[0157] In one embodiment, the transplantable element comprises one of the polymers described herein, modified with a non-fibrous compound (e.g., those shown in Table 2) or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the transplantable element contains 5–50% non-fibrous compounds (e.g., those shown in Table 2) as measured, for example, using a quantitative amine assay. In some embodiments, the transplantable element contains 10–50% non-fibrous compounds (e.g., those shown in Table 2) as measured, for example, 15–45% non-fibrous compounds (e.g., those shown in Table 2), 15–40% non-fibrous compounds (e.g., those shown in Table 2), 15–35% non-fibrous compounds (e.g., those shown in Table 2), 15–30% non-fibrous compounds (e.g., those shown in Table 2), 20–45% non-fibrous compounds (e.g., those shown in Table 2), 20–40% non-fibrous compounds (e.g., those shown in Table 2), 20–35% non-fibrous compounds (e.g., those shown in Table 2), or 20–30% non-fibrous compounds (e.g., those shown in Table 2) as measured, for example, using a quantitative amine assay.

[0159] In some embodiments, the transplantable element comprises an alginate modified with a non-fibrous compound (e.g., one of the alginates described herein) (e.g., one of the alginates described herein).

[0160] In some embodiments, the transplantable element comprises an alginate modified with the compounds shown in Table 2. In some embodiments, the transplantable element comprises an alginate modified with compound 200. In some embodiments, the transplantable element comprises an alginate modified with compound 218. In some embodiments, the transplantable element comprises an alginate modified with compound 219. In some embodiments, the transplantable element comprises an alginate modified with compound 224. In some embodiments, the transplantable element comprises an alginate modified with compound 222.

[0161] Cells and therapeutic agents The transplantable elements of this disclosure may include, but are not limited to, adipocytes, epidermal cells, epithelial cells, endothelial cells, fibroblasts, islet cells, mesenchymal stem cells, pericytes, any subtype of the foregoing, cells derived from any of the foregoing, cells derived from induced pluripotent stem cells, and mixtures of one or more of the foregoing, a wide variety of different cell types (e.g., human cells). Exemplary cell types include those described in WO2017 / 075631 and WO2019 / 195055. In one embodiment, the transplantable elements described herein include a plurality of cells. In one embodiment, the plurality of cells are in the form of a cell suspension before being encapsulated within the transplantable elements described herein. Cells in a suspension may take the form of single cells (e.g., from a monolayer cell culture), or in another form, for example, arranged on a microcarrier (e.g., beads or a matrix), or as a three-dimensional aggregate of cells (e.g., a cell cluster or spheroid). The cell suspension may include a plurality of cell clusters (e.g., as spheroids) or microcarriers. In some embodiments, the device does not include pancreatic islet cells, nor does it include cells capable of producing insulin in response to glucose.

[0162] This disclosure features cells that produce, or are capable of producing, therapeutic agents for the prevention or treatment of diseases, disorders, or pathological conditions described herein. In one embodiment, the cells are engineered cells. In one embodiment, the cells are engineered to sense stimuli, such as chemical signals, and to express a therapeutic agent in response to those stimuli. The therapeutic agent may be any biological substance, such as nucleic acids (e.g., nucleotides, DNA, or RNA), polypeptides, lipids, sugars (e.g., monosaccharides, disaccharides, oligosaccharides, or polysaccharides), or small molecules (each of which is described in further detail below). Exemplary therapeutic agents include those listed in WO2017 / 075631 and WO2019 / 195055.

[0163] In some embodiments, cells (e.g., manipulated cells) produce nucleic acids. The nucleic acids produced by the cells described herein may vary in size and may contain one or more nucleosides or nucleotides, e.g., 2, 3, 4, 5, 10, 25, 50 or more nucleosides or nucleotides. In some embodiments, the nucleic acids are, for example, short fragments of RNA or DNA and may be used as reporters or for diagnostic purposes. Exemplary nucleic acids include single nucleosides or nucleotides (e.g., adenosine, thymidine, cytidine, guanosine, uridine monophosphate, inosine monophosphate), RNA (e.g., mRNA, siRNA, miRNA, RNAi), and DNA (e.g., vectors, chromosomal DNA). In some embodiments, the nucleic acids have an average molecular weight (kD) of about 0.25, 0.5, 1, 1.5, 2, 2.5, 5, 10, 25, 50, 100, 150, 200 or more.

[0164] In some embodiments, the therapeutic agent is a peptide or polypeptide (e.g., a protein) such as a hormone, enzyme, cytokine (e.g., pro-inflammatory or anti-inflammatory cytokine), growth factor, coagulation factor, or lipoprotein. The peptide or polypeptide (e.g., protein, e.g., hormone, growth factor, coagulation factor or coagulation factor, antibody molecule, enzyme, cytokine, cytokine receptor, or chimeric protein including cytokine or cytokine receptor) produced by cells within the transplantable element may have a naturally occurring amino acid sequence or may contain a variant of a naturally occurring sequence. The variant may be a naturally occurring or non-naturally occurring amino acid substitution, mutation, deletion, or addition compared to a naturally occurring reference sequence. The naturally occurring amino acid sequence may be a polymorphic variant. The naturally occurring amino acid sequence may be a human or non-human amino acid sequence. In some embodiments, the naturally occurring amino acid sequence or its naturally occurring variant is a human sequence. Furthermore, the peptide or polypeptide (e.g., protein) for use in the present invention may be modified in any way, for example, by chemical or enzymatic modification (e.g., glycosylation, phosphorylation). In some embodiments, the peptide has approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, or 50 amino acids. In some embodiments, the protein has an average molecular weight (kD) of 5, 10, 25, 50, 100, 150, 200, 250, or 500 or more.

[0165] In some embodiments, the protein is a hormone. Exemplary hormones include antidiuretic hormone (ADH), oxytocin, growth hormone (GH), prolactin, growth hormone-releasing hormone (GHRH), thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), luteinizing hormone-releasing hormone (LHRH), thyroxine, calcitonin, parathyroid hormone, aldosterone, cortisol, epinephrine, glucagon, insulin, estrogen, progesterone, and testosterone. In some embodiments, the protein is insulin (e.g., insulin A-chain, insulin B-chain, or proinsulin). In some embodiments, the protein is growth hormone, e.g., human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, methionine-human growth hormone, des-phenylalanine-human growth hormone, and porcine growth hormone. In some embodiments, the protein is not insulin (e.g., insulin A-chain, insulin B-chain, or proinsulin).

[0166] In some embodiments, the protein is a growth factor, such as vascular endothelial growth factor (VEGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF), and insulin-like growth factors-I and-II (IGF-I and IGF-II).

[0167] In some embodiments, the protein is a coagulation factor or clotting factor, such as a blood coagulation factor or blood clotting factor. In some embodiments, the protein is a protein involved in coagulation, i.e., the process by which blood is converted from a liquid to a solid or gel. Exemplary coagulation and clotting factors include factor I (e.g., fibrinogen), factor II (e.g., prothrombin), factor III (e.g., tissue factor), factor V (e.g., proaccelerin, instability factor), factor VI, factor VII (e.g., stabilization factor, proconvertin), factor VIII (e.g., antihemophilia factor A), factor VIIIC, factor IX (e.g., antihemophilia factor B), factor X (e.g., Stuart-Prower factor), factor XI (e.g., plasma thromboplastin precursor), factor XII (e.g., Hagemann factor), factor XIII (e.g., fibrin stabilizing factor), von Willebrand factor, prekallikrein, heparin cofactor II, high molecular weight kininogen (e.g., Fitzgerald factor), antithrombin III, and fibronectin. In some embodiments, the protein is an anticoagulant, e.g., protein C.

[0168] In some embodiments, the protein is an antibody molecule. As used herein, the term “antibody molecule” refers to a protein such as an immunoglobulin chain or a fragment thereof that contains at least one immunoglobulin variable domain sequence. The term “antibody molecule” includes, for example, monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region). In one embodiment, the antibody molecule comprises a full-length antibody or a full-length immunoglobulin chain. In one embodiment, the antibody molecule comprises an antigen-binding fragment or functional fragment of a full-length antibody or a full-length immunoglobulin chain. In one embodiment, the antibody molecule is a monospecific antibody molecule that binds to a single epitope, for example, a monospecific antibody molecule having multiple immunoglobulin variable domain sequences, each of which binds to the same epitope.

[0169] In one embodiment, the antibody molecule is a polyspecific antibody molecule, for example, comprising multiple immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence has binding specificity to a first epitope, and a second immunoglobulin variable domain sequence has binding specificity to a second epitope. In one embodiment, the first and second epitopes are located on the same antigen, for example, the same protein (or subunit of a multimeric protein). In one embodiment, the polyspecific antibody molecule comprises a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the polyspecific antibody molecule is a dispecific, trispecific, or tetraspecific antibody molecule.

[0170] Cells within the transplantable elements described herein can generate a variety of antibody molecules, including whole immunoglobulins of any class, fragments thereof, and synthetic proteins containing at least the antigen-binding variable domain of an antibody. The antibody molecule may be an antibody such as an IgG antibody, e.g., IgG1, IgG2, IgG3, or IgG4. The antibody molecule may take the form of an antigen-binding fragment containing a Fab fragment, an F(ab')2 fragment, a single-chain variable region, etc. The antibody may be polyclonal or monoclonal (mAb). Monoclonal antibodies may include "chimeric" antibodies (where a portion of the heavy and / or light chain is identical or homogeneous to a corresponding sequence in an antibody from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homogeneous to a corresponding sequence in an antibody from another species or belonging to another antibody class or subclass), and fragments of such antibodies, insofar as they specifically bind to a target antigen and / or exhibit the desired biological activity. In some embodiments, the antibody molecule is a single-domain antibody (e.g., a nanobody). The described antibodies can also be modified by recombinant means, for example, by amino acid deletion, addition, or substitution, to enhance the effectiveness of the antibody in mediating the desired function. Exemplary antibodies include anti-beta-galactosidase, anti-collagen, anti-CD14, anti-CD20, anti-CD40, anti-HER2, anti-IL-1, anti-IL-4, anti-IL-6, anti-IL-13, anti-IL-17, anti-IL-18, anti-IL-23, anti-IL-28, anti-IL-29, anti-IL-33, anti-EGFR, anti-VEGF, anti-CDF, anti-flagellin, anti-IFN-α, anti-IFN-β, anti-IFN-γ, anti-mannose receptor, anti-VEGF, anti-TLR1, anti-TLR2, anti-TLR3, anti-TLR4, anti-TLR5, anti-TLR6, anti-TLR9, anti-PDF, anti-PD1, anti-PDL-1, or anti-nerve growth factor antibodies. In some embodiments, the antibody is an anti-nerve growth factor antibody (e.g., fluranumab, facinumab, tanezumab).

[0171] In some embodiments, the proteins are, for example, tumor necrosis factor alpha and beta, their receptors and derivatives, renin; lipoprotein; colchicine; corticotrophin; vasopressin; somatostatin; ripressin; pancreozymin; leuprolide; alpha-1-antitrypsin; atrial natriuretic factor; pulmonary surfactant; plasminogen activators other than tissue-type plasminogen activator (t-PA), such as urokinase; bombesin; thrombin; enkephalinase; RANTES (regulated on activation normally expressed and secreted); human macrophage inflammatory protein (MIP-1-alpha); serum albumin, e.g., human serum albumin; Müllerian duct inhibitors; relaxin A-chain; relaxin B-chain; prorelaxin; mouse gonadotropin-related peptides; chorionic gonadotropins; microbial proteins, e.g., beta-lactamase; DNase; inhibin; activin; receptors for hormones or growth factors; integrins; protein A or D; rheumatoid factor; platelet-derived growth factor (PDGF); epidermal growth factor (EGF); transform Insulin-like growth factors (TGF), e.g., TGF-α and TGF-β (including TGF-β1, TGF-β2, TGF-β3, TGF-β4, or TGF-β5); insulin-like growth factors-I and-II (IGF-I and IGF-II); DES(1-3)-IGF-I (brain IGF-I), insulin-like growth factor-binding protein; CD proteins, e.g., CD-3, CD-4, CD-8, and CD-19; erythropoietin; bone-inducing factors; antitoxins; interferons, e.g., interferon-alpha (e.g., interferon-alpha).2A) Cytokines or cytokine receptors, or chimeric proteins containing cytokines or their receptors, including precursors, derivatives, prodrugs and analogs of these compounds, as well as pharmaceutically acceptable salts of these compounds or their precursors, derivatives, prodrugs and analogs. Suitable proteins or peptides may be native or recombinant, and include, for example, fusion proteins.

[0172] Examples of polypeptides (e.g., proteins) produced by cells in the transplantable elements described herein also include CCL1, CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL6, CCL7, CCL8, CCL9 (CCL10), CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCL1( KC), CXCL2(SDF1a), CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8(IL8), CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL 1.XCL1, IL4, IL13, IL7, IL9, IL21, IL3, IL5, IL6, IL11, IL27, IL30, IL31, OSM, LIF, CNTF, CTF1, IL12a, IL12b, IL23, IL27, IL35, IL14, IL16, IL32, IL34, IL10, IF NA17, IFNA21, IFNB1, IFNK, IFNW1, IFNG, IL1A(IL1F1), IL1B(IL1F2), IL1Ra(IL1F3), IL1F5(IL36RN), IL1F6(IL36A), IL1F7(IL37), IL1F8(IL36B), IL 1F9(IL36G), IL1F10(IL38), IL33(IL1F11), IL18(IL1G), IL17, KITLG, IL25(IL17E), CSF1(M-CSF), CSF2(GM-CSF), CSF3(G-CSF), SPP1, TGFB1, TGFB2,TGFB3, CCL3L1, CCL3L2, CCL3L3, CCL4L1, CCL4L2, IL17B, IL17C, IL17D, IL17F, AIMP1(SCYE1), MIF, Areg, BC096441, Bmp1, Bmp10, Bmp15, Bmp2, Bmp3, Bmp4, Bmp5, Bmp6, Bmp7, Bmp8a, Bmp8b, C1qtnf4, Ccl21a, Ccl27a, Cd70, Cer1, Cklf, Clcf1, Cmtm2a, Cmtm2b, Cmtm3, Cmtm4, Cmtm5, Cmtm6, Cmtm7, Cmtm8 , Crlf1, Ctf2, Ebi3, Edn1, Fam3b, Fasl, Fgf2, Flt3l, Gdf10, Gdf11, Gdf15, Gdf2, Gdf3, Gdf5, Gdf6, Gdf7, Gdf9, Gm12597, Gm13271, Gm13275, Gm13276, Gm13280, Gm13283, Gm2564, Gpi1, Grem1, Grem2, Grn, Hmgb1, Ifna11, Ifna12, Ifna9, Ifnab, Ifne, Il17a, Il23a, Il25, Il31, Iltifb, Inhba, Lefty1, L efty2, Mstn, Nampt, Ndp, Nodal, Pf4, Pglyrp1, Prl7d1, Scg2, Scgb3a1, Slurp1, Spp1, Thpo, Tnfsf10, Tnfsf11, Tnfsf12, Tnfsf13, Tnfsf13b, Tnfsf14, Tnfsf15, Tnfsf18, Tnfsf4, Tnfsf8, Tnfsf9, Tslp, Vegfa, Wnt1, Wnt2, Wnt5a, Wnt7a, Xcl1, Epinephrine, Melatonin, Triiodothyronine, Prostaglandin, Leukotriene, Prostaglandin Clin, thromboxane, islet amyloid polypeptide, Müllerian duct inhibitor or hormone, adiponectin, corticotropin, angiotensin, vasopressin, arginine vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, cortistatin, enkephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastric inhibitory polypeptide, gastrin, ghrelin, glucagon, glucagon-like peptide-1, gonadotropin-releasing hormone, hepcidin, human chorionic gonadotropin,It contains human placental lactogens, inhibin, somatomedin, leptin, lipotropin, melanocyte-stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptides, pituitary adenylate cyclase-activating peptide, relaxin, renin, secretin, somatostatin, thrombopoietin, thyrotropin, thyrotropin-releasing hormone, vasoactive intestinal peptides, androgens, alpha-glucosidase (also known as acid maltase), glycogen phosphorylase, glycogen debranching enzyme, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, carnitine palimityltransferase, carnitine, and myoadenylate deaminase.

[0173] In some embodiments, the protein is a supplement or supplement protein. In some embodiments, the supplement or supplement protein is a coagulation factor or clotting factor, for example, factor VIII (including, for example, the naturally occurring human factor VIII amino acid sequence or a variant thereof) or factor IX (including, for example, the naturally occurring human factor IX amino acid sequence or a variant thereof).

[0174] In some embodiments, cells are engineered to express factor VIII, such as recombinant factor VIII. In some embodiments, cells are engineered to express factor VIII derived from human tissue, such as recombinant factor VIII. In some embodiments, recombinant factor VIII is B-domain deletion recombinant factor VIII (FVIII-BDD).

[0175] In some embodiments, cells are engineered to express factor IX derived from human tissue, such as recombinant factor IX. In some embodiments, cells are engineered to express factor IX, such as wild-type human factor IX (FIX), or a polymorphic variant thereof. In some embodiments, cells are engineered to express a gain-of-function (GIF) variant of the wild-type FIX protein (FIX-GIF), the GIF variant having a higher specific activity than the corresponding wild-type FIX.

[0176] In some embodiments, the supplement therapy or supplement protein is an enzyme, such as alpha-galactosidase, alpha-L-idulonidase (IDUA), or N-sulfoglucosamine sulfohydrolase (SGSH). In some embodiments, the supplement therapy or supplement protein is an enzyme, such as alpha-galactosidase A (including, for example, the naturally occurring human alpha-galactosidase A amino acid sequence or its variants). In some embodiments, the supplement therapy or supplement protein is a cytokine or antibody.

[0177] In some embodiments, the therapeutic agent is a sugar such as a monosaccharide, disaccharide, oligosaccharide, or polysaccharide. In some embodiments, the sugar comprises a triose, tetrose, pentose, hexose, or heptose moiety. In some embodiments, the sugar comprises a linear monosaccharide or a cyclic monosaccharide. In some embodiments, the sugar comprises a glucose, galactose, fructose, rhamnose, mannose, arabinose, glucosamine, galactosamine, sialic acid, mannosamine, glucuronic acid, galacturonic acid, mannuronic acid, or guluronic acid moiety. In some embodiments, the sugar is bound to a protein (e.g., N-linked glycan or O-linked glycan). Exemplary sugars include glucose, galactose, fructose, mannose, rhamnose, sucrose, ribose, xylose, sialic acid, maltose, amylose, inulin, fructooligosaccharides, galactooligosaccharides, mannan, lectin, pectin, starch, cellulose, heparin, hyaluronic acid, chitin, amylopectin, or glycogen. In some embodiments, the therapeutic agent is a sugar alcohol.

[0178] In some embodiments, the therapeutic agent is a lipid. Lipids may be hydrophobic or amphiphilic and may form tertiary structures such as liposomes, vesicles, or membranes, or insertions into liposomes, vesicles, or membranes. Lipids may include fatty acids, glycerolipids, glycerophospholipids, sterol lipids, prenolipids, sphingolipids, glycolipids, polyketides, or sphingolipids. Examples of lipids produced by cells as described herein include anandamide, docosahexaenoic acid, aprostaglandins, leukotrienes, thromboxanes, eicosanoids, triglycerides, cannabinoids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, ceramides, sphingomyelin, cerebrosides, gangliosides, estrogens, androsterones, testosterones, cholesterol, carotenoids, quinones, hydroquinones, or ubiquinones.

[0179] In some embodiments, the therapeutic agent is a small molecule. The small molecule may include a natural product produced by cells. In some embodiments, the small molecule is either poorly available or does not conform to Lipinski's Rule of Five (a set of guidelines used to estimate whether a small molecule is likely to be an orally active drug in humans; see, for example, Lipinski, CA et al (2001) Adv Drug Deliv 46:2-36). Examples of small molecule natural products include antibacterial drugs (e.g., carmonam, daptomycin, fidaxomicin, fosfomycin, ispamycin, micronomisomycin sulfate, myokamycin, mpiosin, netylmycin sulfate, teicoplanin, thienamecin, rifamycin, erythromycin, vancomycin), antiparasitic drugs (e.g., artemisinin, ivermectin), and anticancer drugs (e.g., doxorubicin, acralubicin, aminolevulinic acid, algravin, omacetaxin mepesuccinate, paclitaxel, pentostatin, peplomycin, romidepsin, trabecto). Examples include din (trabectdin), actinomycin D, bleomycin, chromomycin A, daunorubicin, leucovorin, neocardinostatin, streptozocin, trabectedin, vinblastine, vincristine), antidiabetic drugs (e.g., voglibose), central nervous system drugs (e.g., L-dopa, galantamine, zicontide), statins (e.g., mevastatin), antifungal drugs (e.g., fumagiline, cyclosporine), 1-deoxynojirimycin, and theophylline, sterols (cholesterol, estrogen, testosterone). Additional small molecule natural products are described in Newman, D.J and Cragg, M. (2016) J Nat Prod 79:629-661 and Butler, M. et al. (2014) Nat Prod Rep 31:1612-1661.

[0180] In some embodiments, cells are manipulated to synthesize non-protein or non-peptide small molecules. For example, in one embodiment, cells can produce statins (e.g., taurostatin, pravastatin, fluvastatin, or atorvastatin).

[0181] In some embodiments, the therapeutic agent is an antigen (e.g., a viral antigen, bacterial antigen, fungal antigen, plant antigen, environmental antigen, or tumor antigen). Antigens are recognized by those skilled in the art as immunostimulant, that is, capable of stimulating an immune response or constituting effective immunity against the organism or molecule from which they originate. Antigens may be nucleic acids, peptides, proteins, sugars, lipids, or combinations thereof.

[0182] Cells, for example, manipulated cells, for example, manipulated cells as described herein, may produce a single therapeutic agent or multiple therapeutic agents. In some embodiments, cells produce a single therapeutic agent. In some embodiments, a cell cluster includes cells that produce a single therapeutic agent. In some embodiments, at least about 1 percent of the cells in the cluster, or about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, or 99 percent, produce a single therapeutic agent (for example, the therapeutic agent described herein). In some embodiments, cells produce multiple therapeutic agents, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 therapeutic agents. In some embodiments, a cell cluster includes cells that produce multiple therapeutic agents. In some embodiments, at least about 1 percent of the cells in the cluster, or about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, or 99 percent, produce multiple therapeutic agents (for example, the therapeutic agents described herein).

[0183] These therapeutic agents may be related or form complexes. In some embodiments, the therapeutic agent is secreted or released from the cell in an active form. In some embodiments, the therapeutic agent is secreted or released from the cell in an inactive form, for example, as a prodrug. In the latter case, the therapeutic agent may be activated by a downstream agent, such as an enzyme. In some embodiments, the therapeutic agent is maintained within the cell rather than being secreted or released from the cell. For example, the therapeutic agent may be an enzyme involved in the detoxification or metabolism of unwanted substances, and the detoxification or metabolism of unwanted substances occurs within the cell.

[0184] Treatment method This specification describes methods for preventing or treating a disease, disorder, or condition of interest by administering or transplanting a transplantable element containing a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of the disease, disorder, or condition. In some embodiments, the methods described herein prevent or delay the onset of the disease, disorder, or condition. In some embodiments, the subject is human.

[0185] In some embodiments, the disease, disorder, or condition affects a system of the body, such as the nervous system (e.g., the peripheral or central nervous system), the vascular system, the skeletal system, the respiratory system, the endocrine system, the lymphatic system, the reproductive system, or the gastrointestinal tract. In some embodiments, the disease, disorder, or condition affects a part of the body, such as the blood, eyes, brain, skin, lungs, stomach, mouth, ears, legs, feet, hands, liver, heart, kidneys, bones, pancreas, spleen, large intestine, small intestine, spinal cord, muscles, ovaries, uterus, vagina, or penis.

[0186] In some embodiments, the disease, disorder, or condition is a neurodegenerative disease, diabetes (type 1 or type 2), heart disease, autoimmune disease, cancer, liver disease, lysosomal storage disorders, coagulation disorders, orthopedic conditions, or amino acid metabolic disorders.

[0187] In some embodiments, the disease, disorder, or condition is a neurodegenerative disease. Examples of neurodegenerative diseases include Alzheimer's disease, Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), cerebral pallidoluysian atrophy (DRPLA), intranuclear vitreous inclusion disease (NIHID), Lewy body dementia, Down syndrome, Harrellforden-Spats disease, prion diseases, argyrophilic grain dementia, corticobasal degeneration, Boxer dementia, diffuse neurofibrillary tangle disease, Gerstmann-Streussler-Scheinker disease, Jacob-Creutzfeldt disease, Niemann-Pick disease type 3, progressive supranuclear palsy, subacute sclerosing panencephalitis, spinocerebellar ataxia, Pick's disease, and dentatorubral-pallidoluysian atrophy.

[0188] In some embodiments, the disease, disorder, or condition is an autoimmune disease, such as scleroderma, multiple sclerosis, lupus, or an allergy.

[0189] In some embodiments, the disease is a liver disease such as hepatitis B, hepatitis C, cirrhosis, or NASH.

[0190] In some embodiments, the disease, disorder, or condition is cancer. Examples of cancers include leukemia, lymphoma, melanoma, lung cancer, brain cancer (e.g., glioblastoma), sarcoma, pancreatic cancer, kidney cancer, liver cancer, testicular cancer, prostate cancer, or uterine cancer.

[0191] In some embodiments, the disease, disorder, or condition is an orthopedic condition. Exemplary orthopedic conditions include osteoporosis, osteonecrosis, Paget's disease, or fractures.

[0192] In some embodiments, the disease, disorder, or condition is a lysosomal storage disorder. Exemplary lysosomal storage disorders include Gaucher disease (e.g., types I, II, and III), Tay-Sachs disease, Fabry disease, Faber disease, Haller syndrome (also known as mucopolysaccharidosis type I (MPS I)), Hunter syndrome, lysosomal acid lipase deficiency, Niemann-Pick disease, Salla disease, Sanfilippo syndrome (also known as mucopolysaccharidosis type IIIA (MPS3A)), multiple sulfatase deficiency, Maloto-Lamy syndrome, metachromatic leukodystrophy, Krabbe disease, Schayet syndrome, Haller-Scheyet syndrome, Sly syndrome, hyaluronidase deficiency, Pompe disease, Danon disease, gangliosidosis, or Morquio syndrome.

[0193] In some embodiments, the disease, disorder, or condition is a coagulation disorder or clotting disorder. Exemplary coagulation disorders or clotting disorders include hemophilia (e.g., hemophilia A or hemophilia B), von Willebrand disease, thrombocytopenia, uremia, Bernard-Soulier syndrome, factor XII deficiency, vitamin K deficiency, or congenital afibrinogenemia.

[0194] In some embodiments, the disease, disorder, or condition is an amino acid metabolic disorder, such as phenylketonuria, tyrosinemia (e.g., type 1 or type 2), alkaptonuria, homocystinuria, hyperhomocysteinemia, or maple syrup urine disease.

[0195] In some embodiments, the disease, disorder, or condition is a fatty acid metabolic disorder, such as hyperlipidemia, hypercholesterolemia, or galactosemia.

[0196] In some embodiments, the disease, disorder, or condition is a purine or pyrimidine metabolic disorder, such as Lesch-Nyhan syndrome.

[0197] In some embodiments, the disease, disorder, or condition is not type 1 diabetes and / or type 2 diabetes.

[0198] The present invention further includes a method for identifying a subject having or suspected of having a disease, disorder, or pathological condition as described herein, and, in response to such identification, administering a transplantable element to the subject, which includes cells (e.g., optionally encapsulated by a containment component and optionally modified with a compound of formula (I) or a composition thereof as described herein). In one embodiment, the subject is a human.

[0199] Enumerated embodiments 1. A polysaccharide polymer comprising a sugar monomer, wherein the sugar monomer comprises a hydroxyl modifier covalently bonded to a hydroxyl moiety.

[0200] 2. The polysaccharide polymer according to Embodiment 1, wherein the hydroxyl modifier comprises an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amine, amide, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety.

[0201] 3. The polysaccharide polymer is selected from hyaluronate, alginate, cellulose, chitosan, chitin, amylose, dextran, starch, glycogen, chondroitin, and pectin, as described in any one of Embodiments 1 to 2.

[0202] 4. The polysaccharide polymer according to any one of Embodiments 1 to 3, wherein the sugar monomer is selected from glucose, galactose, mannose, allose, altrose, talose, idose, growth, fructose, ribose, arabinose, lyxose, xylose, rhamnose, glucuronic acid, galacturonic acid, mannuronic acid, and guluronic acid.

[0203] 5. The polysaccharide polymer according to any one of Embodiments 1 to 4, wherein the sugar monomer is mannuronic acid or guluronic acid.

[0204] 6. The sugar monomer is a polysaccharide polymer according to any one of Embodiments 1 to 5, having the structure of formula (I).

[0205] 6. The sugar monomer is of formula (Ia): [ka] or having a pharmaceutically acceptable salt structure thereof, in the formula, X is O, NR 6 , or S; R 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C )C(O)-, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are one or more R 8 It is arbitrarily replaced by; R 2 and R 3 These are, independently, hydrogen and C 1-6 Alkilen-R 9 , C 1-6 Heteroalkylene-R 9 , C(O)-C 1-6 Alkilen-R 9 , C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R) 7a )-R 9 , or C 1-6 Heteroalkylene-N(R 7a )-R 9 Here, each alkylene or alkenyl is one or more R 10 It is arbitrarily substituted by R 2 and R3 It is not the case that both of them are hydrogen; Each R 4 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R 8 It is arbitrarily replaced by; R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, N(R) 7a )(R 7b ), OR A , C(O)R B , C(O)OR A , C(O)N(R C )(R D ), N(R C )C(O)R B , halogen, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are one or more R 8 It is arbitrarily replaced by; R 6 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, or C 1-6 It is a haloalkyl, where alkyl, heteroalkyl, and haloalkyl are one or more R 10 It is arbitrarily replaced by; R 7a and R 7bThese are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is one or more R 10 It is arbitrarily replaced by; Each R 8 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, oxo, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, OR A , N(R C )(R D ), C(O)OR A , C(O)R B , C(O)N(R C )(R D ), or N(R C )C(O)R B Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl has 0 to 12 R 11 It is replaced by; R A R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl has 0 to 12 R 11 It is replaced by; R B , R C , and R Dis a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is one or more R 11 It is arbitrarily replaced by; Or, R B and R C These, together with the atoms to which they are bonded, form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which contains one or more R 10 It is arbitrarily replaced with; R 9 It is a peptide or a non-fibrous compound; Each R 10 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, oxo, OR A , N(R C )(R D ), C(O)OR A , C(O)R B , C(O)N(R C )(R D ), or N(R C )C(O)R B Here, each alkyl, heteroalkyl, and haloalkyl is one or more R 11 It is arbitrarily replaced by; Each R 11 Independently, C 1-6 A polysaccharide polymer according to any one of Embodiments 1 to 5, which is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0206] 7. The polysaccharide polymer according to Embodiment 6, wherein X is O.

[0207] 8.R 1 A polysaccharide polymer according to any one of embodiments 6 to 7, wherein is O.

[0208] 9.R 5 C(O)OR A or C(O)N(R C )(R D A polysaccharide polymer according to any one of embodiments 6 to 8.

[0209] 10.R 5 is C(O)N(R C )(R D ) and R C and R D The polysaccharide polymer according to Embodiment 9, wherein each is independently hydrogen, a non-fibrous compound (e.g., the non-fibrous compounds shown in Table 2), or a peptide (e.g., RGD peptide).

[0210] 11.R C and R D One of them is hydrogen, and R C and R D The polysaccharide polymer according to Embodiment 10, wherein the other is independently a non-fibrous compound (e.g., non-fibrous compounds shown in Table 2) or a peptide (e.g., RGD peptide).

[0211] 12.R 2 is hydrogen or C(O)-C 1-6 Alkilen-R 9 The polysaccharide polymer according to any one of embodiments 6 to 11.

[0212] 13.R 3 is hydrogen or C(O)-C 1-6 Alkilen-R 9 The polysaccharide polymer according to any one of embodiments 6 to 12.

[0213] 14.R 2 and R 3 One of them is independently C(O)-C 1-6 Alkilen-R 9 And R 2 and R 3 The other of the polysaccharide polymers according to any one of embodiments 6 to 13, wherein the other is independently hydrogen.

[0214] 15.R 9 The polysaccharide polymer according to any one of embodiments 6 to 14, wherein the compound is a non-fibrous compound.

[0215] 16. The sugar monomer is of formula (Ia): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 2 , R 3 , R 5 The polysaccharide polymer according to any one of Embodiments 1 to 15, wherein each of the secondary variable elements is as defined in Embodiment 6.

[0216] 17. The sugar monomer is of formula (Ib): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 9 And its secondary variable elements are as defined in claim 6, R 3a A polysaccharide polymer according to any one of Embodiments 1 to 16, wherein n is hydrogen and n is 1, 2, 3, 4, or 5.

[0217] 18. The sugar monomer is of formula (Ic): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 2 , R 3 , R C , R D The polysaccharide polymer according to any one of Embodiments 1 to 17, wherein each of the secondary variable elements is as defined in Embodiment 6.

[0218] 19. The sugar monomer is of formula (Id): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 9 , R C , R D , and each of their sub-variable elements are as defined in Embodiment 6, R 3a The polysaccharide polymer according to any one of claims 1 to 18, wherein n is hydrogen and n is 1, 2, 3, 4, or 5.

[0219] 20.R 9 The polysaccharide polymer according to Embodiment 17 or 19, which is a non-fibrous compound.

[0220] 21. A polysaccharide polymer according to Embodiment 17 or 19, wherein n is 2.

[0221] 22. The sugar monomer is of formula (Ie): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 3 , R 5 , and each of their sub-variable elements are as defined in Embodiment 6; P 1 is an aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is one or more R 12 It is arbitrarily replaced by; L 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R 8It is arbitrarily replaced by; Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 8 It is arbitrarily replaced by; R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 It is a haloalkyl or halo; Each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a and R 8 The polysaccharide polymer according to any one of Embodiments 1 to 21, as defined in Embodiment 6.

[0222] 23. The sugar monomer is given by formula (If): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 3 , R 12 , R C , R D , and each of their sub-variable elements are as defined in Embodiment 6; P 1 is an aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is one or more R 12 It is arbitrarily replaced by; L 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C)C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R 8 It is arbitrarily replaced by; Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 8 It is arbitrarily replaced by; R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 It is a haloalkyl or halo; Each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a and R 8 The polysaccharide polymer according to any one of Embodiments 1 to 22, as defined in Embodiment 6.

[0223] 24.P 1 The polysaccharide according to Embodiment 22 or 23, wherein is a heteroaryl (e.g., triazolyl).

[0224] 25.P 1 teeth [ka] And R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 The polysaccharide polymer according to Embodiment 24, which is a haloalkyl or halo.

[0225] 26.L 1 is non-existent, or C 1-6 A polysaccharide polymer according to any one of embodiments 22 to 25, wherein the polymer is alkylene (e.g., -CH2-).

[0226] 27.Z 1The polysaccharide polymer according to any one of embodiments 22 to 26, wherein is an aryl, heteroaryl, or heterocyclyl.

[0227] 28.Z 1 The polysaccharide polymer according to embodiment 22 or 23, wherein the polysaccharide polymer is a heterocyclyl.

[0228] 29.Z 1 teeth, [ka] The polysaccharide polymer described in Embodiment 28.

[0229] 30. The non-fibrous compound is a polysaccharide polymer according to any one of Embodiments 1 to 29, selected from the sites in Table 2.

[0230] 31. The peptide is a polysaccharide polymer according to any one of Embodiments 1 to 30, comprising the sequence RGD.

[0231] 32. The polysaccharide according to any one of Embodiments 1 to 31, wherein the polysaccharide polymer is an alginate.

[0232] 33. The polysaccharide according to Embodiment 32, wherein the alginate is high guluronic acid (G) alginate or high mannuronic acid (M) alginate.

[0233] 34. The alginate comprises an increase in %N of 0.1 to 10%N by weight (compared to an unmodified polymer), where %N is determined by elemental analysis, as described in any one of Embodiments 32 to 33.

[0234] 35. The polysaccharide according to any one of embodiments 32 to 34, wherein the alginate comprises an increase in %N of 1 to 10%N by weight (compared to an unmodified polymer), where %N is determined by elemental analysis.

[0235] 36. The polysaccharide according to any one of Embodiments 32 to 35, wherein the alginate comprises an increase in %N of 2 to 8%N by weight (compared to the unmodified polymer), where %N is determined by elemental analysis and corresponds to the amount of compound of formula (I) in the modified alginate.

[0236] 37. The polysaccharide according to any one of Embodiments 1 to 36, wherein the polysaccharide comprises a plurality of sugar monomers, each containing a hydroxyl modifier covalently bonded to the hydroxyl moiety.

[0237] 38. An alginate comprising a mannuronate or glulonate monomer, wherein the mannuronate or glulonate monomer comprises a hydroxyl modifier covalently bonded to a hydroxyl moiety.

[0238] 39. The alginate according to Embodiment 38, wherein the hydroxyl modifier comprises an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety.

[0239] 40. The aforementioned alginate is given by formula (I): [ka] or comprising a monomer having the structure of a pharmaceutically acceptable salt thereof, wherein the formula includes, X is O, NR 6 , or S; R 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C)C(O)-, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are one or more R 8 It is arbitrarily replaced by; R 2 and R 3 These are, independently, hydrogen and C 1-6 Alkilen-R 9 , C 1-6 Heteroalkylene-R 9 , C(O)-C 1-6 Alkilen-R 9 , C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R) 7a )-R 9 , or C 1-6 Heteroalkylene-N(R 7a )-R 9 Here, each alkylene or alkenyl is one or more R 10 It is arbitrarily substituted by R 2 and R 3 It is not the case that both of them are hydrogen; Each R 4 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R 8 It is arbitrarily replaced by; R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C1-6 Heteroalkyl, C 1-6 Haloalkyl, N(R) 7a )(R 7b ), OR A , C(O)R B , C(O)OR A , C(O)N(R C )(R D ), N(R C )C(O)R B , halogen, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are one or more R 8 It is arbitrarily replaced by; R 6 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, or C 1-6 It is a haloalkyl, where alkyl, heteroalkyl, and haloalkyl are one or more R 10 It is arbitrarily replaced by; R 7a and R 7b These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is one or more R 10 It is arbitrarily replaced by; Each R 8 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, oxo, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, OR A , N(R C )(R D ), C(O)OR A , C(O)R B , C(O)N(R C )(R D ), or N(R C )C(O)R BHere, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl has 0 to 12 R 11 It is replaced by; R A R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl has 0 to 12 R 11 It is replaced by; R B , R C , and R D is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is one or more R 11 It is arbitrarily replaced by; or, R B and R C These, together with the atoms to which they are bonded, form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which contains one or more R 10 It is arbitrarily replaced with; R 9 It is a peptide or a non-fibrous compound; Each R 10 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, oxo, OR A , N(R C )(R D ), C(O)OR A , C(O)R B , C(O)N(R C )(R D), or N(R C )C(O)R B Here, each alkyl, heteroalkyl, and haloalkyl is one or more R 11 It is arbitrarily replaced by; Each R 11 Independently, C 1-6 The alginate according to any one of embodiments 38 to 39, which is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0240] 41. An alginate according to Embodiment 40, where X is O.

[0241] 42.R 1 The alginate according to any one of embodiments 40 to 41, wherein is O.

[0242] 43.R 5 C(O)OR A or C(O)N(R C )(R D The alginate according to any one of embodiments 40 to 42.

[0243] 44.R 5 is C(O)N(R C )(R D ) and R C and R D The alginate according to any one of Embodiments 40 to 43, wherein each is independently hydrogen, a non-fibrous compound (e.g., the non-fibrous compounds shown in Table 2), or a peptide (e.g., the peptides shown in Table X).

[0244] 45.R C and R D One of them is hydrogen, and R C and R D The alginate according to any one of Embodiments 40 to 44, wherein the other is independently a non-fibrous compound (e.g., non-fibrous compounds shown in Table 2) or a peptide (e.g., a peptide shown in Table X).

[0245] 46.R2 is hydrogen or C 1-6 Alkylene-S(O)2-R 9 The alginate according to any one of embodiments 40 to 45.

[0246] 47.R 3 is hydrogen or C 1-6 Alkylene-S(O)2-R 9 The alginate according to any one of embodiments 40 to 46.

[0247] 48.R 2 and R 3 One of them is independently C 1-6 Alkylene-S(O)2-R 9 And R 2 and R 3 The other of the alginates is independently hydrogen, as described in any one of embodiments 40 to 47.

[0248] 49.R 9 The alginate described in any one of embodiments 40 to 48 is a non-fibrous compound.

[0249] 50. The monomer is of formula (Ia): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 2 , R 3 , R 5 The alginate according to any one of embodiments 40 to 49, wherein each of the secondary variable elements is as defined in embodiment 40.

[0250] 51. The monomer is of formula (Ib): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 9 And its secondary variable elements are as defined in Embodiment 40, R3a The alginate according to any one of embodiments 40 to 50, wherein n is hydrogen and n is 1, 2, 3, 4, or 5.

[0251] 52. The monomer is of formula (Ic): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 2 , R 3 , R C , R D The alginate according to any one of embodiments 40 to 51, wherein each of the secondary variable elements is as defined in embodiment 40.

[0252] 53. The monomer is of formula (Id): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 9 , R C , R D , and each of their sub-variable elements are as defined in Embodiment 40, R 3a The alginate according to any one of embodiments 40 to 52, wherein n is hydrogen and n is 1, 2, 3, 4, or 5.

[0253] 54.R 9 The alginate according to claim 51 or 53, wherein the alginate is a non-fibrous compound.

[0254] 55. The alginate according to claim 51 or 53, wherein n is 2 and m is 1.

[0255] 56. The monomer is of formula (Ie): [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 3, R 5 , and each of their sub-variable elements are as defined in Embodiment 40; P 1 is an aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is one or more R 12 It is arbitrarily replaced by; L 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(R C )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R 8 It is arbitrarily replaced by; Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 8 It is arbitrarily replaced by; R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 It is a haloalkyl or halo; p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a and R 8 The alginate according to any one of embodiments 40 to 55, as defined in embodiment 40.

[0256] 57. The monomer is of formula (If): [ka] or has the structure of its pharmaceutically acceptable salt, wherein R 3 , R 12 , R C , R D , and each of these secondary variable elements is as defined in Embodiment 40; P 1 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted by one or more R 12 ; L 1 is absent, C 1-6 alkylene, C​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​The alginate according to embodiment 56 or 57, which is heteroaryl (e.g., triazolyl).

[0258] 59.P 1 is

Chemical formula

[0259] 60.L 1 is absent or C 1-6 alkylene (e.g., -CH2-), the alginate according to any one of embodiments 57 to 58.

[0260] 61.Z 1 is aryl, heteroaryl, or heterocyclyl, the alginate according to any one of embodiments 57 to 60.

[0261] 62.Z 1 is heterocyclyl, the alginate according to embodiment 61.

[0262] 63.Z 1 is

Chemical formula

[0263] 64. The non-fibrous compound is selected from the sites in Table 1, the alginate according to any one of embodiments 40 to 65.

[0264] 65. A hydrogel comprising the polysaccharide polymer according to any one of embodiments 1 to 39 or the alginate according to any one of embodiments 40 to 64.

[0265] 66. An implantable element comprising a polysaccharide polymer according to any one of Embodiments 1 to 39, an alginate according to any one of Embodiments 40 to 64, or a hydrogel according to Embodiment 65.

[0266] 67. A pharmaceutical composition comprising a polysaccharide polymer according to any one of Embodiments 1 to 39, an alginate according to any one of Embodiments 40 to 64, or a hydrogel according to claim 65, and a pharmaceutically acceptable excipient. [Examples]

[0267] The following examples are provided so that the inventions described herein may be better understood. The synthetic and biological examples described herein are provided to illustrate the compounds, compositions, devices, and methods provided herein and should not be construed as limiting their scope.

[0268] The compounds, modified polymers, implantable elements, and compositions thereof provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols shown below, which will be well known to those skilled in the art. Typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are shown, but it should be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by standard optimization procedures for those skilled in the art.

[0269] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in Greene et al., *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and the references cited in that document.

[0270] Exemplary compounds, modified polymers, implantable elements, and compositions of the present invention can be prepared using any of the strategies described below.

[0271] Example 1: Exemplary Compound Synthesis Outline protocol The following procedure describes a method for preparing exemplary compounds for preparing chemically modified transplantable elements. The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols shown below, which will be well known to those skilled in the art. Typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are shown, but it should be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by a standard optimization procedure for those skilled in the art.

[0272] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in Greene et al., *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and the references cited in that document.

[0273] Synthesis of compound 100 [ka] In a 100 mL round-bottom flask, 0.89 g (1.47 mmol) of TBA alginate and 15 mL of anhydrous DMF were mixed with 1 M TBAF in 2 mL of THF, stirring until homogeneous. Triethylamine (615 μL, 4.41 mmol) was added, followed by (meth)acryloyl chloride (1.76 mmol). The mixture was stirred at room temperature for 3 hours. In a separate 40 mL glass vial, a nucleophile of a specified non-fibrous compound amine (3 mmol) was dissolved in dimethylformamide (8 mL). The amine solution was added to the main mixture and stirred overnight at room temperature, then transferred to a flask containing 150 mL of RINKAN. The resulting suspension was stirred for a while, filtered through a 60 mL disposable filter, and washed with acetone (50 mL x 4) to obtain a solid.

[0274] Next, the wet solid was treated with a 1:1 mixture of EtOH:0.6M HCl (15 mL) and stirred at room temperature for 4 hours. The suspension was filtered through a 60 mL disposable filter, washed with acetone (50 mL x 4), and then stirred at room temperature in 1 N NaHCO3 (15 mL) for 1 to 4 hours. The reaction solution was diluted to approximately 100 mL with physiological saline and purified using a tangential flow filtration system (MWCO 10K) with physiological saline (approximately 1 L), followed by pure water (approximately 1 L), and finally freeze-dried to obtain the product as a solid. Elemental analysis of the final modified alginate revealed that it contained 5.0% nitrogen, 36.3% carbon, and 1.9% sulfur.

[0275] Synthesis of compound 102 [ka] The reaction was carried out using the conditions outlined for compound 100. Elemental analysis of the final modified alginate revealed that it contained 3.8% nitrogen, 36.4% carbon, and 1.4% sulfur.

[0276] Synthesis of compound 104 [ka] The reaction was carried out using the conditions outlined for compound 100. Elemental analysis of the final modified alginate revealed that it contained 4.7% nitrogen, 35.6% carbon, and 2.1% sulfur.

[0277] Synthesis of compound 106 [ka] The reaction was carried out using the conditions outlined for compound 100. Elemental analysis of the final modified alginate revealed that it contained 4.3% nitrogen, 36.2% carbon, and 1.7% sulfur.

[0278] Synthesis of compound 108 [ka] The reaction was carried out using the conditions outlined for compound 100. Elemental analysis of the final modified alginate revealed that it contained 5.1% nitrogen, 37.1% carbon, and 0% sulfur.

[0279] Synthesis of compound 110 [ka] The reaction was carried out using the conditions outlined for compound 108. Elemental analysis of the final modified alginate revealed that it contained 4.7% nitrogen, 39.0% carbon, and 0% sulfur.

[0280] Synthesis of compound 112 [ka] 0.89 g of TBA alginate (approximately 1.47 mmol / monomer) and 15 mL of DMSO were added to a 100 mL round-bottom container, and 1 M TBAF was added in approximately 2 mL of THF. The mixture was stirred at room temperature until homogeneous. 615 μL of triethylamine (4.41 mmol) was added, followed by the dropwise addition of the activating reagent (1.76 mmol). The solution was stirred at room temperature for 30 minutes, then heated to 55 °C and held for 10 minutes. 3 mmol of amine was dissolved separately in 5 mL of DMSO, then added to the main mixture at 55 °C. The mixture was stirred for 4 hours and cooled overnight to room temperature. The mixture was poured into 150 mL of ethyl acetate, the resulting suspension was stirred for a while, filtered through a 60 mL disposable filter, and washed with acetone (50 mL x 4) to obtain a solid. The solid was then treated with a 1:1 mixture of EtOH:0.6 M HCl (15 mL) and stirred at room temperature for 4 hours. The suspension was filtered through a 60 mL disposable filter and washed with acetone (50 mL x 4). The resulting solid was stirred in 15 mL of 1 N NaHCO3 at room temperature for 0.5 to 1 hour. The solution was diluted to approximately 100 mL with physiological saline and purified using a tangential flow filtration system (MWCO 10K) with physiological saline (approximately 1 L) followed by pure water (approximately 1 L). Finally, the solution was freeze-dried to obtain the final product as a solid. Elemental analysis of the final modified alginate revealed that it contained 1.2% nitrogen, 32.3% carbon, and 0.5% sulfur.

[0281] Synthesis of compound 116 [ka] The reaction was carried out using the conditions outlined for compound 112. Elemental analysis of the final modified alginate revealed that it contained 1.1% nitrogen, 32.7% carbon, and 0.9% sulfur.

[0282] Synthesis of compound 118 [ka] The reaction was carried out using the conditions outlined for compound 112. Elemental analysis of the final modified alginate revealed that it contained 1.7% nitrogen, 32.5% carbon, and 0.9% sulfur.

[0283] Synthesis of compound 120 [ka] The reaction was carried out using the conditions outlined for compound 112. Elemental analysis of the final modified alginate revealed that it contained 1.6% nitrogen, 31.9% carbon, and 0.7% sulfur.

[0284] Synthesis of compound 124 [ka] The reaction was carried out using the conditions outlined for compound 112. Elemental analysis of the final modified alginate revealed that it contained 2.8% nitrogen, 40.5% carbon, and 1.5% sulfur.

[0285] Synthesis of compound 128 [ka] The reaction was carried out using the conditions outlined for compound 112. Elemental analysis of the final modified alginate revealed that it contained 1.4% nitrogen, 32.7% carbon, and 0.0% sulfur.

[0286] Synthesis of compound 130 [ka] The reaction was carried out using the conditions outlined for compound 112. Elemental analysis of the final modified alginate revealed that it contained 0.31% nitrogen, 32.31% carbon, and 0.31% sulfur.

[0287] Example 2: Preparation of hydrogel capsules containing modified polysaccharide polymers This example describes the preparation of a two-compartment hydrogel capsule containing the modified polysaccharide polymer described herein. A first 5% (w / w) solution of alginate containing compound 100 was prepared by dissolving 0.25 g of modified alginate in 4.75 g of physiological saline. The solution was mixed overnight until homogeneous. A second alginate solution modified with RGD peptide was also prepared (3% (w / w)) by dissolving 0.25 g of RGD alginate in 8.3 g of physiological saline, and the solution was mixed overnight until homogeneous. 2.16 g of the 3% (w / w) RGD alginate solution was added to the 5% (w / w) modified alginate solution and mixed. The modified alginate solutions were then filled into two separate 10 mL syringes.

[0288] Next, a Matsusada high-voltage generator was connected to a coaxial needle (17 gauge) located in a needle holder and attached to a grounding ring. A Luer lock fitting on the side of the needle was attached to an 8-inch tube extension connected to a syringe filled with a first (5% (w / w)) alginate solution, which formed the outer compartment. A Luer lock fitting on the top of the needle was attached to an 8-inch tube extension connected to a syringe filled with a second (3% (w / w)) RGD alginate, which formed the inner compartment. Using a syringe pump, the first and second alginate solutions were injected into glass dishes containing 250 mL of 20 mM BaCl2 solution to perform crosslinking and hydrogel capsule formation. The crosslinked hydrogel capsules were then collected in glass dishes, washed with buffer solution (15 times), and then imaged to evaluate their morphology and sphere intensity. Using a bright-field microscope, the quality of the hydrogel capsules containing the modified polysaccharide polymer and the non-fibrous compound 219 was monitored, revealing a smooth, defect-free surface. Further testing of the stability and strength of the hydrogel capsules was performed using texture analysis (e.g., as described in Example 7). The crushing data for the hydrogel capsules containing the modified polysaccharide polymer with the monomer of compound 219 is shown in Table 4 below. [Table 4]

[0289] Example 3: Preparation of exemplary cells for encapsulation in hydrogel capsules Engineered ARPE-19 cells for inclusion as single cells. ARPE-19 cells engineered to express therapeutic agents such as coagulation factors (e.g., FVIII or FIX protein) can be cultured according to any method known in the art, for example, according to the following protocol.

[0290] 75cm 2 The culture medium was removed by aspirating the manipulated ARPE-19 cells from the culture flask, and the cell layer was briefly rinsed with 0.05% (w / v) trypsin / 0.53 mM EDTA solution ("TrypsinEDTA") to completely remove any serum containing trypsin inhibitors. 2–3 mL of TrypsinEDTA solution was added to the flask, and the cells were observed under an inverted microscope, usually for 5–15 minutes, until the cell layer dispersed. To avoid aggregation, the cells were handled carefully, and tapping or shaking the flask during the dispersion period was minimized. If the cells did not detach, the flask was left at 37°C to facilitate dispersion. Once the cells were dispersed, 6–8 mL of full growth medium was added, and the cells were aspirated by gentle pipetting. The cell suspension was then transferred to a centrifuge tube and centrifuged at approximately 125xg for 5–10 minutes to remove TrypsinEDTA. The supernatant was then discarded, and the cells were resuspended in fresh growth medium. Add an appropriate aliquot of the cell suspension to a new culture vessel and incubate at 37°C. Change the culture medium 2-3 times per week.

[0291] ARPE-19 cells for encapsulation as a cluster Spheroid clusters of exemplary cells (e.g., engineered ARPE-19 cells) are prepared using AggreWell® spheroid plates (STEMCELL Technologies) and the protocol outlined herein. On day 1, rinse solution (4 mL) is added to each plate, and the plates are centrifuged in a large centrifuge at 3,000 RPM for 5 minutes. The rinse solution is removed by pipette, and 4 mL of full growth medium is added. Engineered ARPE-19 cells are seeded into the plates at the desired cell density and immediately pipetted to prevent aggregation. As a general rule of thumb, 3.9 million cells per well will produce clusters with a diameter of 150 μm. The plates are centrifuged at 800 RPM for 3 minutes, and the plates are left overnight in a 37°C incubator.

[0292] On day 2, remove the plate from incubation. Using a wide-mouth pipette tip, gently pipette the cells to remove the spheroid clusters. Filter the clusters through a 40 μm or 80 μm cell strainer to remove any excess detached single cells, then centrifuge in a centrifuge for 2 × 1 minute. Using a wide-mouth pipette tip, gently resuspend the clusters and gently agitate to disperse them throughout the culture medium or another material (such as alginate).

[0293] Alternatively, ARPE-19 spheroids can be prepared using the following protocol: On day 1, remove the AggreWell® plate from its package in a sterile tissue culture hood. Add 2 mL of AggreWell® rinse solution to each well. Centrifuge the plate at 2,000 g for 5 minutes to remove air bubbles and remove the AggreWell® rinse solution from the wells. Rinse each well with 2 mL of full growth medium and add 2 million manipulated ARPE-19 cells in 3.9 mL of full growth medium to each well. Centrifuge the plate at 100 g for 3 minutes, then incubate the cells at 37°C for 48 hours. On day 3, remove the spheroid clusters using the same protocol as above.

[0294] Alternatively, ARPE19 spheroids can be prepared using a PBS MINI bioreactor (PBS Biotec, Inc., Camarillo, CA, USA) following the protocol: Add cell culture medium and 220 million ARPE19 cells to a 0.1 L or 0.5 L PBS container, then insert this container into a base unit placed in an incubator. Set the PBS MINI speed control dial to 40 rpm and incubate the container at 37°C for at least 48 hours before collecting the spheroids as described above.

[0295] Example 4: Preparation of hydrogel capsules containing cells Capsules containing RPE cells as single cells. Immediately before encapsulation, single ARPE-19 cells engineered to express therapeutic proteins were centrifuged at 1,400 rpm for 1 minute and washed with calcium-free Krebs-Henseleit (KH) buffer (4.7 mM KCl, 25 mM HEPES, 1.2 mM KH2PO4, 1.2 mM MgSO4 × 7H2O, 135 mM NaCl, pH approximately 7.4, approximately 290 mOsm). After washing, the cells were centrifuged again and all of the supernatant was aspirated. In some experiments, the cell pellet was then resuspended in a high molecular weight alginate solution (70:30) to achieve the desired density of suspended single cells per ml of alginate solution.

[0296] Before preparing the 1-compartment and 2-compartment hydrogel capsules, the buffer and alginate solutions are sterilized by filtration through a 0.2 μm filter using a sterile process.

[0297] To prepare a device consisting of a two-compartment hydrogel capsule with a diameter of approximately 1.5 mm, an electrostatic droplet generator can be set up as follows: an ES series 0-100-kV, 20-watt high-voltage generator (EQ series, Matsusada, NC, USA) is connected to the top and bottom of a coaxial needle (inner lumen 22G, outer lumen 18G, Rame-Hart Instrument Co., Succasunna, NJ, USA). The inner lumen is attached to a first 5 mL syringe with a Luer lock, connected to a vertically oriented syringe pump. The outer lumen is connected via a Luer coupling to a second 5 mL syringe, which can be connected to a horizontally oriented second syringe pump. To encapsulate cells only in the first (inner) compartment, a first alginate solution containing cells (as a single-cell suspension) can be placed in the first syringe, and a second cell-free alginate solution containing the compound of formula (I) can be placed in the second syringe. For the control two-compartment hydrogel capsule, a second (outer) compartment can be formed using an alginate solution that does not contain the compound of formula (I). Two syringe pumps move the first and second alginate solutions from the syringe through both lumens of a coaxial needle, and droplets containing both alginate solutions are pushed out of the needle one drop at a time into a glass dish containing the crosslinking solution. The settings of each syringe pump can be adjusted to achieve the optimal flow rate ratio of the two alginate solutions.

[0298] To prepare two-compartment capsules, after extruding the desired volume of alginate solution, the alginate droplets are crosslinked for 5 minutes in a crosslinking solution containing 25 mM HEPES, 20 mM BaCl2, 0.2 M mannitol, and poloxamer 188. The capsules that fall to the bottom of the crosslinking container are collected in a conical tube by pipetting. After the capsules have settled in the tube, the crosslinking buffer is removed and the capsules are washed. Capsules that do not contain cells are washed four times with HEPES buffer (2 liters of deionized water, 15.428 g NaCl, 0.70 g KCl, 0.488 g MgCl2·6H2O, 50 ml of HEPES (1M) buffer solution (Gibco, Life Technologies, California, USA)) and stored at 4°C until use. The capsules containing the cells are washed four times with HEPES buffer, twice with 0.9% physiological saline, and twice with culture medium, and then stored in an incubator at 37°C.

[0299] Example 5. In vivo assay of exemplary compounds The non-fibrous properties of the exemplary compounds of this disclosure can be analyzed by implanting hydrogel capsules prepared as described in Example 2 or 4 into the intraperitoneal (IP) space of C57BL / 6J mice according to the following procedure.

[0300] Preparation: Anesthetize the mice under a continuous flow of 1-4% isoflurane with oxygen at 0.5 L / min and prepare for surgery. Preoperatively, all mice should be subcutaneously administered 0.5 ml of 0.9% saline to prevent dehydration, and 0.05-0.1 mg / kg body weight of buprenorphine may be administered subcutaneously as a preoperative analgesic. Using a shaver with a size #40 clipper blade, remove hair from an area of ​​approximately 2 cm x 2 cm on the ventral midline of the animal's abdomen. Prepare the entire shaved area aseptically by rinsing with 70% alcohol after scrubbing with povidine at least three times (centrifugally from the center outward if possible). Apply a final skin coating with povidine. After disinfecting the tabletop surface with 70% ethanol, cover the surgical site with disposable sterile paper to prevent surrounding hair from coming into contact with the surgical site. Workers should use appropriate PPE, gowns, surgical masks, and surgical gloves.

[0301] Surgical Procedure: Using a sharp surgical scalpel or scissors, make a 0.5–0.75 mm midline incision in the abdomen of the target mouse, penetrating the skin and linea alba. The surgeon should strive to keep the incision as small as possible. Using flat, sterile forceps, transfer a 0.5 mL aliquot of each capsule composition into the peritoneal cavity of each mouse (4 mice per composition). Suture the abdominal muscles with 5-0 Ethicon black silk or PDS absorbable 5.0–6.0 monofilament absorbable suture, and close the outer layer of skin with a wound clip. Remove blood and tissue debris from surgical instruments between procedures, and re-sterilize instruments using a hot bead sterilizer for each animal. After surgery, return the animals to their cages and place them on a heat pad or under a heat lamp, monitoring them until they recover from anesthesia.

[0302] Intraoperative care: Keep the animal warm using a Deltaphase isothermal pad. Keep the animal's eyes moist with sterile eye ointment during surgery. Take care not to over-wet the surgical site to avoid hypothermia. Continuously monitor respiratory rate and respiratory characteristics. If vital signs indicate extreme pain and distress, euthanize the animal by placing it in a carbon dioxide chamber and then performing cervical dislocation.

[0303] Postoperative Analysis: Four weeks after transplantation, the majority of capsules are harvested from the mice, and the number of cells in each capsule (one capsule twice per mouse) is measured using the CellTiter Glo® 3D cell viability assay (Promega Corporation, Madison, WI USA). Briefly, one capsule per well is analyzed twice and compared to a standard curve of plated cells. 100 μl of CellTiter Glo® 3D reagent is added to each well containing 100 μl of culture medium, the plate is placed on a 400 rpm shaker for 15 minutes, and the luminescence is read with a plate reader. Additionally, a texture analyzer is used to measure the mechanical strength (initial disruption) of capsules in aliquots of each composition before transplantation and upon harvesting one month after transplantation.

[0304] Example 6: Conjugation of additional compounds to polymers Exemplary polymers may be further modified by conjugating one or more additional compounds to monomers at other positions on the monomer, such as free carboxylates. For example, compounds can be conjugated to reactive carboxylic acid groups on alginate polymers. Any component that can be coupled to a carboxylic acid, such as the amines described herein, can be a suitable partner in this coupling reaction.

[0305] Exemplary compounds containing free amines can be conjugated to alginates using the methods outlined herein. The alginate polymer is dissolved in water (30 mL / 1 g of alginate) and treated with 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.5 eq) and N-methylmorpholine (1 eq). The amine-containing compound of interest is then dissolved in acetonitrile (0.3 M) and added to the alginate solution. The reaction mixture is then heated at 55°C for 16 hours, cooled to room temperature, concentrated by rotary evaporation, and then dissolved in water. The mixture is then filtered through a cyano-modified silica gel (Silicycle) bed, and the filter cake is washed with water. The resulting solution is then dialyzed against water for 24 hours (10,000 MWCO membrane), with the water changed twice during this period. The resulting solution is concentrated by lyophilization to obtain further functionalized alginates.

[0306] Example 7: Particle Analysis The various properties of the particle preparations can be analyzed in vitro or at various time points after transplantation into test animals or human patients.

[0307] For example, the mechanical strength of particles (e.g., hydrogel capsules) can be determined by performing a crushing test using a texture analyzer after manufacturing, but before implantation. In one embodiment, a TA.XT plus Texture Analyzer (Stable Micro Systems, Surrey, United Kingdom) is used to mechanically test hydrogel capsules using a 5 mm probe attached to a 5 kg load cell. Individual capsules are placed on a platform and compressed from above by the probe at a fixed speed of 0.5 mm / second. Contact between the probe and the capsule is detected when a rebound force of 1 g is measured. The probe then moves 90% of the distance between the probe's contact height and the platform, compressing the capsule until it bursts. The probe's resistance to the compressive force is measured and can be plotted as a function of probe movement (force-displacement curve). Typically, the capsule will crush slightly before completely bursting, and the force applied to the probe will decrease slightly. The analysis macro can be programmed to detect the first instance where a decrease of 0.25–0.5 g occurs in the force-displacement curve. The force applied by the probe when this occurs is called the initial crushing force. In one embodiment, the crushing force of a capsule preparation produced using the apparatus described herein is the average of the initial crushing forces of at least 10, 20, 30, or 40 capsules.

[0308] The average particle size in a particle preparation can be estimated by determining the average particle size in aliquots using any analytical technique known in the art. In one embodiment, a desired number of particles (e.g., at least 10, 20, or 30) are taken from the preparation and examined by optical microscopy, such as bright-field imaging.

[0309] Example 8: Preparation and characterization of hydrogel capsules containing modified polysaccharide polymers This example describes the preparation of a two-compartment hydrogel capsule comprising an outer layer made of a modified polysaccharide polymer described herein and an inner layer made of an unmodified polysaccharide polymer. A first 5% (w / w) solution of alginate containing compound 101 was prepared by dissolving 0.25 g of modified alginate in 4.75 g of physiological saline. The solution was mixed overnight until homogeneous. A second alginate solution (3% (w / w)) was also prepared by dissolving 0.25 g of alginate in 8.3 g of physiological saline, and mixed overnight until homogeneous. 2.16 g of 3% (w / w) unmodified alginate solution was added to the 5% (w / w) modified alginate solution and mixed. The modified alginate solutions were then filled into two separate 10 mL syringes.

[0310] Next, a Matsusada high-voltage generator was connected to a coaxial needle (17 gauge) located in a needle holder and attached to a grounding ring. A Luer lock fitting on the side of the needle was attached to an 8-inch tube extension connected to a syringe filled with a first (5% (w / w)) alginate solution, which formed the outer compartment. A Luer lock fitting on the top of the needle was attached to an 8-inch tube extension connected to a syringe filled with a second (3% (w / w)) unmodified alginate, which formed the inner compartment. Using a syringe pump, the first and second alginate solutions were injected into glass dishes containing 250 mL of 20 mM BaCl2 solution to perform crosslinking and hydrogel capsule formation. The crosslinked hydrogel capsules were then collected in glass dishes, washed with buffer solution (15 times), and then imaged to evaluate their morphology and sphere intensity.

[0311] Equivalents and range This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any of the incorporated references and this specification, this specification shall prevail. Furthermore, any particular embodiment of the Invention that falls into the prior art may be expressly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art and may be excluded even if the exclusion is not expressly indicated herein. Any particular embodiment of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the prior art.

[0312] Those skilled in the art will be able to recognize or confirm many equivalents to the particular embodiments described herein using only conventional experiments. The scope of the embodiments described herein is not intended to be limited to the above specification, drawings, or examples, but is set forth in the appended claims. Those skilled in the art will understand that various modifications and modifications to this specification may be made without departing from the spirit or scope of the invention, as defined in the following claims.

Claims

1. A polysaccharide polymer containing a sugar monomer, wherein the sugar monomer is of formula (I-a): 【Chemistry 1】 or having a pharmaceutically acceptable salt structure thereof, in the formula, X is O, NR ６ , or S; R １ is absent, C １－６ alkylene, C ２－６ alkenylene, C ２－６ alkynylene, C １－６ heteroalkylene, C １－６ haloalkylene, -N(R ７ａ ), -O-, -C(O)-, -C(O)O-, -C(O)N(R Ｃ ), or -N(R Ｃ )(O)-, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are optionally substituted by one or more R ８ ; R ２ and R ３ These are, independently, hydrogen and C １－６ Alkilen-R ９ , C １－６ Heteroalkylene-R ９ , C(O)-C １－６ Alkilen-R ９ , C(O)-C １－６ Heteroalkylene-R ９ , C １－６ Alkylene-C(O)-R ９ , C １－６ Heteroalkylene-C(O)-R ９ , C １－６ Alkylene-N(R) ７ａ )-R ９ , or C １－６ Heteroalkylene-N(R) ７ａ )-R ９ Here, each alkylene or alkenyl is one or more R １０ It is arbitrarily replaced by R ２ and R ３ It is not the case that both of them are hydrogen; Each R ４ is non-existent, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C １－６ Heteroalkylene, C １－６ Haloalkylene, -N(R) ７ａ )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R Ｃ )-, or -N(R Ｃ )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R ８ It is arbitrarily replaced by; R ５ is hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, N(R) ７ａ ) (Caution ７ｂ ), OR Ａ , C(O)R Ｂ , C(O)OR Ａ , C(O)N(R Ｃ ) (Caution Ｄ ), N (R Ｃ ) C(O)R Ｂ , halogen, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are one or more R ８ It is arbitrarily replaced by; R ６ is hydrogen, C １－６ Alkyl, C １－６ Heteroalkyl, or C １－６ It is a haloalkyl, where alkyl, heteroalkyl, and haloalkyl are one or more R １０ It is arbitrarily replaced by; R ７ａ and R ７ｂ These are, independently, hydrogen and C １－６ Alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is one or more R １０ It is arbitrarily replaced by; Each R ８ is, independently, C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, C １ -C ６ -heteroalkyl, C １ -C ６ -haloalkyl, halogen, oxo, cyano, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, OR Ａ , N(R Ｃ )(R Ｄ ), C(O)OR Ａ , C(O)R Ｂ , C(O)N(R Ｃ )(R Ｄ ), or N(R Ｃ )C(O)R Ｂ where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is substituted by 0 to 12 R １１ ; R Ａ is hydrogen, C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, C １ -C ６ -heteroalkyl, C １ -C ６ -haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is substituted by 0 to 12 R １１ ; R Ｂ , R Ｃ , and R Ｄ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Heteroalkyl, C １ -C ６ Haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is one or more R １１ It is arbitrarily replaced by; Or, R Ｂ and R Ｃ These, together with the atoms to which they are bonded, form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which contains one or more R １０ It is arbitrarily replaced with; R ９ It is a peptide or a non-fibrous compound; Each R １０ Independently, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Haloalkyl, halogen, oxo, OR Ａ , N(R Ｃ ) (Caution Ｄ ), C(O)OR Ａ , C(O)R Ｂ , C(O)N(R Ｃ ) (Caution Ｄ ), or N (R Ｃ ) C(O)R Ｂ Here, each alkyl, heteroalkyl, and haloalkyl is one or more R １１ It is arbitrarily replaced by; Each R １１ Independently, C １－６ The polysaccharide polymer is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

2. The polysaccharide polymer according to claim 1, wherein X is O.

3. R １ The polysaccharide polymer according to claim 1, wherein is O.

4. R ５ C(O)OR Ａ or C(O)N(R) Ｃ ) (Caution Ｄ The polysaccharide polymer according to claim 1, which is the same as the one described in claim 1.

5. R ５ is C(O)N(R) Ｃ ) (Caution Ｄ ) and R Ｃ and R Ｄ The polysaccharide polymer according to claim 1, wherein each is independently hydrogen, a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2), or a peptide (e.g., an RGD peptide).

6. R Ｃ and R Ｄ One of them is hydrogen, and R Ｃ and R Ｄ The polysaccharide polymer according to claim 5, wherein the other is independently a non-fibrous compound (e.g., non-fibrous compounds shown in Table 2) or a peptide (e.g., RGD peptide).

7. R ２ is hydrogen or C(O)-C １－６ Alkilen-R ９ The polysaccharide polymer according to claim 1.

8. R ３ is hydrogen or C(O)-C １－６ Alkilen-R ９ The polysaccharide polymer according to claim 1.

9. R ２ and R ３ One of them is independently C(O)-C １－６ Alkilen-R ９ And R ２ and R ３ The polysaccharide polymer according to claim 1, wherein the other is independently hydrogen.

10. R ９ The polysaccharide polymer according to claim 1, wherein the compound is non-fibrous.

11. The aforementioned sugar monomer is given by formula (I-b): 【Chemistry 2】 or having a pharmaceutically acceptable salt thereof, in the formula R ２ , R ３ , R ５ The polysaccharide polymer according to claim 1, wherein each of the secondary variable elements is as defined in claim 1.

12. The aforementioned sugar monomer is given by formula (I-c): 【Transformation 3】 or having a pharmaceutically acceptable salt thereof, in the formula R ９ And its secondary variable elements are as defined in claim 1, R ３ａ The polysaccharide polymer according to claim 1, wherein n is hydrogen and n is 1, 2, 3, 4, or 5.

13. The aforementioned sugar monomer is given by formula (I-d): 【Chemistry 4】 or having a pharmaceutically acceptable salt thereof, in the formula R ２ , R ３ , R Ｃ , R Ｄ The polysaccharide polymer according to claim 1, wherein each of the secondary variable elements is as defined in claim 1.

14. The aforementioned sugar monomer is given by formula (I-e): 【Transformation 5】 or having a pharmaceutically acceptable salt thereof, in the formula R ９ , R Ｃ , R Ｄ , and each of their sub-variable elements is as defined in claim 1, R ３ａ The polysaccharide polymer according to claim 1, wherein n is hydrogen and n is 1, 2, 3, 4, or 5.

15. R ９ The polysaccharide polymer according to claim 1, wherein the compound is non-fibrous.

16. The polysaccharide polymer according to claim 1, wherein n is 2.

17. The aforementioned sugar monomer is given by formula (I-f): 【Transformation 6】 or having a pharmaceutically acceptable salt thereof, in the formula R ３ , R ５ , and each of their sub-variable elements is as defined in claim 1; P １ is an aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is one or more R １２ It is arbitrarily replaced by; L １ is non-existent, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C １－６ Heteroalkylene, C １－６ Haloalkylene, -N(R) ７ａ )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R Ｃ )-, or -N(R Ｃ )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R ８ It is arbitrarily replaced by; Z １ is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R ８ It is arbitrarily replaced by; R １２ is hydrogen, deuterium, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ It is a haloalkyl or halo; Each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R ７ａ and R ８ The polysaccharide polymer according to claim 1, as defined in claim 6.

18. The aforementioned sugar monomer is given by formula (I-g): 【Transformation 7】 or having a pharmaceutically acceptable salt thereof, in the formula R ３ , R １２ , R Ｃ , R Ｄ , and each of their sub-variable elements is as defined in claim 1; P １ is an aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is one or more R １２ It is arbitrarily replaced by; L １ is non-existent, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C １－６ Heteroalkylene, C １－６ Haloalkylene, -N(R) ７ａ )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R Ｃ )-, or -N(R Ｃ )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R ８ It is arbitrarily replaced by; Z １ is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R ８ It is arbitrarily replaced by; R １２ is hydrogen, deuterium, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ It is a haloalkyl or halo; Each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R ７ａ and R ８ The polysaccharide polymer according to claim 1, wherein it is as defined in claim 1.

19. P １ The polysaccharide polymer according to claim 17 or 18, wherein is a heteroaryl (e.g., triazolyl).

20. P １ teeth 【Transformation 8】 And R １２ is hydrogen, deuterium, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ The polysaccharide polymer according to claim 17 or 18, wherein it is a haloalkyl or a halo.

21. L １ is non-existent, or C １－６ Alkylenes (e.g., -CH ２ The polysaccharide polymer according to claim 17 or 18, wherein it is -).

22. Z １ The polysaccharide polymer according to claim 17 or 18, wherein is an aryl, heteroaryl, or heterocyclyl.

23. Z １ The polysaccharide polymer according to claim 22, wherein the polysaccharide polymer is a heterocyclyl.

24. Z １ teeth, 【Chemistry 9】 The polysaccharide polymer according to claim 23.

25. The non-fibrous compound is selected from the sites in Table 2, as described in claim 1, for the polysaccharide polymer.

26. The polysaccharide polymer according to claim 1, wherein the peptide comprises sequence RGD.

27. The polysaccharide according to claim 1, wherein the polysaccharide polymer is an alginate.

28. The polysaccharide according to claim 27, wherein the alginate is high guluronic acid (G) alginate or high mannuronic acid (M) alginate.

29. An alginate comprising a mannuronate or gluronate monomer, wherein the mannuronate or gluronate monomer is of formula (I-a): 【Chemistry 10】 or having a pharmaceutically acceptable salt structure thereof, in the formula, X is O, NR ６ , or S; R １ is non-existent, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C １－６ Heteroalkylene, C １－６ Haloalkylene, -N(R) ７ａ )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R Ｃ )-, or -N(R Ｃ )C(O)-, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are one or more R ８ It is arbitrarily replaced by; R ２ and R ３ These are, independently, hydrogen and C １－６ Alkilen-R ９ , C １－６ Heteroalkylene-R ９ , C(O)-C １－６ Alkilen-R ９ , C(O)-C １－６ Heteroalkylene-R ９ , C １－６ Alkylene-C(O)-R ９ , C １－６ Heteroalkylene-C(O)-R ９ , C １－６ Alkylene-N(R) ７ａ )-R ９ , or C １－６ Heteroalkylene-N(R) ７ａ )-R ９ Here, each alkylene or alkenyl is one or more R １０ It is arbitrarily replaced by R ２ and R ３ It is not the case that both of them are hydrogen; Each R ４ is non-existent, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C １－６ Heteroalkylene, C １－６ Haloalkylene, -N(R) ７ａ )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R Ｃ )-, or -N(R Ｃ )C(O)-, where each alkylene, alkenylene, alkynylene, and heteroalkylene is one or more R ８ It is arbitrarily replaced by; R ５ is hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, N(R) ７ａ ) (Caution ７ｂ ), OR Ａ , C(O)R Ｂ , C(O)OR Ａ , C(O)N(R Ｃ ) (Caution Ｄ ), N (R Ｃ ) C(O)R Ｂ , halogen, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are one or more R ８ It is arbitrarily replaced by; R ６ is hydrogen, C １－６ Alkyl, C １－６ Heteroalkyl, or C １－６ It is a haloalkyl, where alkyl, heteroalkyl, and haloalkyl are one or more R １０ It is arbitrarily replaced by; R ７ａ and R ７ｂ These are, independently, hydrogen and C １－６ Alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is one or more R １０ It is arbitrarily replaced by; Each R ８ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Heteroalkyl, C １ -C ６ Haloalkyl, halogen, oxo, cyano, azide, aryl, heteroaryl, cycloalkyl, heterocyclyl, OR Ａ , N(R Ｃ ) (Caution Ｄ ), C(O)OR Ａ , C(O)R Ｂ , C(O)N(R Ｃ ) (Caution Ｄ ), or N (R Ｃ ) C(O)R Ｂ Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl has 0 to 12 R １１ It is replaced by; R Ａ is hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Heteroalkyl, C １ -C ６ Haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl has 0 to 12 R １１ It is replaced by; R Ｂ , R Ｃ , and R Ｄ C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Heteroalkyl, C １ -C ６ Haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is one or more R １１ It is arbitrarily replaced by; or, R Ｂ and R Ｃ These, together with the atoms to which they are bonded, form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which contains one or more R １０ It is arbitrarily replaced with; R ９ It is a peptide or a non-fibrous compound; Each R １０ Independently, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Haloalkyl, halogen, oxo, OR Ａ , N(R Ｃ ) (Caution Ｄ ), C(O)OR Ａ , C(O)R Ｂ , C(O)N(R Ｃ ) (Caution Ｄ ), or N (R Ｃ ) C(O)R Ｂ Here, each alkyl, heteroalkyl, and haloalkyl is one or more R １１ It is arbitrarily replaced by; Each R １１ Independently, C １－６ The alginate is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

30. The alginate according to claim 29, wherein X is O.

31. R １ The alginate according to claim 29, wherein is O.

32. R ５ C(O)OR Ａ or C(O)N(R) Ｃ ) (Caution Ｄ The alginate according to claim 29, which is the same as the one described in claim 29.

33. R ５ is C(O)N(R) Ｃ ) (Caution Ｄ ) and R Ｃ and R Ｄ The alginate according to claim 29, wherein each is independently hydrogen, a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2), or a peptide (e.g., a peptide shown in Table 3).

34. R Ｃ and R Ｄ One of them is hydrogen, and R Ｃ and R Ｄ The alginate according to claim 29, wherein the other is independently a non-fibrous compound (e.g., non-fibrous compounds shown in Table 2) or a peptide (e.g., a peptide shown in Table X).

35. R ２ is hydrogen or C １－６ Alkylene-S(O) ２ -R ９ The alginate according to claim 39.

36. R ３ is hydrogen or C １－６ Alkylene-S(O) ２ -R ９ The alginate according to claim 29.

37. R ２ and R ３ One of them is independently C １－６ Alkylene-S(O) ２ -R ９ And R ２ and R ３ The alginate according to claim 29, wherein the other is independently hydrogen.

38. R ９ The alginate according to claim 29, wherein the alginate is a non-fibrous compound (for example, one of those shown in Table 2).

39. The monomer is given by formula (I-b): 【Chemistry 11】 or having a pharmaceutically acceptable salt thereof, in the formula R ２ , R ３ , R ５ The alginate according to claim 29, wherein each of the sub-variable elements is as defined in claim 29.

40. The monomer is of formula (I-c): 【Chemistry 12】 or having a pharmaceutically acceptable salt thereof, in the formula R ９ And its secondary variable elements are as defined in claim 29, R ３ａ The alginate according to claim 29, wherein n is hydrogen and n is 1, 2, 3, 4, or 5.

41. The monomer is of formula (I-d): 【Chemistry 13】 or having a pharmaceutically acceptable salt thereof, in the formula R ２ , R ３ , R Ｃ , R Ｄ The alginate according to claim 29, wherein each of the sub-variable elements is as defined in claim 29.

42. The aforementioned monomer is given by formula (I-e): 【Chemistry 14】 or having a pharmaceutically acceptable salt thereof, in the formula R ９ , R Ｃ , R Ｄ , and each of their sub-variable elements is as defined in claim 29, R ３ａ The alginate according to claim 29, wherein n is hydrogen and n is 1, 2, 3, 4, or 5.

43. The non-fibrous compound is an alginate according to claim 29, selected from the sites in Table 2.

44. A hydrogel comprising a polysaccharide polymer according to any one of claims 1 to 28 or an alginate according to any one of claims 29 to 43.

45. A transplantable element comprising a polysaccharide polymer according to any one of claims 1 to 39, an alginate according to any one of claims 40 to 64, or a hydrogel according to claim 65.

46. The transplantable element according to claim 45, further comprising cells (e.g., manipulated cells).

47. The transplantable element according to claim 46, wherein the cells produce therapeutic substances (e.g., enzymes, antibodies, hormones, or blood coagulation factors).

48. A pharmaceutical composition comprising a polysaccharide polymer according to any one of claims 1 to 28, an alginate according to any one of claims 29 to 43, a hydrogel according to claim 44, or an implantable element according to any one of claims 45 to 47, and a pharmaceutically acceptable excipient.

49. A method for treating a disease, disorder, or pathological condition of a subject requiring treatment, comprising administering an implantable element described in any one of embodiments 45 to 47 or a pharmaceutical composition described in embodiment 48 to the subject, thereby treating the disease, disorder, or pathological condition of the subject.

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