Modified polysaccharide polymers and related compositions and methods

Abstract

Described herein are polysaccharide polymers that include sugar moieties (e.g., sugar monomers of formula (I)) that have been modified with a hydroxyl modifier, as well as related compositions, hydrogels, implantable elements, and methods of use thereof.

Description

[Background technology]

[0001] Claiming priority This application claims priority to U.S. Patent Application No. 63 / 295,268, filed December 30, 2022, the entire contents of which are incorporated herein by reference in their entirety.

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

[0003] Described herein are polymers containing certain hydroxyl group modifications, as well as related compositions and methods. In one aspect, the disclosure features a polysaccharide polymer comprising a sugar monomer having a hydroxyl moiety, the sugar monomer comprising a hydroxyl modifier covalently attached to the hydroxyl moiety. In one embodiment, the sugar monomer has multiple hydroxyl moieties, the sugar monomer comprising a hydroxyl modifier covalently attached to the hydroxyl moiety. In another aspect, the disclosure features a polysaccharide polymer comprising a sugar monomer having a hydroxyl moiety, the sugar monomer comprising a hydroxyl modifier at the hydroxyl moiety. In some embodiments, 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 polysaccharide polymer is selected from hyaluronate, alginate, cellulose, chitosan, chitin, amylose, dextran, starch, glycogen, chondroitin, and pectin. In one embodiment, the hydroxyl modifying agent is a nitrogen-containing hydroxyl modifying agent. In one embodiment, the hydroxyl modifying agent comprises an amine or an amide.

[0004] In another aspect, the present disclosure provides a polysaccharide polymer comprising a sugar monomer, the sugar monomer having formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables X, R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 5a , R 5band their subvariables are defined herein. In some embodiments, the glycomonomer of formula (I), or a pharma- ceutically acceptable salt thereof, has the structure of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im). In some embodiments, the glycomonomer of formula (I), or a pharma- ceutically acceptable salt thereof, is set forth in Table 1 herein. In one embodiment, the polysaccharide polymer is an alginate, chitosan, dextran, or hyaluronate. In one embodiment, the polysaccharide polymer is an alginate. In one embodiment, X is O. In one embodiment, R 1 and R 4 are each independently O. In one embodiment, R 5a and R 5b is independently hydrogen, and R 5a and R 5b and the other is independently C(O)R, where R is OH or NHR'. In one embodiment, R' is hydrogen, a non-fibrous compound, or a peptide.

[0005] In another aspect, the present disclosure provides an alginate comprising a glycomonomer, the glycomonomer having formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables X, R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 5a , R 5band their subvariables are defined herein. In some embodiments, the glycomonomer of formula (I), or a pharma- ceutically acceptable salt thereof, has the structure of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im). In some embodiments, the glycomonomer of formula (I), or a pharma- ceutically acceptable salt thereof, is set forth in Table 1 herein. In one embodiment, the polysaccharide polymer is an alginate. In one embodiment, X is O. In one embodiment, R 1 and R 4 are each independently O. In one embodiment, R 5a and R 5b is independently hydrogen, and R 5a and R 5b and the other is independently C(O)R, where R is OH or NHR'. In one embodiment, R' is hydrogen, a non-fibrous compound, or a peptide.

[0006] In another aspect, the disclosure features a hydrogel comprising a polysaccharide polymer (e.g., alginate) described herein, and an implantable element (e.g., a device or material) comprising the same. In some embodiments, the hydrogel or implantable element comprises a cell. Exemplary cell types include epithelial cells, endothelial cells, fibroblasts, keratinocytes, pancreatic islet cells, and stem cells (e.g., iPSCs or MSCs). In some embodiments, the hydrogel or implantable element comprises an epithelial cell, such as a retinal pigment epithelial cell (RPE cell). In some embodiments, the hydrogel or implantable element comprises a pancreatic islet cell. In some embodiments, the hydrogel or implantable element comprises a stem cell (e.g., iPSCs or MSCs). In some embodiments, the hydrogel or implantable element comprises an engineered cell (e.g., an engineered epithelial cell, such as an engineered RPE cell, an engineered pancreatic islet cell, or an engineered stem cell).

[0007] In some embodiments, the cells (e.g., engineered cells) produce a substance, e.g., a therapeutic agent. 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, the implantable element may include engineered cells capable of producing a protein (e.g., an enzyme, a blood clotting factor (e.g., factor VIII protein), or a hormone (e.g., insulin)).

[0008] In another aspect, the disclosure features a method of providing a substance (e.g., a therapeutic agent) to a subject, the method including administering to the subject a hydrogel or implantable element that includes (i) a polysaccharide polymer (e.g., alginate) that includes a glycomonomer of formula (I) described herein, and (ii) cells capable of producing the substance (e.g., the therapeutic agent). In some embodiments, the substance is a therapeutic agent, such as a protein (e.g., an enzyme, an antibody, a blood clotting factor (e.g., factor VIII protein), or a hormone (e.g., insulin)).

[0009] In another aspect, the disclosure features a method of treating a disease, disorder, or condition in a subject with a therapeutic agent capable of treating the disease, disorder, or condition, comprising administering to the subject a hydrogel or implantable element comprising (i) a polysaccharide polymer (e.g., alginate) comprising a glycomonomer of formula (I) as 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.

[0010] In some embodiments, the method of providing a substance or method of treating includes reducing a foreign body reaction to the administered implantable element (e.g., minimizing the formation of pericapsular fibrotic overgrowth (PFO) in the implantable element).

[0011] In all aspects of the disclosure, in some embodiments, the polysaccharide polymers described herein, e.g., those comprising a sugar monomer of formula (I), or hydrogels or implantable elements (e.g., devices or materials) thereof, are not 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.

[0012] The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will become apparent from the detailed description, drawings, examples, and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure provides polysaccharide polymers comprising sugar monomers having hydroxyl moieties modified with hydroxyl modifiers, and related compositions and methods of making and using thereof. In one embodiment, the sugar monomers comprise a hydroxyl modifier covalently attached to the hydroxyl moiety. In one embodiment, for example, polysaccharide polymers comprising sugar monomers of formula (I), and hydrogels and implantable elements (e.g., devices and materials) comprising same, and related compositions and methods of use thereof. In particular, the polysaccharide polymers, hydrogels, and implantable elements described herein may be used in methods of prevention and treatment of diseases, disorders, or conditions in a subject. In some embodiments, the polysaccharide polymers comprising sugar monomers of formula (I), and hydrogels and implantable elements comprising same, and pharma- ceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotopically labeled derivatives thereof, are capable of mitigating immune responses in a subject.

[0014] definition So that the present invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0015] As used in this specification, including the appended claims, the singular forms of terms such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0016] "About" when used herein to modify a numerically defined parameter (e.g., a 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), means that the parameter may vary by 15% above or below the numerical value stated for that parameter. For example, an implantable element defined as having an average diameter of about 1.5 millimeters (mm) and encapsulating about 5 million (M) cells may have an average diameter of 1.275-1.725 mm and encapsulate about 4.25M-5.75M cells. In some embodiments, the term "about" means that the parameter may vary by 10% or 5% above or below the numerical value stated for that parameter.

[0017] "Obtain" or "obtaining", as used herein, refers to obtaining a possession of a value, e.g., a numerical value, or an image, or a physical entity (e.g., a sample), by "directly obtaining" or "indirectly obtaining" the value or physical entity. "Directly obtaining" means performing a process (e.g., performing an analytical method or protocol) to obtain the value or physical entity. "Indirectly obtaining" refers to receiving a value or physical entity from another 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 fluorescent microscope, to obtain fluorescent microscopy data.

[0018] "Administer", "administering", or "administration", as used herein, refers to implanting, absorbing, ingesting, injecting, placing, or otherwise introducing into a subject an entity described herein (e.g., a polysaccharide polymer described herein, or a hydrogel or implantable element comprising same, e.g., a hydrogel or implantable element encapsulating cells), or a composition comprising said particles), or providing said entity to a subject for administration.

[0019] "Nonfibrotic" as used herein means a compound or material that reduces at least one aspect of a foreign body response (FBR) to an implant containing the compound or material, e.g., minimizes the formation of pericapular fibrotic overgrowth (PFO) in the implant. For example, the FBR induced in a biological tissue or tissue fluid by implanting a polysaccharide polymer or device (e.g., a hydrogel or implantable element) containing a nonfibrotic compound (e.g., a hydrogel containing a polysaccharide polymer covalently modified with a compound listed in Table 1) in the tissue or tissue fluid occurs in a lower amount or at a later time point than the FBR induced by implantation of a nonfibrotic null reference polymer or device (i.e., one having substantially the same composition except lacking any nonfibrotic compound) (e.g., a hydrogel capsule formed from the same unmodified polymer and having substantially the same shape and size). In one embodiment, the extent of FBR can be measured using assays known in the art, e.g., as described in WO2017 / 075630, or as described in Vegas, A., et al., Nature 1999, 14, 1411-1415 ... Immunologic responses in tissues or tissue fluids containing the implanted device (e.g., hydrogel capsules) may include, for example, protein adsorption, macrophages, multinucleated foreign body giant cells, eosinophils, neutrophils, T cells, B cells, fibroblasts, and angiogenesis, using one or more of the assays / methods described in Biotechnol (supra) (e.g., subcutaneous cathepsin measurements of implanted capsules, Masson's Trichrome (MT), hematoxylin or eosin staining of tissue sections, quantification of collagen density, cell staining and confocal microscopy of macrophages (CD68 or F4 / 80), granulocytes (Siglec-F, Ly-6G), myofibroblasts (alpha muscle actin, SMA) or general cellular deposition, quantification of RNA sequences of 79 known inflammatory factors and immune cell markers, or FACS analysis of macrophage and neutrophil cells in devices (e.g., capsules) harvested after placement in the peritoneal cavity of suitable test subjects, such as immunocompetent mice, for 14 days.In one embodiment, FBR is assessed by measuring the levels of one or more immune response biomarkers, such as cathepsin, TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-1, IL-4, IL-5, CCL2, CCL4, TIMP-1, etc., in tissues or tissue fluids containing the implant. In some embodiments, FBR is assessed by examining the amount of PFO in the implant (e.g., hydrogel capsule) at one or more time points after administration to a suitable test subject (e.g., an immunocompetent mouse). This assessment can be performed using any of the assays known in the art, such as those described in this definition. In some embodiments, an aspect of the FBR (e.g., PFO) induced by a modified polymer or device of the invention (e.g., a hydrogel capsule comprising a non-fibrous compound described herein disposed on its exterior surface) is at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% lower, or occurs at least about 10%, about 20%, about 40%, or about 50% slower than an aspect of the FBR induced by a non-fibrous null reference polymer or device. In some embodiments, the FBR (e.g., the level of biomarker(s)) is measured after about 30 minutes, about 1 hour, about 6 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 1 week, about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, or more.

[0020] As used herein, "cell" refers to an engineered or non-engineered cell.

[0021] As used herein, "effective amount" refers to an amount of a compound, modified polymer, or implantable element (e.g., further including a cell, such as an engineered cell, or an agent, such as a therapeutic agent, produced by a cell, such as an engineered cell) described herein sufficient to reduce or induce a biological response, e.g., minimize an immune response, or treat a disease, disorder, or condition. As will be appreciated by those skilled in the art, an effective amount can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the therapeutic agent, composition, or implantable element, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatments. For example, to reduce a foreign body response (e.g., PFO) induced by an implantable element, a compound described herein can 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 spread of fibrotic tissue on or near the implantable element.

[0022] An "endogenous nucleic acid," as used herein, is a nucleic acid that is naturally present in a subject cell.

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

[0024] An "engineered cell," as used herein, is a cell that has a non-naturally occurring modification, typically comprising a nucleic acid sequence (e.g., DNA or RNA) (e.g., an exogenous nucleic acid sequence) or polypeptide that is not present (or is present at different levels) in an otherwise similar cell under similar conditions that is not engineered. In one embodiment, an engineered cell comprises an exogenous nucleic acid (e.g., a vector or an engineered chromosomal sequence). In one embodiment, an engineered cell comprises an exogenous polypeptide. In one embodiment, an engineered cell comprises an exogenous nucleic acid sequence, e.g., a sequence, e.g., DNA or RNA, that is not present in a similar cell that is not engineered. In one embodiment, the exogenous nucleic acid sequence is chromosomal, e.g., the exogenous nucleic acid sequence is an exogenous sequence 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 comprises an RNA sequence, e.g., an mRNA. In one embodiment, the exogenous nucleic acid sequence comprises a chromosomal or extrachromosomal exogenous nucleic acid sequence comprising a sequence that is expressed as an RNA, e.g., an mRNA or a regulatory RNA. In one embodiment, the exogenous nucleic acid sequence comprises a chromosomal or extrachromosomal exogenous nucleic acid sequence comprising a sequence that encodes or is expressed as a polypeptide. In one embodiment, the exogenous nucleic acid sequence comprises a first chromosomal or extrachromosomal exogenous nucleic acid sequence that regulates the conformation or expression of a second nucleic acid sequence, and the second amino acid sequence can be exogenous or endogenous. For example, an engineered cell can comprise an exogenous nucleic acid that controls the expression of an endogenous sequence. In one embodiment, an engineered cell comprises a polypeptide that is present at a level or distribution that differs from the level found in a similar cell that is not engineered. In one embodiment, an engineered cell comprises a cell that has been engineered to produce an RNA or a polypeptide. For example, an engineered cell can comprise an exogenous nucleic acid sequence comprising a chromosomal or extrachromosomal exogenous nucleic acid sequence comprising a sequence that is expressed as an RNA, e.g., an mRNA or a regulatory RNA. In one embodiment, the engineered cell comprises an exogenous nucleic acid sequence, including a chromosomal or extrachromosomal nucleic acid sequence that comprises a sequence that encodes or is expressed as a polypeptide.In one embodiment, the engineered cells contain an exogenous nucleic acid sequence that regulates the conformation or expression of an endogenous sequence. In one embodiment, the engineered cells (e.g., RPE cells) are cultured from a population of stably transfected cells or from a monoclonal cell line.

[0025] An "exogenous nucleic acid," as used herein, is a nucleic acid that does not naturally occur in a subject cell, such as an engineered cell.

[0026] An "exogenous polypeptide," as used herein, is a polypeptide that does not naturally occur in a subject cell, such as an engineered cell.

[0027] As used herein, an "implantable element" includes a cell, e.g., a plurality of cells, e.g., a cell cluster, where a cell or group of cells is disposed wholly or partially within a containment component (wherein the containment component is other than a cell), e.g., the containment component includes a non-cellular component. The term "implantable element" includes a device or material described herein. In one embodiment, the implantable element inhibits an immune attack or the effects of an immune attack on the contained cell or group of cells. 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) that includes a sugar monomer having the structure of formula (I) or a pharma- ceutically acceptable salt thereof. The implantable element described herein may include a polymer (e.g., a polysaccharide polymer, e.g., alginate) or other material, optionally modified with another compound (e.g., a non-fibrous compound or peptide).

[0028] "Pericapsular fibrotic overgrowth" or "PFO" as used herein refers to a layer of fibrous cells that develops over part or all of the hydrogel or implantable element as a result of a foreign body reaction to the implantable element.

[0029] "Polypeptide," as used herein, refers to a polymer comprising amino acid residues linked via peptide bonds and having at least 2, and in embodiments at least 10, 100, or 200 amino acid residues.

[0030] "Prevention," "prevent," and "preventing," as used herein, refer to treatments that involve administering or applying a therapy, e.g., administering a composition of an implantable element encapsulating cells (e.g., as described herein), prior to the onset of a disease, disorder, or condition to prevent the physical signs of said disease, disorder, or condition. In some embodiments, "prevention," "prevent," and "preventing" require that no sign or symptom of the disease, disorder, or condition develops or is observed.

[0031] A "replacement therapy" or "replacement protein" is a therapeutic protein or functional fragment thereof that replaces or enhances a protein that is reduced, insufficiently present, altered (e.g., mutated), or absent in a subject having a disease or condition associated with the reduced, altered, or absent protein. Examples include a given blood clotting factor in a given blood clotting disorder, or a given lysosomal enzyme in a given lysosomal storage disease. In one embodiment, the replacement therapy or replacement protein provides the function of an endogenous protein. In one embodiment, the replacement therapy or replacement protein has the same amino acid sequence as a naturally occurring variant of the protein to be replaced, such as a wild-type allele or a non-disorder-associated allele. In one embodiment, the replacement therapy or replacement protein differs in amino acid sequence from a naturally occurring variant, such as a wild-type allele or a non-disorder-associated allele, such as an allele carried by the subject, at no more than about 1, 2, 3, 4, 5, 10, 15, or 20% of the amino acid residues.

[0032] "Subject" as used herein refers to a human or a non-human animal. In one embodiment, the subject is a human (i.e., e.g., male or female of any age group, a pediatric subject (e.g., infant, childhood, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)). In one embodiment, the subject is a non-human animal, e.g., a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey)). In one embodiment, the subject is a commercially relevant mammal (e.g., a cow, 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 certain embodiments, the animal is a mammal. The animal can be male or female and at any stage of development. The non-human animal can be a transgenic animal.

[0033] "Treatment", "treat", and "treating" as used herein refer to one or more of reducing, reversing, alleviating, delaying the onset, or inhibiting the progression of one or more of the symptoms, signs, or underlying causes of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset, or inhibiting the progression of a symptom of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset, or inhibiting the progression of a sign of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, reducing, or delaying the onset of an underlying cause of a disease, disorder, or condition. In some embodiments, "treatment", "treat", and "treating" require that a sign or symptom of a disease, disorder, or condition has developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or condition, e.g., in a prophylactic treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in view of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence. In some embodiments, treatment includes prophylaxis, while in other embodiments it does not include prophylaxis.

[0034] Selected Chemical Definitions Definitions of certain functional groups and chemical terms are described in more detail below. Chemical elements are defined in the Handbook of Chemistry and Physics, 75 thEd. (inside cover), and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional sites and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0035] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas depicted herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0036] When a range of values ​​is listed, it is intended to encompass each value and sub-range within the range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0037] As used herein, "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group is an alkyl group having 1 to 12 carbon atoms ("C1-C 12In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, an 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), and the like. Each example of an alkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl").

[0038] As used herein, "alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C2-C 24 In some embodiments, an alkenyl group refers to an alkyl group having 2 to 10 carbon atoms ("C-C 10alkenyl"), 2 to 8 carbon atoms ("C2-C8 alkenyl"), 2 to 6 carbon atoms ("C2-C6 alkenyl"), 2 to 5 carbon atoms ("C2-C5 alkenyl"), 2 to 4 carbon atoms ("C2-C4 alkenyl"), 2 to 3 carbon atoms ("C2-C3 alkenyl"), or 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., as in 2-butenyl) or terminal (e.g., as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the C2-C6 alkenyl groups discussed above. 2-4 Alkenyl groups include 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, for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl").

[0039] 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-C 24 In some embodiments, an alkynyl group refers to an alkynyl group having 2 to 10 carbon atoms ("C-C 10alkynyl"), 2 to 8 carbon atoms ("C2-C8 alkynyl"), 2 to 6 carbon atoms ("C2-C6 alkynyl"), 2 to 5 carbon atoms ("C2-C5 alkynyl"), 2 to 4 carbon atoms ("C2-C4 alkynyl"), 2 to 3 carbon atoms ("C2-C3 alkynyl"), or 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each instance of an alkynyl group may independently be optionally substituted, that is, unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents; for example, with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkynyl").

[0040] As used herein, the term "heteroalkyl" refers to an acyclic stable straight or branched chain, or combinations thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen, phosphorus, silicon, or sulfur atom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be replaced at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)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, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A "heteroalkyl" is described followed by the particular heteroalkyl group, such as, for example, -CHO, -NR C RD etc., the term heteroalkyl and -CH2O or -NR C R D It is understood that the terms "heteroalkyl" and "heteroalkyl-alkyl" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to provide clarity. Thus, the term "heteroalkyl" refers to specific heteroalkyl groups, such as, for example, -CHO, -NR C R D etc. should not be construed herein as excluding such.

[0041] The terms "alkylene," "alkenylene," "alkynylene," or "heteroalkylene," alone or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, or heteroalkyl, respectively. An alkylene, alkenylene, alkynylene, or heteroalkylene group may be described, for example, as 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 termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- may represent both -C(O)2R'- and -R'C(O)2-.

[0042] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared by the cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared by the cyclic array). 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 Aryl"; e.g., anthracyl). Aryl groups include, e.g., C6-C 10 The term "membered" refers to a non-hydrogen ring atom in the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").

[0043] As used herein, "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, if valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, with the point of attachment being at either the aryl or heteroaryl ring, in such cases the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing a heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl). Heteroaryl groups can be described as, for example, 6- to 10-membered heteroaryl, with the term "member" referring to the non-hydrogen ring atoms in the moiety.

[0044] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom being 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 ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom being 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 ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, each heteroatom being 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 has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group independently may be optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl").

[0045] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0046] The terms "arylene" and "heteroarylene," as used herein, alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.

[0047] As used herein, "cycloalkyl" refers to a group having 3 to 10 ring carbon atoms in a non-aromatic ring system ("C3-C 10 Cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having no heteroatoms. In some embodiments, a cycloalkyl group has from 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), from 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"), or from 5 to 10 ring carbon atoms ("C5-C 10 Cycloalkyl groups may be described, for example, as C4-C7 membered cycloalkyl, where the term "membered" refers to a non-hydrogen ring atom in the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the C3-C6 cycloalkyl groups previously described as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C 10 Cycloalkyl groups include, but are not limited to, the C3-C8 cycloalkyl groups mentioned above as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the preceding examples illustrate, in certain embodiments, cycloalkyl groups are monocyclic ("monocyclic cycloalkyl") or contain fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic cycloalkyl"), and can be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused with one or more aryl groups, and the point of attachment is on the cycloalkyl ring, in which case the number of carbons continues to refer to the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl").

[0048] "Heterocyclyl," as used herein, is a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, with the point of attachment being on either the cycloalkyl or heterocyclyl ring, or a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Heterocyclyl groups may be described, for example, as 3- to 7-membered heterocyclyl, with the term "member" referring to the non-hydrogen ring atoms in the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0049] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0050] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl or thiomorpholinyl-1,1-dioxide. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0051] "Amino" as used herein refers to the radical -NR C R D (In the formula, R C and R D are each independently hydrogen, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclyl, C6-C 10 Aryl and C5-C 10 In some embodiments, amino refers to NH2.

[0052] As used herein, "cyano" refers to the radical --CN.

[0053] As used herein, "halo" or "halogen," independently or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0054] As used herein, "hydroxyl" or "hydroxy" refers to the radical --OH.

[0055] As used herein, a "hydroxyl modifier" is a moiety, such as a substance or compound, that can be attached to a material that includes a hydroxyl moiety (i.e., -OH) at the hydroxyl moiety. For example, the hydroxyl modifier can be attached to a carbon atom that is covalently attached to the hydroxyl moiety. Exemplary hydroxyl modifiers include amines, esters, and thiols. The hydroxyl modifier can be covalently or non-covalently attached to a material that includes a hydroxyl moiety. For example, as described herein, to covalently attach a hydroxyl modifier to a material that includes a hydroxyl moiety, a sugar moiety that includes a hydroxyl moiety can be subjected to a predetermined reaction, such as oxidation, reduction, or amination, to activate the hydroxyl moiety and / or the atoms surrounding the hydroxyl moiety.

[0056] As used herein, "saccharide" or "sugar" refers to a molecule that includes carbon, hydrogen, and oxygen atoms. In some embodiments, the sugar further includes another heteroatom (e.g., sulfur, phosphorus, or nitrogen). The sugar may form a ring structure (e.g., 4-, 5-, 6-, 7-, 8-, 9-membered ring) or may be acyclic (e.g., linear). Exemplary sugars include glucose, glucosamine, N-acetylglucosamine, glucuronic acid, galactose, galatosamine, N-acetylgalactosamine, galacturonic acid, mannose, mannosamine, N-acetylmannosamine, mannuronic acid, guluronic acid, idose, xylose, talose, fructose, and variants thereof.

[0057] As used herein, "polysaccharide" refers to a polymer of monosaccharides. Polysaccharides can have any number of repeating units. Polysaccharides can be composed of the same type of monosaccharides ("homopolysaccharides") or multiple types of monosaccharides ("heteropolysaccharides"). Polysaccharides can be naturally or non-naturally occurring. Exemplary polysaccharides include starch, glycogen, dextran, chitin, cellulose, hyaluronate, and alginate.

[0058] Alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). Typically, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that provides for a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, such as any of the substituents described herein, that result in the formation of a stable compound. The present invention contemplates all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0059] Two or more substituents may be optionally connected to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure generate a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure generate a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0060] The compounds of formula (I) described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0061] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess over the "R" form. The term "enantiomerically pure" or "pure enantiomer" indicates 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 certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0062] The compounds of formula (I) described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3 H can be in any isotopic form, including T or tritium; 12 C. 13 C, and 14 It can be in any isotopic form, including C; O is 16 O and 18 It can be any isotopic form including O; and so forth.

[0063] The term "pharmaceutically acceptable salts" is meant to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound used in this disclosure contains a relatively acidic functionality, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound used in this disclosure contains a relatively basic functionality, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids, such as arginates, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge et al, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds used in this disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those of ordinary skill in the art. Other pharma- ceutically acceptable carriers known to those of ordinary skill in the art are suitable for use in the present disclosure.

[0064] In addition to salt forms, the present disclosure may use compounds of formula (I) in prodrug form. Prodrugs are those compounds that readily undergo chemical changes under physiological conditions to provide compounds useful in the present invention. Also, prodrugs can be converted to useful compounds of formula (I) by chemical or biochemical methods in an ex vivo environment.

[0065] Certain compounds of formula (I) described herein may exist in solvated forms, including unsolvated forms and hydrated forms. In general, solvated forms are equivalent to unsolvated 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. In general, all physical forms are equivalent for the use contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0066] The term "solvate" refers to a form of a compound associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates.

[0067] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is within a defined ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is a compound and x is a number greater than 0.

[0068] As used herein, the term "tautomer" refers to a compound structure that is an interchangeable form, with changes in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium between the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological effects of a compound of interest.

[0069] symbol [ka] As used herein, refers to a connection 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 an implantable element, or may refer to a linkage to an entity via a linking group. "Linking group," as described herein, refers to a site for linking a compound of formula (I) to an entity (e.g., a polymer or an implantable element described herein) and may include any linking chemistry known in the art. A list of exemplary linking groups can be found in Bioconjugate Techniques (3 rd ed. Greg T. Hermanson, Waltham, MA: Elsevier, Inc, 2013). In some embodiments, the linking group is an 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 metal-containing, R A , R C , R D , R F , R G Each of x, y, and y is independently as described herein. In some embodiments, the linking group comprises an amine, a ketone, an ester, an amide, an alkyl, an alkenyl, an alkynyl, or a thiol. In some embodiments, the linking group is a crosslinker. In some embodiments, the linking group is -C(O)(C1-C6-alkylene)-, where the alkylene is R 1 is replaced by R 1 is as described herein. In some embodiments, the linking group is -C(O)(C1-C6-alkylene)-, where the alkylene is substituted with 1-2 alkyl groups (e.g., 1-2 methyl groups). In some embodiments, the linking group is -C(O)C(CH3)2-. In some embodiments, the linking group is -C(O)(methylene)-, where the alkylene is substituted with 1-2 alkyl groups (e.g., 1-2 methyl groups). In some embodiments, the linking group is -C(O)CH(CH3)-. In some embodiments, the linking group is -C(O)C(CH3)-.

[0070] Modified Sugar Monomers The invention features polysaccharide polymers that include a sugar monomer, the sugar monomer including a hydroxyl modifying agent covalently attached to the sugar monomer. In some embodiments, the hydroxyl modifying agent is covalently attached to an atom (e.g., a carbon atom) that has or previously had a hydroxyl moiety. In some embodiments, the hydroxyl modifying agent is covalently attached to the hydroxyl moiety. In some embodiments, the hydroxyl modifying agent includes an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amine, amide, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety. In some embodiments, the hydroxyl modifying agent includes an amine.

[0071] The sugar monomer can be any sugar monomer, for example, a naturally occurring or non-naturally occurring sugar monomer. The sugar monomer can include 1, 2, 3, 4, 5, 6, 7, 8, or more hydroxyl moieties. In one embodiment, the sugar monomer is a triose, tetrose, pentose, hexose, heptose, or octose. In one embodiment, the sugar monomer further includes an additional functional group, for example, a carboxylic acid or an amine. In one embodiment, the sugar monomer further includes multiple 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. In one embodiment, the sugar monomer is activated prior to modification. In one embodiment, the sugar monomer undergoes a ring-opening reaction prior to modification with a hydroxyl modifying agent. In one embodiment, the sugar monomers are oxidized (e.g., with periodate, IO 4- (according to.

[0072] In one embodiment, the glycomonomer has formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O, NR 6 , or S;R 1 and R 4 Each of is independently absent, alkylene, alkenylene, alkynylene, heteroalkylene, 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 each independently selected from one or more R 8 Optionally substituted by; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, alkyl, heteroalkyl, haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R 9 is optionally replaced by R 2a and R 2b At least one of and R 3a and R 3b At least one of R is not hydrogen; 5a and R 5b Each of is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, 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, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more R 8 Optionally substituted by; R 6 is hydrogen, alkyl, heteroalkyl, or haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently selected from one or more R 9 Optionally substituted by; R 7a and R 7b are each independently hydrogen, alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is selected from one or more R 9 and each R 8 are independently alkyl, alkenyl, alkynyl, heteroalkyl, 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 wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R 10 is replaced by; R A is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, 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 selected from 0 to 12 R 10 is replaced by; R B , R C, and R D is an alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R 10 or R B and R C together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from the group consisting of one or more R 10 and each R 9 are independently alkyl, heteroalkyl, 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 where each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 10 and each R 10 is independently 1-6 It is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0073] In one embodiment, the glycomonomer has formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O, NR 6 , or S;R 1 is absent, alkylene, alkenylene, alkynylene, heteroalkylene, haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-, or -N(RC )C(O)—, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are each independently selected from one or more R 8 Optionally substituted by; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, alkyl, heteroalkyl, haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R 9 is optionally replaced by R 2a and R 2b At least one of and R 3a and R 3b At least one of R is not hydrogen; 4 is absent, alkylene, alkenylene, alkynylene, heteroalkylene, 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 selected from one or more R 8 Optionally substituted by; R 5 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, 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, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more R 8 Optionally substituted by; R 6 is hydrogen, alkyl, heteroalkyl, or haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently selected from one or more R 9 Optionally substituted by; R 7a and R 7b are each independently hydrogen, alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is selected from one or more R 9 and each R 8 are independently alkyl, alkenyl, alkynyl, heteroalkyl, 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 wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R 10 is replaced by; R A is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, 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 selected from 0 to 12 R 10 is replaced by; R B , R C, and R D is an alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound (e.g., a), or a peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R 10 or R B and R C together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from the group consisting of one or more R 10 and each R 9 are independently alkyl, heteroalkyl, 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 where each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 10 and each R 10 is independently alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0074] In one embodiment, the glycomonomer has formula (Ib): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O, NR 6 , or S;R 1 is non-existent, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R7a )-, -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 each independently selected from one or more R 8 Optionally substituted by; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R 9 is optionally replaced by R 2a and R 2b At least one of and R 3a and R 3b At least one of R is not hydrogen; 4 is non-existent, 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R 8 Optionally substituted by; R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, N(R 7a )(R 7b ), ORA , C(O)R B , C(O)OR A , C(O)N(R C )(R D ), N(R C )C(O)R B , halogen, cyano, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more R 8 Optionally substituted by; R 6 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, or C 1-6 haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently selected from one or more R 9 Optionally substituted by; R 7a and R 7b are each independently hydrogen, C 1-6 alkyl, cycloalkyl, or heterocyclyl, where the alkyl, cycloalkyl, or heterocyclyl is selected from one or more R 9 and each R 8 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 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 wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R 10 is replaced by; R Ais hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 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 selected from 0 to 12 R 10 is replaced by; R B , R C , and R D is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R 10 or R B and R C together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from the group consisting of one or more R 10 and each R 9 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 where each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 10 and each R 10 is independently 1-6 It is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0075] In one embodiment, X is O. In one embodiment, R 1 OR A In one embodiment, R 5 is C(O)OR A or C(O)N(R C )(R D In one embodiment, R 5 is C(O)OR A In one embodiment, R A is hydrogen. In one embodiment, R 5 is C(O)N(R C )(R D In one embodiment, R C and R D are each independently hydrogen, a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2), or a peptide. C and R D One of the groups is hydrogen, and the other is R C and R D the other is independently a non-fibrous compound (eg, a non-fibrous compound shown in Table 2) or a peptide.

[0076] In one embodiment, R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl. In one embodiment, R 3 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl. In one embodiment, R 2 and R 3 One of them is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6Haloalkyl, C(O)R B and R 2 and R 3 and the other is independently hydrogen. 4 OR A It is.

[0077] In one embodiment, the non-fibrotic compound is selected from the compounds in Table 2. In one embodiment, the non-fibrotic compound is a compound disclosed in one of U.S. Pat. No. 11,266,606, U.S. Patent Publication No. US20200263196 A1, or U.S. Patent Publication No. US20200039943 A1, each of which is incorporated herein by reference in its entirety.

[0078] In one embodiment, the glycomonomer has formula (Ic): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R 5 and each of their subvariables are as defined in formula (Ia).

[0079] In one embodiment, the glycomonomer has formula (Id): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R 5 and each of their subvariables are as defined in formula (Ia), and G 1 and G 2 Each of is independently hydrogen, a non-fibrous compound, or a peptide.

[0080] In one embodiment, the glycomonomer has formula (Ie): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R C , and R D and each of their subvariables are as defined in formula (Ia).

[0081] In one embodiment, the glycomonomer has the formula (If): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R C , and R D and each of their subvariables are as defined in formula (Ia), and G 1 and G 2 Each of is independently hydrogen, a non-fibrillar compound (e.g., a compound in Table 2), or a peptide (e.g., a peptide in Table 3).

[0082] In one embodiment of formula (If), G 1 and G 2 is independently a non-fibrous compound. 1 and G 2 is independently a non-fibrous compound. In one embodiment of formula (If), G 1 and G 2 is independently a compound selected from Table 2. In one embodiment of formula (If), G 1 and G 2 is independently a compound selected from Table 2; R 2a , R 3a , R C , and R D Each of is hydrogen. In one embodiment of formula (If), G 1 and G 2is independently a compound selected from Table 2; R 2a and R 3a Each of R is hydrogen; C and R D Each of is independently hydrogen or a peptide selected from Table 3.

[0083] In one embodiment, the glycomonomer has the formula (Ig): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R 5 , R 7a , R 8 and each of their subvariables is as defined in formula (Ia); P 1 and P 2 are each independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is selected from one or more R 11 Optionally substituted by; L 1 and L 2 are each independently 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R 8 Optionally substituted by; Z 1 and Z 2 are each independently hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 8each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 11 is alkyl, alkenyl, alkynyl, heteroalkyl, halo, or cyano.

[0084] In one embodiment, the glycomonomer has formula (Ih): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R C , R D , R 7a , R 8 , R 11 , P 1 , P 2 , L 1 , L 2 , Z 1 , Z 2 and each of their subvariables are as defined in formulas (Ia)-(Ig); each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0085] In one embodiment, the glycomonomer has formula (Ii): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R 5 , P 1 , P 2 , L 1 , L 2 , Z 1 , Z 2 and each of their subvariables are as defined in formulas (Ia)-(Ih); R 13a and R 13b are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C1-6 haloalkyl, or halo; each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0086] In one embodiment, the glycomonomer has formula (Ij): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R C , R D , P 1 , P 2 , L 1 , L 2 , Z 1 , Z 2 , R 13a , and R 13b and each of their subvariables are as defined in formulas (Ia)-(Ii);

[0087] In one embodiment, the glycomonomer has the formula (Ik): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R 5 , L 1 , L 2 , Z 1 , Z 2 , R 13a , and R 13b and each of their subvariables are as defined in formulas (Ia)-(Ij); R 14a and R 14b are each independently hydrogen, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Heteroalkylene, C 1-6haloalkylene, halo, or cyano; each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0088] In one embodiment, the glycomonomer has formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R C , R D , L 1 , L 2 , Z 1 , Z 2 , R 13a , R 13b , R 14a , R 14b and each of their subvariables are as defined in formulas (Ia)-(Ik); each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0089] In one embodiment, P 1 and P 2 are each independently heteroaryl. 1 and P 2 is independently a monocyclic heteroaryl. 1 and P 2 are each independently a nitrogen-containing heteroaryl. 1 and P 2 are each independently a monocyclic nitrogen-containing heteroaryl. 1 and P 2 is independently a 5-membered heteroaryl. In some embodiments, P is a 5-membered nitrogen-containing heteroaryl.

[0090] In one embodiment, P 1 and P 2 Each of these is one or more R 12In one embodiment, R is a triazolyl substituted by 12 is 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 , cycloalkyl, heterocyclyl, aryl, heteroaryl. In one embodiment, R 12 is deuterium, alkyl, heteroalkyl, halogen, cyano, or azido. 12 is chloro. In one embodiment, P 1 and P 2 are each independently [ka] and R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 It is haloalkyl, or halo.

[0091] In one embodiment, the glycomonomer has the formula (Im): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R 5 , P 1 , P 2 , L 1 , L 2 , Z 1 , Z 2 , R14a , R 14b and each of their subvariables are as defined in formulas (Ia)-(Il); R 15a and R 15b each is independently hydrogen, deuterium, alkyl, heteroalkyl, haloalkyl, or halo; and each of m and n is independently 1, 2, 3, 4, or 5.

[0092] In one embodiment, the glycomonomer has the formula (In): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R 5 , P 1 , P 2 , L 1 , L 2 , Z 1 , Z 2 , R 14a , R 14b , R 15a , R 15b and each of their subvariables are as defined in formulas (Ia)-(Im); each of m and n is independently 1, 2, 3, 4, or 5.

[0093] In one embodiment, P 1 and P 2 are each independently [ka] In one embodiment, P 1 and P 2 are each independently [ka] In one embodiment, P 1 and P 2 are each independently [ka] In one embodiment, P 1 and P 2 are each independently [ka] In one embodiment, P 1 and P 2 are each independently [ka] In one embodiment, P 1 and P 2 are each independently [ka] In one embodiment, P 1 and P 2 are each independently [ka] In one embodiment, P 1 and P 2 are each independently [ka] In one embodiment, P 1 and P 2 are each independently [ka] It is.

[0094] In one embodiment, L 1 and L 2 are each independently absent or C 1-6 Alkylene (eg, -CH2-).

[0095] In one embodiment, Z 1 and Z 2 are each independently aryl, heteroaryl, or heterocyclyl. 1 and Z 2 are each independently heterocyclyl. 1 and Z 2 are each independently a monocyclic or bicyclic heterocyclyl. 1 and Z 2 are each independently a 4-membered heterocyclyl, a 5-membered heterocyclyl, or a 6-membered heterocyclyl. 1 and Z 2 are each independently 4-membered heterocyclyl. 1 and Z 2 are each independently 6-membered heterocyclyl. 1 and Z 2 are each independently a nitrogen-containing heterocyclyl. 1 and Z 2 are each independently a sulfur-containing heterocyclyl. 1 and Z 2 are each independently a 4-membered nitrogen-containing heterocyclyl. 1 and Z 2 are each independently a 6-membered nitrogen-containing heterocyclyl. 1 and Z 2 are each independently a 6-membered sulfur-containing heterocyclyl. 1 and Z 2 are each independently a 6-membered heterocyclyl containing a nitrogen atom and a sulfur atom. 1 and Z 2 Each independently represents one R 8 4-membered nitrogen heterocyclyl optionally substituted with (e.g., -S(O) x R E1 In one embodiment, R 8is -S(O)2CH3.

[0096] In one embodiment, Z 1 and Z 2 are each independently 3-(methylsulfonyl)azetidinyl. 1 and Z 2 are each independently [ka] In one embodiment, Z 1 and Z 2 are each independently thiomorpholinyl-1,1-dioxydiyl. 1 and Z 2 are each independently [ka] In one embodiment, the sugar moiety is selected from the compounds in Table 1, or a pharma- ceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0097] In one embodiment, the sugar moiety is selected from compounds 100-130. In one embodiment, the sugar moiety is selected from compounds 100, 101, and 102. 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.

[0098] In one embodiment, the saccharide moiety further comprises a non-fibrous compound, e.g., covalently attached to another functional group on the saccharide moiety (e.g., the saccharide moiety of formula (I)). 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]

[0099] In one embodiment, the non-fibrous compound is selected from compounds 200-254 or salts thereof. 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.

[0100] In one embodiment, the sugar moiety further comprises a peptide, e.g., covalently attached 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. "Cell-binding peptide (CBP)" as used herein means a linear or cyclic peptide that includes an amino acid sequence derived from a cell-binding domain of a ligand of a cell adhesion molecule (CAM) (e.g., mediating cell-matrix or cell-cell connections). The CBP is less than 50, 40, 30, 25, 20, 15, or 10 amino acids in length. In one embodiment, the CBP is 3-12 amino acids in length, 4-10 amino acids in length, or 3, 4, 5, 6, 7, 8, 9, or 10 amino acids in length. The CBP amino acid sequence may be identical to a naturally occurring binding domain sequence or may be a conservatively substituted variant thereof. In one embodiment, the CAM ligand is a mammalian protein. In one embodiment, the CAM ligand is a human protein selected from the group of proteins listed in Table 1 below. In one embodiment, the CBP comprises a cell-binding sequence listed in Table 1 below, or a conservatively substituted variant thereof. In one embodiment, the CBP comprises at least one of the cell-binding sequences listed in Table 3 below. In one embodiment, the CBP consists essentially of a cell-binding sequence listed in Table 3 below. In one embodiment, the CBP is an RGD peptide, meaning that the peptide comprises the amino acid sequence RGD (SEQ ID NO: 20), optionally including one or more additional amino acids located at either or both of the N-terminus and C-terminus. In one embodiment, the peptide is a peptide shown in Table 3. In this table, exemplary cell-binding proteins are listed with their associated cell-binding sequences. [Table 3]

[0101] In one embodiment, the peptide comprises SEQ ID NO:1. In one embodiment, the peptide comprises SEQ ID NO:2. In one embodiment, the peptide comprises SEQ ID NO:3. In one embodiment, the peptide comprises SEQ ID NO:4. In one embodiment, the peptide comprises SEQ ID NO:5. In one embodiment, the peptide comprises SEQ ID NO:6. In one embodiment, the peptide comprises SEQ ID NO:7. In one embodiment, the peptide comprises SEQ ID NO:8. In one embodiment, the peptide comprises SEQ ID NO:9. In one embodiment, the peptide comprises SEQ ID NO:10. In one embodiment, the peptide comprises SEQ ID NO:11. In one embodiment, the peptide comprises SEQ ID NO:12. In one embodiment, the peptide comprises SEQ ID NO:13. In one embodiment, the peptide comprises SEQ ID NO:14. In one embodiment, the peptide comprises SEQ ID NO:15. In one embodiment, the peptide comprises SEQ ID NO:16. In one embodiment, the peptide comprises SEQ ID NO:17. In one embodiment, the peptide comprises SEQ ID NO:18. In one embodiment, the peptide comprises SEQ ID NO:19. In one embodiment, the peptide comprises SEQ ID NO:20. In one embodiment, the peptide comprises SEQ ID NO:21. In one embodiment, the peptide comprises SEQ ID NO:22. In one embodiment, the peptide comprises SEQ ID NO:23. In one embodiment, the peptide comprises SEQ ID NO:24. In one embodiment, the peptide comprises SEQ ID NO:25. In one embodiment, the peptide comprises SEQ ID NO: 26. In one embodiment, the peptide comprises SEQ ID NO: 27. In one embodiment, the peptide comprises SEQ ID NO: 28.

[0102] In one embodiment, the peptide is a peptide disclosed in WO2020069429A1, which is incorporated by reference in its entirety.

[0103] Modified Polymers The polysaccharide polymers described herein include sugar moieties modified with hydroxyl modifiers. In one embodiment, the polysaccharide polymers can 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 can include one or more of the following types: star polymers, comb polymers, brush polymers, dendrimerized polymers, graft co(polymers), ladder polymers, and dendrimers. The polysaccharide polymers can be thermoresponsive polymers, such as gels (e.g., that become solid or liquid upon exposure to heat or a predetermined temperature) or photocrosslinkable polymers. In some embodiments, the polysaccharide polymers are composed of a single type of repeating monomer unit. In other embodiments, the polysaccharide polymers are composed of different types of repeating monomer units (e.g., two types of repeating monomer units, three types of repeating monomer units, e.g., polymer blends).

[0104] In one embodiment, the polysaccharide polymer is a cellulose, such as carboxymethylcellulose. In one embodiment, the polysaccharide polymer is a polylactide, polyglycoside, or polycaprolactone. In one embodiment, the polysaccharide polymer is a hyaluronate, such as sodium hyaluronate. In one embodiment, the polymer is collagen, elastin, or gelatin.

[0105] In some embodiments, the polysaccharide polymer is a hydrogel-forming polymer. Hydrogel-forming polymers include hydrophilic structures and are therefore capable of retaining 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 amorphous, semi-crystalline, or crystalline in nature, for example, as described in Ahmed (2015) J Adv Res 6:105-121. Exemplary hydrogel-forming polymers include proteins (such as collagen), gelatin, polysaccharides (such as starch, alginate, hyaluronate, agarose, and the like), and synthetic polysaccharides.

[0106] Exemplary polysaccharides include alginate, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, amylose, chitin, chitosan, or derivatives or variants thereof (e.g., those described in Laurienzo (2010), Mar Drugs 9:2435-65). The polysaccharide polymer may include heparin, chondroitin sulfate, dermatan, dextran, or carboxymethylcellulose. In some embodiments, the polysaccharide polymer is a cross-linked polymer. In some embodiments, the polysaccharide polymer is a cell surface polysaccharide.

[0107] In some embodiments, the polysaccharide polymer is an alginate. Alginates are polysaccharides composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G). In some embodiments, the alginate is a high guluronic acid (G) alginate, comprising about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more guluronic acid (G). In some embodiments, the alginate is a high mannuronic acid (M) alginate, comprising about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more mannuronic acid (M). In some embodiments, the ratio of M:G is about 1. In some embodiments, the ratio of M:G is less than 1. In some embodiments, the ratio of M:G is greater than 1. In some embodiments, the alginate has an approximate molecular weight of <75 kDa, and optionally has a G:M ratio of >1.5. In some embodiments, the alginate has an approximate molecular weight of between 75 kDa and 150 kDa, and optionally has a G:M ratio of >1.5. In some embodiments, the alginate has an approximate molecular weight of between 150 and 250 kDa, and optionally has a G:M ratio of >1.5.

[0108] A polysaccharide polymer (e.g., any of the polymers described herein, e.g., any of the alginates described herein) comprising a saccharide moiety having the structure of formula (I) or a pharma- ceutically acceptable salt thereof may be modified at one or more monomer units. In some embodiments, at least 0.5 percent of the saccharide monomers of the polysaccharide polymer have the structure of formula (I) (e.g., at least 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99 percent, or more of the saccharide monomers have the structure of formula (I). In some embodiments, between 0.5 and 50%, between 10 and 90%, between 10 and 50%, or between 25 and 75% of the saccharide monomers of the polysaccharide polymer have the structure of formula (I). In some embodiments, between 1 and 20% of the saccharide monomers of the polysaccharide polymer have the structure of formula (I). In some embodiments, between 1-10% of the sugar monomers of the polysaccharide polymer have the structure of formula (I).

[0109] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having the structure of Formula I) comprises an increase in %N (when compared to the unmodified polymer) of at least 0.1, 0.2, 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10%N by weight, where %N corresponds to the amount of the compound of Formula (I) in the modified polymer, as determined by elemental analysis.

[0110] In some embodiments, the polysaccharide polymer (when it comprises a sugar monomer having the structure of formula (I)) comprises an increase in %N (when compared to the unmodified polymer) of 0.1 to 10%N by weight, where %N corresponds to the amount of the compound of formula (I) in the modified polymer, as determined by elemental analysis.

[0111] In some embodiments, the polysaccharide polymer (when it comprises a sugar monomer having the structure of formula (I)) comprises an increase in %N (when compared to the unmodified polymer) of 0.1-2%N by weight, where %N corresponds to the amount of the compound of formula (I) in the modified polymer, as determined by elemental analysis.

[0112] In some embodiments, the polysaccharide polymer (when it comprises a sugar monomer having the structure of formula (I)) comprises an increase in %N (when compared to the unmodified polymer) of 2-4%N by weight, where %N corresponds to the amount of the compound of formula (I) in the modified polymer, as determined by elemental analysis.

[0113] In some embodiments, the polysaccharide polymer (when it comprises a sugar monomer having the structure of formula (I)) comprises an increase in %N (when compared to the unmodified polymer) of 4-8%N by weight, where %N corresponds to the amount of the compound of formula (I) in the modified polymer, as determined by elemental analysis.

[0114] In some embodiments, any of the polysaccharide polymers (e.g., alginates) described herein comprise a sugar monomer having one or more of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), or a pharma- ceutically acceptable salt thereof. In some embodiments, the polymer (e.g., alginate) is modified with a compound shown in Table 2. In some embodiments, the polymer (e.g., alginate) modified with a compound of Formula (I) is not a modified polymer described in any one of WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 187225, WO2016 / 019391, WO2017 / 075630, WO2017 / 075631, WO2018 / 067615, WO2019 / 169333, and US2016-0030359.

[0115] portable elements The present disclosure also features an implantable element (e.g., a device or material) comprising a polysaccharide polymer of formula (I) or a pharma- ceutically acceptable salt thereof as described herein. 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 (e.g., the external or internal surface) of the implantable element. An implantable element comprising a polysaccharide polymer of formula (I) may have improved properties compared to a reference implantable element (e.g., an otherwise identical implantable element lacking the polysaccharide polymer of formula (I)). In one embodiment, the improved property is a reduction in foreign body reaction (e.g., a reduction in the amount and / or a delay in the onset of PFO) to the implantable element when administered to a subject.

[0116] In some embodiments, the implantable element comprises cells. In some embodiments, the cells are engineered cells. In some embodiments, the cells are disposed wholly or partially with the implantable element. The implantable element may comprise a containment element that partially or wholly encapsulates or coats the cells. In one embodiment, the implantable element comprises a containment component, which is or can be formed in situ on or around a cell, e.g., a plurality of cells, e.g., a cell cluster, or on a microcarrier, e.g., a bead, or matrix that contains the cell or group of cells.

[0117] The implantable element can include any material, such as a polymer or other material described herein. In some embodiments, the implantable element is composed of one material or many types of materials. The implantable element can include inorganic or metallic components or materials, such as steel (e.g., stainless steel), titanium, other metals or alloys. The implantable element can include non-metallic components or materials, such as ceramic or hydroxyapatite components.

[0118] The implantable element may include components or materials made of conductive materials (such as gold, platinum, palladium, titanium, copper, aluminum, silver, metals, any combination thereof, etc.).

[0119] The implantable element can include multiple components, such as multiple components disclosed herein, such as multiple of a metal, plastic, ceramic, composite, or hybrid material.

[0120] Exemplary implantable elements include materials such as metals, metal alloys, ceramics, polymers, fibers, inert materials, and combinations thereof. An implantable element may be composed entirely of one type of material or may involve only a surface or surfaces of the implantable element (e.g., an outer or inner surface).

[0121] In some embodiments, the implantable element (e.g., device or material) comprises a metal or metal alloy. Exemplary metals or metal alloys include titanium and titanium-family alloys (e.g., nitinol, nickel-titanium alloys, thermal memory alloy materials), platinum, platinum-family alloys, stainless steel, tantalum, palladium, zirconium, niobium, molybdenum, nickel-chromium, chromium-molybdenum alloys, or certain cobalt alloys (e.g., cobalt-chromium and cobalt-chromium-nickel alloys). For example, the metal material can 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., weight %, actual weight) can 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., less than 20 percent, e.g., less than 20, 15, 10, 5, 1, 0.5, 0.1 percent, or less, w / w.

[0122] 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, can also be used. In ceramic-containing implantable elements, the amount of ceramic (e.g., weight %, actual weight) can 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., less than 20 percent, e.g., less than 20, 15, 10, 5, 1, 0.5, 0.1 percent, or less, w / w.

[0123] 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, polyhydroxyalkanoates (PHAs), or other bioabsorbable plastics), polycarbonate, polyvinyl chloride (PVC), polyethersulfone (PES), polyacrylate (e.g., acrylic or PMMA), hydrogel (e.g., acrylic polymer or blend of acrylic polymer and silicone polymer), polysulfone, polyetheretherketone, thermoplastic elastomer (TPE or TPU), thermoset 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., weight %, actual weight) can 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., less than 20 percent, e.g., less than 20, 15, 10, 5, 1, 0.5, 0.1 percent, or less, w / w.

[0124] In some embodiments, the implantable element (e.g., device or material) comprises a polymer, which is (i) modified with a compound of formula (I) and (ii) covalently or non-covalently associated with a component of the implantable element (e.g., the surface of the implantable element). In some embodiments, the polymer is covalently associated with a component 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 a component of the implantable element (e.g., on the inner or outer surface of the implantable element). The polymer may be applied to the implantable element by various techniques in the art, including, but not limited to, spraying, wetting, immersing, dipping, such as dip coating (e.g., intraoperative dip coating), painting, or otherwise applying a hydrophobic polymer to the surface of the implantable element.

[0125] In one embodiment, the implantable element comprises a flexible polymer such as, for example, alginate (e.g., any of the chemically modified alginates described herein), PLA, PLG, PEG, CMC, or mixtures thereof (referred to herein as a "polymer-encapsulated implantable device").

[0126] In some embodiments, the implantable element comprises a hydrogel-forming polymer. The hydrogel-forming polymer comprises a hydrophilic structure and is therefore capable of retaining large amounts of water within a three-dimensional network. The hydrogel-forming polymer may comprise a polymer that forms a homopolymer hydrogel, a copolymer hydrogel, or a multipolymer interpenetrating polymer hydrogel, and may be amorphous, semi-crystalline, or crystalline in nature, for example, as described in Ahmed (2015) J Adv Res 6:105-121. Exemplary hydrogel-forming polymers include proteins (such as collagen), gelatin, polysaccharides (such as starch, alginate, hyaluronate, agarose, and the like), and synthetic polymers. In some embodiments, the hydrogel-forming polymer is a polysaccharide (e.g., alginate).

[0127] In some embodiments, the implantable element comprises a polysaccharide. Exemplary polysaccharides include alginate, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, amylose, chitin, chitosan, or derivatives or variants thereof (e.g., those described in Laurienzo (2010), Mar Drugs 9:2435-65). The implantable element may comprise a polysaccharide including heparin, chondroitin sulfate, dermatan, dextran, or carboxymethylcellulose. In some embodiments, the polysaccharide is a cross-linked polymer. In some embodiments, the polysaccharide is a cell surface polysaccharide.

[0128] In some embodiments, the implantable element comprises an alginate. In some embodiments, the ratio of M:G in the alginate is about 1. In some embodiments, the ratio of M:G in the alginate is less than 1. In some embodiments, the ratio of M:G in the alginate is greater than 1. In some embodiments, the alginate is any of the modified alginates described herein.

[0129] In one embodiment, the implantable element is or can be formed in situ on or around a cell, e.g., a plurality of cells, e.g., a cell cluster, or on a microcarrier, e.g., a bead, or matrix that contains the cell or cell groups.

[0130] In one embodiment, the implantable element is preformed prior to combination with the encapsulated cells, e.g., a plurality of cells, e.g., a cell cluster, or on a microcarrier, e.g., a bead, or a matrix containing the cells or cell groups. The implantable element can include a protein or polypeptide, such as an antibody, a protein, an enzyme, or a growth factor. The implantable element can include an active or inactive fragment of a protein or polypeptide, such as glucose oxidase (e.g., for glucose sensors), a kinase, a phosphatase, an oxygenase, a hydrogenase, or a reductase.

[0131] The implantable elements included herein include implantable elements configured with a lumen, such as a tubular device, e.g., a catheter, configured with one, two, or more openings. A typical stent is an example of a device configured with a lumen and having two openings. Other examples include shunts.

[0132] Implantable elements included herein include, for example, flexible implantable elements configured to conform to the shape of the body.

[0133] Implantable elements included herein include components that stabilize the position of the implantable element, such as adhesives, or fasteners, such as torque- or friction-based fasteners, such as screws or pins.

[0134] The implantable elements contained herein may be configured to monitor a substance, such as an exogenous substance, e.g., a therapeutic agent or a toxin, or an endogenous body product, e.g., a polypeptide, e.g., insulin or glucose, hi some embodiments, the implantable element is a diagnostic tool.

[0135] The implantable elements included herein can be configured to release a substance, such as an exogenous substance, such as, for example, a therapeutic agent described herein. In some embodiments, the therapeutic agent is a compound of formula (I) or a pharma- ceutically 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, an enzyme, an antibody, an antibody fragment, an antigen, or an epitope), a small molecule, a lipid, a drug, a vaccine, or any derivative thereof.

[0136] The implantable elements herein may be configured to change conformation in response to bodily signals or movements, such as, for example, an artificial joint, such as a knee, hip, or other artificial joint.

[0137] Exemplary 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, intragastric implants, facial implants, hip implants, bone implants, cochlear implants, penile implants, incontinence control implants), skin covering devices, dialysis media, drug delivery devices, artificial or engineered organs (e.g., spleen, kidney, liver, or heart), drainage devices (e.g., bladder drainage devices, etc.). devices, cell selection systems, adhesives (e.g., cements, clamps, clips), contraceptive devices, intrauterine devices, defibrillators, dosimeters, electrodes, pumps (e.g., infusion pumps), filters, embolization devices, fasteners, fillers, fixation agents, grafts, hearing aids, cardiac or cardiac-related devices (e.g., pacemakers, heart valves), batteries or power sources, hemostatic agents, incontinence devices, intervertebral body fusion devices, intraoral devices, lenses, meshes, needles, nervous system stimulants, patches, peritoneal access devices, plates, plugs, pressure monitoring devices, rings, transponders, and valves. Also included are devices used in one or more of anesthesiology, cardiology, clinical chemistry, otolaryngology, dentistry, gastroenterology, urology, hematology, immunology, microbiology, neurology, obstetrics / gynecology, ophthalmology, orthopedics, pathology, physical therapy, radiology, general or plastic surgery, veterinary medicine, psychiatry, surgery, and / or clinical toxicology.

[0138] Implantable elements included herein include FDA class 1, 2, or 3 devices, such as devices that are unclassified or unclassified, or classified as compassionate use devices (HUDs).

[0139] In some embodiments, the implantable element comprises encapsulated or entrapped cells or tissue. The cells or tissue may be encapsulated or entrapped in a polymer. In some embodiments, the implantable element comprises cells, such as cells disposed within a polymeric encapsulating component (e.g., alginate).

[0140] In some embodiments, the implantable element targets or is designed for a given system of the body, such as, for example, the nervous system (e.g., the peripheral nervous system (PNS) or 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 implantable element targets the CNS. In some embodiments, the implantable element targets or is designed for a given 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.

[0141] 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); heat 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 durability; sterilization capability (e.g., 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), such as heat resistance to autoclave / steam conditions, hydrolytic stability during steam sterilization, chemical resistance to EtO, resistance to high energy radiation (e.g., electron beam, UV, and gamma); or crystal structure.

[0142] Implantable elements can be constructed in vivo (eg, an injectable material that forms a structured shape in vivo, eg, at body temperature) or can be constructed ex vivo.

[0143] The implantable element can have nano-dimensions and can include nanoparticles, such as nanoparticles made from polymers described herein, such as PLA. The nanoparticles can be chemically modified nanoparticles, for example, modified to prevent uptake by macrophages and Kupfer cells (e.g., a process called opsonization) or modified to alter the circulatory half-life of the nanoparticles. The nanoparticles can include iron nanoparticles (injectable) (e.g., Advanced Magnetics iron nanoparticles). Exemplary nanoparticles are described in Veiseh et al (2010) Adv Drug Deliv Rev 62:284-304.

[0144] The implantable element may be configured for implantation, administration to, or administered to, implanted in, or otherwise disposed in or on any body site of a subject, including, but not limited to, the skin, mucosal surfaces, body cavities, intraperitoneal (IP) space, central nervous system (CNS) (e.g., brain or spinal cord), peripheral nervous system, organs (e.g., heart, liver, kidneys, bladder, pancreas, prostate, spleen, lungs), lymphatic system, vascular system, oral cavity, nasal cavity, teeth, gums, gastrointestinal tract, bone, hip joint, adipose tissue (e.g., subcutaneous fat), muscle tissue, breast tissue, circulating blood, eye, breast, vagina, uterus, joints (e.g., knee, hip, or spine), adjacent to nerves, and malignant or non-malignant tumors located on, in, or near any of the foregoing.

[0145] In some embodiments, the implantable element is configured for implantation, administration, or implantation or placement in an IP space, such as the peritoneal cavity, omentum, or omental bursa. The lesser sac, also known as the omental bursa, refers to a cavity located in the abdomen formed by the omentum, and is in close proximity to, for example, the greater omentum, the lesser omentum, the stomach, the small intestine, the large intestine, the liver, the spleen, the gastrosplenic ligament, the adrenal glands, and the pancreas. Typically, the omental bursa is connected to the greater sac via a greater omental foramen (i.e., the foramen of Winslow). The implantable element may be implanted or administered into the IP space, the peritoneal cavity (e.g., the omentum, e.g., the omental bursa) via injection or catheter, or placed on a surface within the peritoneal cavity (e.g., the omentum, e.g., the omental bursa). Additional considerations for implantation, administration, or placement of an implantable element into the omentum (e.g., the omental bursa) are provided in M. Pellicciaro et al. (2017) CellR4 5(3):e2410.

[0146] In some embodiments, the implantable element is configured for, or is implanted, administered, or otherwise disposed within the CNS (e.g., brain or spinal cord) and their 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, or is implanted, administered, or otherwise disposed within an intracerebral space (e.g., intraparenchymal, intraventricular, or subdural space). The implantable element may be implanted within the CNS through a hole drilled in the skull or placed superficially within the CNS and delivered by injection or catheter.

[0147] In some embodiments, the implantable element is configured for implantation, administration, or is implanted, administered, or otherwise disposed within the eye, for example, at one or more of any surface or cavity within the eye, such as the retina, cornea, epithelium, aqueous humor, or vitreous space. The implantable element may be implanted within the eye by incision and / or injection or disposed on a surface within the eye.

[0148] The implantable element can include an electrochemical sensor, e.g., an electrochemical sensor including a working electrode and a reference electrode. For example, the electrochemical sensor includes a working electrode and a reference electrode, which reacts with an analyte to generate a sensor measurement related to the concentration of the analyte in a fluid to which the ocular wearable device is exposed. The implantable element can include, for example, a window of a transparent polymeric material having a concave and convex surface, e.g., a substrate at least partially embedded in the transparent polymeric material. The implantable element can also include an electronics module including one or more antennas and a controller electrically connected to the electrochemical sensor and the antenna, the controller 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., the wearable implantable element) is exposed, and to indicate the sensor measurement using the antenna.

[0149] The implantable element can be of any suitable shape, such as a sphere, ellipsoid, oval, disk, cylinder, torus, cube, stadium, cone, pyramid, triangle, rectangle, square, or rod, or can include curved or flat portions. Any shape, curved or flat implantable element 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 pharma- ceutical acceptable salt thereof, or may be chemically derivatized.

[0150] In some embodiments, the implantable 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, e.g., any of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mm. In some embodiments, the implantable element has an LLD, average diameter or size of greater than 0.5 mm, 1 mm, or 1.5 mm. In some embodiments, the implantable elements described herein are 1 mm to 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mm to 6 mm, 1.5 mm to 5 mm, 1.5 mm to 4 mm, 1.5 mm to 3 mm, 1.5 mm to 2 mm, 2 mm to 8 mm, 2 mm to 7 mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 2.5 mm to 8 mm, 2.5 mm to 7 mm, 2.5 mm to 6 mm, 2.5 mm to 5 mm, 2.5 mm to 4 mm, 2.5 mm to 3 mm, 3 mm to 8 mm, 3 mm to 7 mm. m, 3 mm to 6 mm, 3 mm to 5 mm, 3 mm to 4 mm, 3.5 mm to 8 mm, 3.5 mm to 7 mm, 3.5 mm to 6 mm, 3.5 mm to 5 mm, 3.5 mm to 4 mm, 4 mm to 8 mm, 4 mm to 7 mm, 4 mm to 6 mm, 4 mm to 5 mm, 4.5 mm to 8 mm, 4.5 mm to 7 mm, 4.5 mm to 6 mm, 4.5 mm to 5 mm, 5 mm to 8 mm, 5 mm to 7 mm, 5 mm to 6 mm, 5.5 mm to 8 mm, 5.5 mm to 7 mm, 5.5 mm to 6 mm, 6 mm to 8 mm, 6 mm to 7 mm, 6.5 mm to 8 mm, 6.5 mm to 7 mm, 7 mm to 8 mm, or 7.5 mm to 8 mm. In some embodiments, the implantable element has an LLD, average diameter or size of 0.5 mm to 1 mm or 1 mm to 4 mm. In some embodiments, the implantable element has an LLD, average diameter or size, between 1 mm and 2 mm, hi some embodiments, the implantable element has a spherical shape and an average diameter within any of the numerical ranges given above.

[0151] In some embodiments, the implantable element includes at least one hole or opening, for example, to allow free flow of material. In some embodiments, the average pore size of the implantable element is about 0.1 μm to about 10 μm. For example, the average pore size can 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 implantable element is between about 0.1 μm and 10 μm. In some embodiments, the average pore size of the implantable element is between about 0.1 μm and 5 μm. In some embodiments, the average pore size of the implantable element is between about 0.1 μm and 1 μm.

[0152] In some embodiments, the implantable element is capable of preventing passage of materials over a certain size through holes or openings, hi some embodiments, the implantable element is capable of preventing passage of materials over 50 kD, 75 kD, 100 kD, 125 kD, 150 kD, 175 kD, 200 kD, 250 kD, 300 kD, 400 kD, 500 kD, 750 kD, 1,000 kD.

[0153] An implantable element (e.g., an implantable element described herein) may be provided as a preparation or composition for implantation or administration to a subject. In some embodiments, at least 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the implantable elements in the preparation or composition have the characteristics described herein, such as average pore size.

[0154] In some embodiments, the implantable element may be configured or used for a variety of time periods ranging from minutes to years. For example, the implantable element may be configured or used for about 1 hour to about 10 years. In some embodiments, the implantable element is configured or used for a period longer than any of the following periods: about 1-24 hours, about 1-7 days, about 1-4 weeks, about 1-24 months, about 2-10 years, or more. The implantable element may be configured to function over the expected implantation period, e.g., to resist inactivation by a PFO over all or a portion of the expected period.

[0155] In some embodiments, the implantable element is easily retrievable from the subject, e.g., without causing injury to the subject or significant disruption of surrounding tissues, hi one embodiment, the implantable element can be retrieved with minimal or no surgical separation of the implantable element from the surrounding tissues, e.g., by minimally invasive surgical dissection, extraction, or excision.

[0156] In some embodiments, the implantable element is not an implantable element disclosed in any of WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 187225, WO2016 / 019391, WO2017 / 075630, WO2017 / 075631, WO2018 / 067615, WO2019 / 169333, or US2016-0030359.

[0157] In some embodiments, the implantable element is associated with a polysaccharide polymer of formula (I). In some embodiments, the implantable element comprises a polysaccharide polymer of formula (I) and cells disposed wholly or partially within the implantable element.

[0158] In some embodiments, the surface of an implantable element comprising cells (e.g., engineered cells) is chemically modified with a non-fibrous compound (e.g., those shown in Table 2). In some embodiments, the surface comprises an exterior or interior surface of the implantable element. In some embodiments, the surface (e.g., the exterior surface) of an implantable element comprising cells (e.g., engineered cells) is chemically modified with a non-fibrous compound (e.g., those shown in Table 2). In some embodiments, the surface (e.g., the exterior surface) is covalently bound to a non-fibrous compound (e.g., those shown in Table 2).

[0159] The implantable element may be coated with a non-fibrous compound (e.g., those shown in Table 2) or a pharma- ceutically acceptable salt thereof, or a polymer comprising a non-fibrous compound (e.g., those shown in Table 2) or a pharma- ceutically acceptable salt thereof. In one embodiment, the non-fibrous compound (e.g., those shown in Table 2) is disposed on a surface, such as an inner or outer surface, of the implantable element. In some embodiments, the non-fibrous compound (e.g., those shown in Table 2) is disposed on a surface, such as an inner or outer surface, of an encapsulating component associated with the implantable element. In one embodiment, the non-fibrous compound (e.g., those shown in Table 2) is distributed uniformly throughout the surface. In one embodiment, the non-fibrous compound (e.g., those shown in Table 2) is distributed non-uniformly throughout the surface.

[0160] In some embodiments, the implantable element (or its encapsulating component, etc.) is coated (e.g., partially or fully covered) with a non-fibrous compound (e.g., those shown in Table 2), or a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharma- ceutically acceptable salt thereof. In some embodiments, the implantable element (or its encapsulating component, etc.) is coated with a monolayer 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), e.g., at least 2, 3, 4, 5, 10, 20, 50 or more layers of a non-fibrous compound (e.g., those shown in Table 2).

[0161] In one embodiment, a first portion of the surface of the implantable element comprises a non-fibrous compound (e.g., those shown in Table 2) and a second portion of the implantable element is free of that compound or has a substantially lower density of that compound.

[0162] In some embodiments, the implantable element is symmetrically coated or chemically derivatized with a non-fibrous compound (e.g., those shown in Table 2), or a material that includes a non-fibrous compound (e.g., those shown in Table 2), or a pharma- ceutically acceptable salt thereof. In some embodiments, the implantable element is asymmetrically coated or chemically derivatized with a non-fibrous compound (e.g., those shown in Table 2), or a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharma-ceutically acceptable salt thereof. For example, exemplary implantable elements may be partially coated (e.g., 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% coated) with a compound of formula (I), or a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharma- ceutically acceptable salt thereof.

[0163] Exemplary implantable elements coated or chemically derivatized with a non-fibrous compound (e.g., those shown in Table 2), or a polymer modified with a non-fibrous compound (e.g., those shown in Table 2), or a pharma- ceutically acceptable salt thereof, can be prepared using any method known in the art, such as self-assembly (e.g., by block copolymers, adsorption (e.g., competitive adsorption), phase separation, microfabrication, or masking).

[0164] In some embodiments, the implantable element comprises a surface that exhibits two or more distinct physicochemical properties (eg, 3, 4, 5, 6, 7, 8, 9, 10, or more distinct physicochemical properties).

[0165] 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 pharma- ceutically acceptable salt thereof, is described as the average number of compounds attached per given area, e.g., density. For example, the density of the coating or chemical derivatization of an exemplary implantable element can 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 mm on or within said implantable element.

[0166] An implantable element comprising a non-fibrous compound (e.g., those shown in Table 2) or a pharma- ceutically acceptable salt thereof may have a reduced immune response (e.g., an immune response marker) compared to an otherwise identical implantable element that does not comprise a non-fibrous compound (e.g., those shown in Table 2) or a pharma- ceutically acceptable salt thereof. The immune response marker is one or more of PFO, cathepsin levels, or levels of immune response markers, e.g., TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-4, CCL2, or CCL4, as measured by ELISA or the like. In some embodiments, the immune response to an implantable element comprising a non-fibrous compound (e.g., those shown in Table 2) or a pharma- ceutically acceptable salt thereof is reduced by at least about 1 percent and up to about 100 percent, e.g., 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., immune response marker) is measured after 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, about 6 months, or more. In some embodiments, an implantable element comprising a non-fibrous compound (e.g., those shown in Table 2) is coated with a non-fibrous compound (e.g., those shown in Table 2) or is encapsulated within a layer (e.g., a polymer layer) comprising a non-fibrous compound (e.g., those shown in Table 2).

[0167] The implantable element may have a smooth surface or may have projections, depressions, wells, slits, or holes, or any combination thereof. The projections, depressions, wells, slits, or holes may be of any size, for example, 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 projections, 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 pharma- ceutically acceptable salt thereof, or may be chemically derivatized.

[0168] In one embodiment, the implantable element comprises any of the polymers described herein modified with a non-fibrous compound (e.g., those shown in Table 2) or a pharma- ceutically acceptable salt thereof.

[0169] In some embodiments, the implantable element comprises 5-50% non-fibrous compounds (e.g., those shown in Table 2), e.g., as measured using a quantitative amine assay. In some embodiments, the implantable element comprises 10-50% non-fibrous compounds (e.g., those shown in Table 2), e.g., 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 using a quantitative amine assay.

[0170] In some embodiments, the implantable element comprises an alginate (eg, any of the alginates described herein) modified with a non-fibrous compound (eg, those shown in Table 2).

[0171] In some embodiments, the implantable element comprises an alginate modified with a compound shown in Table 2. In some embodiments, the implantable element comprises an alginate modified with compound 200. In some embodiments, the implantable element comprises an alginate modified with compound 218. In some embodiments, the implantable element comprises an alginate modified with compound 219. In some embodiments, the implantable element comprises an alginate modified with compound 224. In some embodiments, the implantable element comprises an alginate modified with compound 222.

[0172] Cells and therapeutic agents The implantable elements of the present disclosure can include a wide variety of different cell types (e.g., human cells), including, but not limited to, adipocytes, epidermal cells, epithelial cells, endothelial cells, fibroblasts, pancreatic islet cells, mesenchymal stem cells, pericytes, subtypes of any of the foregoing, cells derived from any of the foregoing, cells derived from induced pluripotent stem cells, and mixtures of one or more of any of the foregoing. Exemplary cell types include those described in WO2017 / 075631 and WO2019 / 195055. In one embodiment, the implantable elements described herein include a plurality of cells. In one embodiment, the plurality of cells is in the form of a cell suspension before being encapsulated within the implantable elements described herein. The cells in the suspension can be in the form of single cells (e.g., from a monolayer cell culture) or can be provided in another form, for example, disposed on a microcarrier (e.g., a bead or matrix) or as a three-dimensional aggregate of cells (e.g., cell clusters or spheroids). The cell suspension can include a plurality of cell clusters (e.g., as spheroids) or microcarriers. In some embodiments, the device does not contain pancreatic islet cells and does not contain cells capable of producing insulin in response to glucose.

[0173] The present disclosure features cells that produce or are capable of producing a therapeutic agent for the prevention or treatment of a disease, disorder, or condition described herein. In one embodiment, the cell is an engineered cell. In one embodiment, the cell is engineered to sense a stimulus, such as a chemical signal, and express a therapeutic agent in response to the stimulus. The therapeutic agent can be any biological substance, such as a nucleic acid (e.g., a nucleotide, DNA, or RNA), a polypeptide, a lipid, a sugar (e.g., a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide), or a small molecule, each of which is described in further detail below. Exemplary therapeutic agents include those listed in WO2017 / 075631 and WO2019 / 195055.

[0174] In some embodiments, the cells (e.g., engineered cells) produce nucleic acids. The nucleic acids produced by the cells described herein can be of various sizes and can contain one or more nucleosides or nucleotides, e.g., 2, 3, 4, 5, 10, 25, 50 or more nucleosides or nucleotides. In some embodiments, the nucleic acids can be short fragments of, e.g., RNA or DNA, and can 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.

[0175] In some embodiments, the therapeutic agent is a peptide or polypeptide (e.g., a protein), such as a hormone, an enzyme, a cytokine (e.g., a pro-inflammatory or anti-inflammatory cytokine), a growth factor, a clotting factor, or a lipoprotein. The peptide or polypeptide (e.g., a protein, e.g., a hormone, a growth factor, a clotting factor, an antibody molecule, an enzyme, a cytokine, a cytokine receptor, or a chimeric protein comprising a cytokine or a cytokine receptor) produced by cells in the implantable element can have a naturally occurring amino acid sequence or can include a variant of a naturally occurring sequence. A variant can be a naturally occurring or non-naturally occurring amino acid substitution, mutation, deletion, or addition compared to a naturally occurring reference sequence. A naturally occurring amino acid sequence can be a polymorphic variant. A naturally occurring amino acid sequence can be a human or non-human amino acid sequence. In some embodiments, a naturally occurring amino acid sequence or a naturally occurring variant thereof is a human sequence. Additionally, a peptide or polypeptide (e.g., a protein) for use in the present invention can be modified in some way, for example by chemical or enzymatic modification (e.g., glycosylation, phosphorylation). In some embodiments, the peptides have about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, or 50 amino acids. In some embodiments, the proteins have an average molecular weight (kD) of 5, 10, 25, 50, 100, 150, 200, 250, 500 or more.

[0176] In some embodiments, the protein is a hormone. Exemplary hormones include antidiuretic hormone (ADH), oxytocin, growth hormone (GH), prolactin, growth hormone releasing hormone (GHRH), thyroid stimulating hormone (TSH), thyrotropin releasing hormone (TRH), adrenocorticotropic hormone (ACTH), follicle stimulating hormone (FSH), luteinizing hormone (LH), luteinizing hormone releasing hormone (LHRH), thyroxine, calcitonin, parathyroid hormone, aldosterone, cortisol, epinephrine, glucagon, insulin, estrogen, progesterone, and testosterone. In some embodiments, the protein is insulin (e.g., insulin A-chain, insulin B-chain, or proinsulin). In some embodiments, the protein is a growth hormone, such as human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, methionine-human growth hormone, des-phenylalanine human growth hormone, and porcine growth hormone. In some embodiments, the protein is not insulin (eg, insulin A-chain, insulin B-chain, or proinsulin).

[0177] In some embodiments, the protein is a growth factor, such as vascular endothelial growth factor (VEGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF), and insulin-like growth factor-I and -II (IGF-I and IGF-II).

[0178] In some embodiments, the protein is a clotting factor or coagulation factor, e.g., a blood clotting factor or blood coagulation factor, hi some embodiments, the protein is a protein involved in coagulation, the process by which blood is converted from a liquid to a solid or gel. Exemplary clotting and coagulation factors include Factor I (e.g., fibrinogen), Factor II (e.g., prothrombin), Factor III (e.g., tissue factor), Factor V (e.g., proaccelerin, labile factor), Factor VI, Factor VII (e.g., stable factor, proconvertin), Factor VIII (e.g., antihemophilic factor A), Factor VIIIC, Factor IX (e.g., antihemophilic factor B), Factor X (e.g., Stuart-Prower factor), Factor XI (e.g., plasma thromboplastin precursor), Factor XII (e.g., Hageman factor), Factor XIII (e.g., fibrin stabilizing factor), von Willebrand factor, prekallikrein, heparin cofactor II, high molecular weight kininogen (e.g., Fitzgerald factor), antithrombin III, and fibronectin. In some embodiments, the protein is an anticoagulant, e.g., protein C.

[0179] 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 comprises 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 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, e.g., a monospecific antibody molecule that has multiple immunoglobulin variable domain sequences, each of which binds to the same epitope. In one embodiment, the antibody molecule is a multispecific antibody molecule, e.g., a monospecific antibody molecule that comprises multiple immunoglobulin variable domain sequences, a first immunoglobulin variable domain sequence of the plurality having binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality having binding specificity for a second epitope. In one embodiment, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In one embodiment, the multispecific antibody molecule comprises a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule.

[0180] Various types of antibody molecules may be produced by the cells in the implantable element described herein, including whole immunoglobulins of any class, fragments thereof, and synthetic proteins that contain 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 be in the form of an antigen-binding fragment, including a Fab fragment, a F(ab')2 fragment, a single chain variable region, and the like. The antibody may be polyclonal or monoclonal (mAb). Monoclonal antibodies may include "chimeric" antibodies (wherein a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass), and fragments of such antibodies, so long 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 deletion, addition or substitution of amino acids, to increase the effectiveness of the antibody in mediating a 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-IL6, anti-IL-13, anti-IL17, anti-IL18, 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., fulranumab, fasinumab, tanezumab).

[0181] In some embodiments, the protein is, for example, tumor necrosis factors alpha and beta, their receptors and their derivatives, renin; lipoproteins; colchicine; corticotrophin; vasopressin; somatostatin; lypressin; pancreozymin; leuprolide; alpha-1-antitrypsin; atrial natriuretic factor; pulmonary surfactant; plasminogen activators other than tissue-type plasminogen activator (t-PA), such as urokinase; bombesin; thrombin; enkephalinase; RANTES (regulated on activation normally T-cell expressed and secreted);human macrophage inflammatory protein (MIP-1-alpha);serum albumins, e.g., human serum albumin;Mullerian inhibitory substance;relaxin A-chain;relaxin B-chain;prorelaxin;mouse gonadotropin-related peptide;chorionic gonadotropin;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);transformation factor Transforming growth factors (TGFs), such as TGF-α and TGF-β (including TGF-β1, TGF-β2, TGF-β3, TGF-β4, or TGF-β5); insulin-like growth factors-I and -II (IGF-I and IGF-II); des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding proteins; CD proteins, such as CD-3, CD-4, CD-8, and CD-19; erythropoietin; osteoinductive factors; antitoxins; interferons, such as interferon-alpha (e.g., interferon.alpha.2A), -beta, -gamma, -lambda and consensus interferons; colony stimulating factors (CSF), such as M-CSF, GM-CSF, and G-CSF; interleukins (IL), such as IL-1 to IL-10; superoxide dismutase; T cell receptors; surface membrane proteins; degradation-promoting factors; transport proteins; homing receptors; addressins; conception inhibitors, such as prostaglandins; conception promoters; regulatory proteins; antibodies (including fragments thereof) and chimeric proteins, such as immunoadhesins; cytokines or cytokine receptors, or chimeric proteins comprising cytokines or their receptors, including precursors, derivatives, prodrugs and analogues of these compounds, as well as pharmacologic and therapeutically acceptable salts of these compounds, or precursors, derivatives, prodrugs and analogues thereof. Suitable proteins or peptides may be native or recombinant, including, for example, fusion proteins.

[0182] Examples of polypeptides (e.g., proteins) produced by cells in the implantable 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, prostaglandins, leukotrienes, prostacyclin, Clin, thromboxane, islet amyloid polypeptide, Müllerian inhibitory factor or hormone, adiponectin, corticotropin, angiotensin, vasopressin, arginine vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, cortistatin, enkephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastric inhibitory polypeptide, gastrin, ghrelin, glucagon, glucagon-like peptide-1, gonadotropin-releasing hormone, hepcidin, human chorionic gonadotropin,These include human placental lactogen, inhibin, somatomedin, leptin, lipotropin, melanocyte stimulating hormone, motilin, orexin, oxytocin, pancreatic polypeptide, pituitary adenylate cyclase activating peptide, relaxin, renin, secretin, somatostatin, thrombopoietin, thyrotropin, thyrotropin releasing hormone, vasoactive intestinal peptide, androgens, alpha-glucosidase (also known as acid maltase), glycogen phosphorylase, glycogen debranching enzyme, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, carnitine palytyltransferase, carnitine, and myoadenylate deaminase.

[0183] In some embodiments, the protein is a replacement therapy or replacement protein. In some embodiments, the replacement therapy or replacement protein is a clotting factor or coagulation factor, such as factor VIII (e.g., comprising a naturally occurring human factor VIII amino acid sequence or a variant thereof) or factor IX (e.g., comprising a naturally occurring human factor IX amino acid sequence or a variant thereof).

[0184] In some embodiments, the cells are engineered to express factor VIII, e.g., recombinant factor VIII. In some embodiments, the cells are derived from human tissue and engineered to express factor VIII, e.g., recombinant factor VIII. In some embodiments, the recombinant factor VIII is recombinant B-domain deleted factor VIII (FVIII-BDD).

[0185] In some embodiments, the cells are derived from human tissue and engineered to express factor IX, e.g., recombinant factor IX. In some embodiments, the cells are engineered to express factor IX, e.g., wild-type human factor IX (FIX), or a polymorphic variant thereof. In some embodiments, the cells are engineered to express a gain-of-function (GIF) variant of the wild-type FIX protein (FIX-GIF), where the GIF variant has a higher specific activity than the corresponding wild-type FIX.

[0186] In some embodiments, the replacement therapy or replacement protein is an enzyme, such as alpha-galactosidase, alpha-L-iduronidase (IDUA), or N-sulfoglucosamine sulfohydrolase (SGSH). In some embodiments, the replacement therapy or replacement protein is an enzyme, such as alpha-galactosidase A (e.g., comprising a naturally occurring human alpha-galactosidase A amino acid sequence or a variant thereof). In some embodiments, the replacement therapy or replacement protein is a cytokine or an antibody.

[0187] 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 or cyclic monosaccharide. In some embodiments, the sugar comprises a glucose, galactose, fructose, rhamnose, mannose, arabinose, glucosamine, galactosamine, sialic acid, mannosamine, glucuronic acid, galacturonic acid, mannuronic acid, or guluronic acid moiety. In some embodiments, the sugar is attached to a protein (e.g., an N-linked 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.

[0188] In some embodiments, the therapeutic agent is a lipid. The lipid may be hydrophobic or amphiphilic and may form a tertiary structure such as a liposome, vesicle, or membrane, or an insert in a liposome, vesicle, or membrane. The lipid may include a fatty acid, a glycerolipid, a glycerophospholipid, a sterol lipid, a prenol lipid, a sphingolipid, a glycolipid, a polyketide, or a sphingolipid. Examples of lipids produced by the cells described herein include anandamide, docosahexaenoic acid, aprostaglandins, leukotrienes, thromboxanes, eicosanoids, triglycerides, cannabinoids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, ceramide, sphingomyelin, cerebrosides, gangliosides, estrogens, androsterone, testosterone, cholesterol, carotenoids, quinones, hydroquinones, or ubiquinones.

[0189] In some embodiments, the therapeutic agent is a small molecule. Small molecules may include natural products produced by cells. In some embodiments, the small molecule has low bioavailability or does not meet Lipinski's Rule of Five (a set of guidelines used to estimate whether a small molecule is likely to become an orally active drug in humans; see, e.g., Lipinski, CA et al (2001) Adv Drug Deliv 46:2-36). Exemplary small molecule natural products include antibacterial drugs (e.g., carumonam, daptomycin, fidaxomicin, fosfomycin, ispamycin, micronomycin sulfate, miokamycin, mupiocin, netilmicin sulfate, teicoplanin, thienamycin, rifamycin, erythromycin, vancomycin), antiparasitic drugs (e.g., artemisinin, ivermectin), anticancer drugs (e.g., doxorubicin, aclarubicin, aminolevulinic acid, aruglavin, omacetaxine mepesuccinate, paclitaxel, pentostatin, peplomycin, romidepsin, trabectoside, cyclosporine ... trabectdin, actinomycin D, bleomycin, chromomycin A, daunorubicin, leucovorin, neocarzinostatin, streptozocin, trabectedin, vinblastine, vincristine), antidiabetic drugs (e.g., voglibose), central nervous system drugs (e.g., L-dopa, galantamine, zicontide), statins (e.g., mevastatin), antifungal drugs (e.g., fumagillin, cyclosporine), 1-deoxynojirimycin, and theophylline, sterols (cholesterol, estrogen, testosterone). Additional small molecule natural products are described in Newman, DJ and Cragg, M. (2016) J Nat Prod 79:629-661 and Butler, MS et al (2014) Nat Prod Rep 31:1612-1661.

[0190] In some embodiments, the cells are engineered to synthesize non-protein or non-peptide small molecules. For example, in one embodiment, the cells are capable of producing a statin (e.g., taurostatin, pravastatin, fluvastatin, or atorvastatin).

[0191] In some embodiments, the therapeutic agent is an antigen (e.g., a viral antigen, a bacterial antigen, a fungal antigen, a plant antigen, an environmental antigen, or a tumor antigen). Antigens are recognized by those skilled in the art as being immunostimulatory, i.e., capable of stimulating an immune response or providing effective immunity against the organism or molecule from which they are derived. Antigens can be nucleic acids, peptides, proteins, sugars, lipids, or combinations thereof.

[0192] Cells, e.g., engineered cells, e.g., engineered cells described herein, may produce a single therapeutic agent or multiple therapeutic agents. In some embodiments, the cells produce a single therapeutic agent. In some embodiments, the cell clusters include cells that produce a single therapeutic agent. In some embodiments, at least about 1 percent, or about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, or 99 percent of the cells in the cluster produce a single therapeutic agent (e.g., a therapeutic agent described herein). In some embodiments, the cells produce multiple therapeutic agents, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 different therapeutic agents. In some embodiments, the cell clusters include cells that produce multiple therapeutic agents. In some embodiments, at least about 1 percent, or about 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 95, or 99 percent of the cells in the cluster produce multiple therapeutic agents (e.g., a therapeutic agent described herein).

[0193] These therapeutic agents may be associated or may form a complex. 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 an unwanted substance, which occurs within the cell.

[0194] Treatment Described herein is a method for preventing or treating a disease, disorder, or condition in a subject by administering or implanting an implantable element comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the method described herein directly or indirectly reduces or alleviates at least one symptom of the disease, disorder, or condition. In some embodiments, the method described herein prevents or delays the onset of the disease, disorder, or condition. In some embodiments, the subject is a human.

[0195] In some embodiments, the disease, disorder, or condition affects a system of the body, such as the nervous system (e.g., the peripheral nervous system or the central nervous system), the vascular system, the skeletal system, the respiratory system, the endocrine system, the lymphatic system, the reproductive system, or the gastrointestinal tract. In some embodiments, 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.

[0196] In some embodiments, the disease, disorder or condition is a neurodegenerative disease, diabetes (type 1 or type 2), heart disease, autoimmune disease, cancer, liver disease, lysosomal storage disease, a clotting or coagulation disorder, an orthopedic condition, or an amino acid metabolism disorder.

[0197] In some embodiments, the disease, disorder or condition is a neurodegenerative disease. Exemplary neurodegenerative diseases include Alzheimer's disease, Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and cerebral palsy (CP), dentatorubro-pallidoluysian atrophy (DRPLA), neuronal intranuclear vitreous inclusion disease (NIHID), dementia with Lewy bodies, Down's syndrome, Hallervorden-Spatz disease, prion diseases, argyrophilic grain dementia, corticobasal degeneration, dementia pugilistica, diffuse neurofibrillary tangle disease, Gerstmann-Straussler-Scheinker disease, Jakob-Creutzfeldt disease, Niemann-Pick disease type 3, progressive supranuclear palsy, subacute sclerosing panencephalitis, spinocerebellar ataxia, Pick's disease, and dentatorubral-pallidoluysian atrophy.

[0198] In some embodiments, the disease, disorder, or condition is an autoimmune disease, such as scleroderma, multiple sclerosis, lupus, or an allergy.

[0199] In some embodiments, the disease is a liver disease, such as Hepatitis B, Hepatitis C, cirrhosis, or NASH.

[0200] In some embodiments, the disease, disorder, or condition is cancer. Exemplary cancers include leukemia, lymphoma, melanoma, lung cancer, brain cancer (e.g., glioblastoma), sarcoma, pancreatic cancer, kidney cancer, liver cancer, testicular cancer, prostate cancer, or uterine cancer.

[0201] In some embodiments, the disease, disorder, or condition is an orthopedic condition. Exemplary orthopedic conditions include osteoporosis, osteonecrosis, Paget's disease, or bone fracture.

[0202] In some embodiments, the disease, disorder or condition is a lysosomal storage disease. Exemplary lysosomal storage diseases include Gaucher disease (e.g., type I, type II, type III), Tay-Sachs disease, Fabry disease, Farber disease, Hurler syndrome (also known as mucopolysaccharidosis type I (MPS I)), Hunter syndrome, lysosomal acid lipase deficiency, Niemann-Pick disease, Salla disease, Sanfilippo syndrome (also known as mucopolysaccharidosis type IIIA (MPS3A)), multiple sulfatase deficiency, Maroteaux-Lamy syndrome, metachromatic leukodystrophy, Krabbe disease, Scheie syndrome, Hurler-Scheie syndrome, Sly syndrome, hyaluronidase deficiency, Pompe disease, Danon disease, gangliosidosis, or Morquio syndrome.

[0203] In some embodiments, the disease, disorder, or condition is a clotting disorder or coagulation disorder. Exemplary clotting disorders or coagulation disorders include hemophilia (e.g., hemophilia A or hemophilia B), von Willebrand's disease, thrombocytopenia, uremia, Bernard-Soulier syndrome, factor XII deficiency, vitamin K deficiency, or congenital afibrinogenemia.

[0204] In some embodiments, the disease, disorder, or condition is an amino acid metabolism disorder, such as phenylketonuria, tyrosinemia (e.g., type 1 or type 2), alkaptonuria, homocystinuria, hyperhomocysteinemia, maple syrup urine disease.

[0205] In some embodiments, the disease, disorder, or condition is a fatty acid metabolism disorder, e.g., hyperlipidemia, hypercholesterolemia, galactosemia.

[0206] In some embodiments, the disease, disorder, or condition is a purine or pyrimidine metabolism disorder, e.g., Lesch-Nyhan Syndrome.

[0207] In some embodiments, the disease, disorder, or condition is not Type I diabetes and / or is not Type II diabetes.

[0208] The invention further includes a method of identifying a subject having or suspected of having a disease, disorder, or condition described herein, and, upon such identification, administering to the subject an implantable element comprising cells (e.g., optionally encapsulated by an encapsulation component and optionally modified with a compound of formula (I) or a composition thereof described herein). In one embodiment, the subject is a human.

[0209] Enumerated Embodiments 1. A polysaccharide polymer comprising sugar monomers, the sugar monomers comprising a hydroxyl modifying agent covalently attached to a hydroxyl moiety.

[0210] 2. The polysaccharide polymer of embodiment 1, wherein the hydroxyl modifying agent comprises an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amine, amide, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety.

[0211] 3. The polysaccharide polymer according to any one of the preceding embodiments, wherein the polysaccharide polymer is selected from hyaluronate, alginate, cellulose, chitosan, chitin, amylose, dextran, starch, glycogen, chondroitin, and pectin.

[0212] 4. The polysaccharide polymer according to any one of the preceding claims, wherein the sugar monomers are 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.

[0213] 5. The polysaccharide polymer of any one of embodiments 1 to 4, wherein the sugar monomer is mannuronic acid or guluronic acid.

[0214] 6. The glycomonomer has the formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X is O, NR 6 , or S; R 1 and R 4 Each of is independently absent, alkylene, alkenylene, alkynylene, heteroalkylene, 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 each independently selected from one or more R 8 is optionally replaced by; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, alkyl, heteroalkyl, haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R 9 is optionally replaced by R 2a and R 2b At least one of and R 3a and R 3b at least one of is not hydrogen; R 5a and R 5b Each of is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, 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, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more R 8 is optionally replaced by; R 6 is hydrogen, alkyl, heteroalkyl, or haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently selected from one or more R 9 is optionally replaced by; R 7a and R 7b are each independently hydrogen, alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is selected from one or more R 9 is optionally replaced by; Each R 8 are independently alkyl, alkenyl, alkynyl, heteroalkyl, 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 wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R 10 has been replaced by; R A is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, 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 selected from 0 to 12 R10 has been replaced by; R B , R C , and R D is each independently an alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R 10 or R B and R C together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from the group consisting of one or more R 10 is optionally substituted with; Each R 9 are independently alkyl, heteroalkyl, 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 where each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 10 is optionally replaced by; Each R 10 is independently 1-6 The polysaccharide polymer according to any one of the preceding embodiments, wherein the aryl group is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0215] 7. The glycomonomer has formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X is O, NR6 , or S; R 1 is non-existent, 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 )C(O)—, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are each independently selected from one or more R 8 is optionally replaced by; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R 9 is optionally replaced by R 2a and R 2b At least one of and R 3a and R 3b at least one of is not hydrogen; Each R 4 is non-existent, 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)C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R 8 is optionally replaced by; R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more R 8 is optionally replaced by; R 6 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, or C 1-6 haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently selected from one or more R 9 is optionally replaced by; R 7a and R 7b are each independently hydrogen, C 1-6 alkyl, cycloalkyl, or heterocyclyl, where the alkyl, cycloalkyl, or heterocyclyl is selected from one or more R 9 is optionally replaced by; Each R 8are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 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 wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R 10 has been replaced by; R A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 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 selected from 0 to 12 R 10 has been replaced by; R B , R C , and R D is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R 10 or R B and R C together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from the group consisting of one or more R10 is optionally substituted with; Each R 9 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 where each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 10 is optionally replaced by; Each R 10 is independently 1-6 The polysaccharide polymer according to any one of the preceding embodiments, wherein the aryl group is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0216] 8. The polysaccharide polymer according to any one of embodiments 6 to 7, wherein X is O.

[0217] 9.R 1 OR A The polysaccharide polymer according to any one of embodiments 6 to 8,

[0218] 10.R 5 is C(O)OR A or C(O)N(R C )(R D 9. The polysaccharide polymer according to any one of embodiments 6 to 8, wherein

[0219] 11.R 5 is C(O)N(R C )(R D ) and R C and R D is each independently hydrogen, a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2), or a peptide (e.g., an RGD peptide).

[0220] 12.R C and R D is independently hydrogen, and R C and R D The polysaccharide polymer of embodiment 11, wherein the other is independently a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2) or a peptide (e.g., an RGD peptide).

[0221] 13.R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl.

[0222] 14.R 3 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl.

[0223] 15.R 2 and R 3 One of them is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B and R 2 and R 3 and the other is independently hydrogen.

[0224] 16.R 4 OR A 16. The polysaccharide polymer according to any one of embodiments 6 to 15,

[0225] 17. The glycomonomer has formula (Ic): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R 5 and each of their subvariables are as defined in embodiment 6.

[0226] 18. The glycomonomer has the formula (Id): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R 5 and each of their subvariants is as defined in embodiment 6; and G 1 and G 2 18. The polysaccharide polymer of any one of the preceding embodiments, wherein each of is independently hydrogen, a non-fibrous compound, or a peptide.

[0227] 19. The glycomonomer has formula (Ie): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R C , and R D and each of their subvariables are as defined in embodiment 6.

[0228] 20. The glycomonomer has the formula (If): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R C , and R D and each of their subvariants is as defined in embodiment 6; and 1 and G 2 20. The polysaccharide polymer of any one of the preceding embodiments, wherein each of is independently hydrogen, a non-fibrous compound, or a peptide.

[0229] 21.G 1 and G 2 21. The polysaccharide polymer according to any one of embodiments 18 to 20, wherein one of said compounds is independently a non-fibrous compound (eg, a non-fibrous compound shown in Table 2).

[0230] 22.G 1 and G 2 The polysaccharide polymer of any one of embodiments 18 to 20, wherein both of are independently a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2).

[0231] 23. The glycomonomer has formula (Ig): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R 5 and each of their subvariables are as defined in claim 6; P 1 and P 2 are each independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is selected from one or more R 12 is optionally replaced by; L 1 and L 2 are each independently 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R 8 is optionally replaced by; Z 1 and Z 2 are each independently hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 8 is optionally replaced by; Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a , R 8 , and R 12 23. The polysaccharide polymer according to any one of embodiments 1 to 22, wherein is as defined in embodiment 6.

[0232] 24. The glycomonomer has formula (Ih): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R C , R D and each of their subvariables is as defined in embodiment 6; P 1 and P 2are each independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is selected from one or more R 12 is optionally replaced by; L 1 and L 2 are each independently 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R 8 is optionally replaced by; Z 1 and Z 2 are each independently hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 8 is optionally replaced by; Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a , R 8 , and R 12 The polysaccharide polymer according to any one of embodiments 1 to 23, wherein is as defined in embodiment 6.

[0233] 25.P 1 and P 2 and R is independently heteroaryl (eg, triazolyl).

[0234] 26.P 1 and P 2 are each independently [ka] where R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 26. The polysaccharide polymer of embodiment 25, which is haloalkyl, or halo.

[0235] 27.L 1 and L 2 are each independently absent or C 1-6 26. The polysaccharide polymer of any one of embodiments 22 to 25, wherein the alkylene is -CH2-.

[0236] 28.Z 1 and Z 2 and R is independently aryl, heteroaryl, or heterocyclyl.

[0237] 29.Z 1 and Z 2 The polysaccharide polymer according to any one of embodiments 22 to 28, wherein each is independently heterocyclyl.

[0238] 30.Z 1 and Z 2 are each independently [ka] 30. The polysaccharide polymer according to embodiment 29, wherein

[0239] 31. The polysaccharide polymer of any one of claims 1 to 30, wherein the non-fibrous compound is selected from the moieties of Table 2 (e.g., compound 218, compound 219, or compound 222).

[0240] 32. The polysaccharide polymer according to any one of the preceding embodiments, wherein the peptide comprises the sequence RGD.

[0241] 33. The polysaccharide polymer according to any one of the preceding embodiments, wherein the polysaccharide polymer is an alginate.

[0242] 34. The polysaccharide polymer according to embodiment 33, wherein the alginate is a high guluronic acid (G) alginate or a high mannuronic acid (M) alginate.

[0243] 35. The polysaccharide polymer of any one of embodiments 33-34, wherein the alginate comprises an increased %N (when compared to the unmodified polymer) of 0.1-10%N by weight, where %N is determined by elemental analysis.

[0244] 36. The polysaccharide polymer of any one of embodiments 33 to 35, wherein the alginate comprises an increased %N (when compared to the unmodified polymer) of 1 to 10%N by weight, where %N is determined by elemental analysis.

[0245] 37. The polysaccharide polymer according to any one of embodiments 33 to 36, wherein the alginate comprises an increased %N (when compared to the unmodified polymer) of 2 to 8%N by weight, where %N is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified alginate.

[0246] 38. The polysaccharide polymer of any one of the preceding embodiments, wherein the polysaccharide comprises a plurality of sugar monomers comprising a hydroxyl modifier covalently attached to the hydroxyl moieties.

[0247] 39. An alginate comprising mannuronate or guluronate monomers, the mannuronate or guluronate monomers comprising a hydroxyl modifier covalently attached to a hydroxyl moiety.

[0248] 40. The alginate of embodiment 39, wherein the hydroxyl modifying agent comprises an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety.

[0249] 41. The alginate has the formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O, NR 6 , or S; R 1 and R 4 Each of is independently absent, alkylene, alkenylene, alkynylene, heteroalkylene, 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 each independently selected from one or more R 8 is optionally replaced by; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, alkyl, heteroalkyl, haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R 9 is optionally replaced by R 2a and R 2b At least one of and R 3a and R 3b at least one of is not hydrogen; R 5a and R5b Each of is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, 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, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more R 8 is optionally replaced by; R 6 is hydrogen, alkyl, heteroalkyl, or haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently selected from one or more R 9 is optionally replaced by; R 7a and R 7b are each independently hydrogen, alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, or heterocyclyl is selected from one or more R 9 is optionally replaced by; Each R 8 are independently alkyl, alkenyl, alkynyl, heteroalkyl, 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 Bwherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R 10 has been replaced by; R A is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, 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 selected from 0 to 12 R 10 has been replaced by; R B , R C , and R D is each independently an alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R 10 or R B and R C together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from the group consisting of one or more R 10 is optionally substituted with; Each R 9 are independently alkyl, heteroalkyl, 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 where each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 10 is optionally replaced by; Each R 10 is independently 1-6 The alginate of any one of embodiments 39 to 40, which is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0250] 42. The alginate has the formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O, NR 6 , or S; R 1 is non-existent, 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 )C(O)—, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are each independently selected from one or more R 8 is optionally replaced by; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R 9 is optionally replaced by R 2a and R 2b At least one of and R 3aand R 3b at least one of is not hydrogen; Each R 4 is non-existent, 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R 8 is optionally replaced by; R 5 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more R 8 is optionally replaced by; R 6 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, or C 1-6 haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently selected from one or more R 9 is optionally replaced by; R 7a and R 7bare each independently hydrogen, C 1-6 alkyl, cycloalkyl, or heterocyclyl, where the alkyl, cycloalkyl, or heterocyclyl is selected from one or more R 9 is optionally replaced by; Each R 8 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 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 wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R 10 has been replaced by; R A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 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 selected from 0 to 12 R 10 has been replaced by; R B , R C , and R Dis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R 10 or R B and R C together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from the group consisting of one or more R 10 is optionally substituted with; Each R 9 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 where each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 10 is optionally replaced by; Each R 10 is independently 1-6 The alginate of any one of embodiments 39 to 41, wherein the alginate is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

[0251] 43. The alginate according to any one of embodiments 41 to 42, wherein X is O.

[0252] 44.R 1 OR A 44. The alginate according to any one of embodiments 41 to 43, wherein

[0253] 45.R 5is C(O)OR A or C(O)N(R C )(R D 45. The alginate according to any one of embodiments 41 to 44, wherein

[0254] 46.R 5 is C(O)N(R C )(R D ) and R C and R D The alginate of any one of embodiments 41 to 45, 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).

[0255] 47.R C and R D is independently hydrogen, and R C and R D The alginate of any one of embodiments 41 to 46, wherein the other is independently a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2) or a peptide (e.g., an RGD peptide).

[0256] 48.R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl.

[0257] 49.R 3 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B , aryl, heteroaryl, cycloalkyl, or heterocyclyl.

[0258] 50.R 2 and R 3 One of them is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C(O)R B and R 2 and R 3 and the other is independently hydrogen.

[0259] 51.R 4 OR A 51. The alginate according to any one of embodiments 41 to 50, wherein

[0260] 52. The monomer has formula (Ic): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R 5 and each of their subvariables are as defined in embodiment 41.

[0261] 53. The monomer has the formula (Id): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R 5 and each of their subvariants is as defined in embodiment 41; 1 and G 2 The alginate of any one of embodiments 41-52, wherein each of is independently hydrogen, a non-fibrous compound, or a peptide.

[0262] 54. The monomer has the formula (Ie): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R C , and R D 54. The alginate of any one of embodiments 41 to 53, wherein each of the subvariables is as defined in embodiment 41.

[0263] 55. The monomer has the formula (If): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 3b , R C , and R D and each of their subvariants is as defined in embodiment 41; 1 and G 2 The alginate of any one of embodiments 41-54, wherein each of is independently hydrogen, a non-fibrous compound, or a peptide.

[0264] 56.G 1 and G 2 56. The alginate of any one of embodiments 53 to 55, wherein one of said compounds is, independently, a non-fibrous compound.

[0265] 57.G 1 and G 2 56. The alginate of embodiments 53-55, wherein both of said components are independently non-fibrous compounds.

[0266] 58. The monomer has the formula (Ig): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R 5 and each of their subvariables are as defined in claim 40; P 1 and P 2 are each independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is selected from one or more R 12 is optionally replaced by; L 1 and L 2 are each independently 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R 8 is optionally replaced by; Z 1 and Z 2 are each independently hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 8 is optionally replaced by; Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a , R 8 , and R 12 An alginate according to any one of embodiments 41 to 55, wherein said alginate is as defined in embodiment 41.

[0267] 59. The monomer has the formula (Ih): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2a , R 3a , R C , R D and each of their subvariables is as defined in embodiment 41; P 1 and P 2 are each independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is selected from one or more R 12 is optionally replaced by; L 1 and L 2 are each independently 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R 8 is optionally replaced by; Z 1 and Z 2 are each independently hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 8 is optionally replaced by; Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 7a , R 8 , and R 12An alginate according to any one of embodiments 41 to 58, wherein said alginate is as defined in embodiment 41.

[0268] 60.P 1 and P 2 The alginate of any one of embodiments 58 to 59, wherein each is independently heteroaryl (e.g., triazolyl).

[0269] 61.P 1 and P 2 are each independently [ka] and R 12 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 The alginate of embodiment 60, which is haloalkyl, or halo.

[0270] 62.L 1 and L 2 are each independently absent or C 1-6 The alginate of any one of embodiments 60 to 61, wherein the alginate is alkylene (e.g., -CH2-).

[0271] 63.Z 1 and Z 2 The alginate of any one of embodiments 60 to 62, wherein each is independently aryl, heteroaryl, or heterocyclyl.

[0272] 64.Z 1 and Z 2 and each is independently heterocyclyl.

[0273] 65.Z 1 and Z 2 are each independently [ka] 65. The alginate of embodiment 64, wherein

[0274] 66. The alginate of any one of claims 40 to 65, wherein the non-fibrous compound is selected from the group consisting of those in Table 2.

[0275] 67. A hydrogel comprising a polysaccharide polymer according to any one of embodiments 1 to 40 or an alginate according to any one of claims 41 to 66.

[0276] 68. An implantable element comprising a polysaccharide polymer according to any one of embodiments 1 to 40, an alginate according to any one of embodiments 41 to 66, or a hydrogel according to embodiment 67.

[0277] 69. The implantable element of embodiment 68, further comprising cells (e.g., engineered cells).

[0278] 70. The implantable element of embodiment 69, wherein the cells produce a therapeutic substance (e.g., an enzyme, a blood clotting factor, an antibody, or a hormone).

[0279] 71. A pharmaceutical composition comprising a polysaccharide polymer according to any one of embodiments 1 to 40, an alginate according to any one of embodiments 41 to 66, a hydrogel according to embodiment 67, or an implantable element according to any one of embodiments 68 to 70, and a pharma- ceutically acceptable excipient.

[0280] 72. A method for treating a disease, disorder, or condition in a subject, such as a subject in need of treatment, comprising administering to the subject an implantable element described in any one of embodiments 68 to 70 or a pharmaceutical composition described in embodiment 71, thereby treating the disease, disorder, or condition in the subject. EXAMPLES

[0281] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, compositions, devices, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0282] The compounds, modified polymers, implantable elements, and compositions thereof provided herein can be prepared from readily available starting materials using modifications to the specific synthetic protocols shown below that will be familiar to those skilled in the art. Although typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are shown, it is understood that other process conditions can be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures.

[0283] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, 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 references cited therein.

[0284] Exemplary compounds, modified polymers, implantable elements, and compositions of the invention can be prepared using any of the strategies described below.

[0285] Example 1: Synthesis of exemplary compounds Schematic protocol The following procedures describe methods for preparing exemplary compounds for preparing chemically modified implantable elements. The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthetic protocols shown below that will be familiar to those skilled in the art. Although typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are shown, it is understood that other process conditions can be used unless otherwise indicated. Optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0286] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, 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 references cited therein.

[0287] Step 1: Periodate oxidation of alginate [ka] Pronova UP VLVG (Novamatrix, 2 g, ca. 10.7 mmol / monomer) was dissolved in purified water (100 mL) with vigorous stirring at room temperature, and then 1-propanol (10 mL) was added as a free radical scavenger. The solution was degassed for 15 min with nitrogen purging. Separately, sodium (meta)periodate (2.3 g, 10.7 mmol) was dissolved in purified water (45 mL) and degassed for 15 min before being added to the reaction solution. The reaction mixture was stirred at 4°C for 48 h in the dark and purified by a tangential flow filtration system (MWCO 10K) against saline (ca. 1 L) followed by purified water (ca. 1 L) and finally lyophilized to obtain a solid (1.72 g).

[0288] Step 2: Reductive amination of oxidized alginate The oxidized alginate product from step 1 (0.5 g, approximately 2.7 mmol / monomer) was dissolved in purified water (83 mL) in a 500 mL beaker to a concentration of 6 mg / mL. Methanol (11 mL) was added to a final concentration of 12% v / v. An exemplary amine to be coupled (6.6 mmol) was dissolved separately in purified water (10 mL) at room temperature. 2-Methylpyridine borane complex (Pic-BH3, 2.9 g, 27.1 mmol) was dissolved separately in methanol (40 mL). The amine solution was added to the oxidized alginate solution, followed by the Pic-BH3 solution to obtain a suspension. The pH of the mixture was adjusted to 5.8 by adding 3 M sodium acetate buffer, and then 20 mL of water was added to a final alginate concentration of 3 mg / mL. The reaction mixture was vigorously stirred at room temperature for 24 h, and the floating pic-BH3 solid was filtered off. The filtrate was purified by a tangential flow filtration system (MWCO 10K) against saline (~1 L) followed by purified water (~1 L) and finally freeze-dried to obtain the final modified alginate as a solid. Exemplary alginates were prepared as outlined below.

[0289] Synthesis of alginate modified with compound 219 [ka] The oxidized alginate and aminated product were prepared following the protocols outlined above in steps 1 and 2. The final modified alginate containing compound 219 was analyzed by elemental analysis and shown to have 7.4% nitrogen, 37.7% carbon, and 3.2% sulfur.

[0290] Synthesis of alginate modified with compound 222 [ka] The oxidized alginate and aminated product were prepared following the protocols outlined above in steps 1 and 2. The final modified alginate was analyzed by elemental analysis and shown to contain 6.5% nitrogen, 36.5% carbon, and 2.8% sulfur.

[0291] Synthesis of alginate modified with compound 225 [ka] The oxidized alginate and aminated product were prepared following the protocols outlined above in steps 1 and 2. The final modified alginate was analyzed by elemental analysis and shown to contain 10.5% nitrogen, 41.7% carbon, and 0% sulfur.

[0292] Example 2: Preparation of hydrogel capsules containing modified polysaccharide polymers This example describes the preparation of a two-compartment hydrogel capsule containing an exemplary modified polysaccharide polymer described herein. A first 5% (w / w) solution of alginate containing compound 219 was prepared by dissolving 0.25 g of modified alginate in 4.75 g of saline. The solution was mixed overnight until the solution was homogenous. A second alginate solution with or without RGD peptide was also prepared (3% (w / w)) by dissolving 0.25 g of RGD alginate in 8.3 g of saline and mixed overnight until homogenous. 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 solution was then loaded into two separate 10 mL syringes.

[0293] A Matsuda high voltage generator was then connected to a coaxial needle (17 gauge) in a needle holder and attached to a ground ring. A Luer lock fitting on the side of the needle was attached to an 8 inch tubing extension connected to a syringe filled with the first (5% (w / w)) alginate solution, which represented the outer compartment. A Luer lock fitting on the top of the needle was also attached to an 8 inch tubing extension connected to a syringe filled with the second (3% (w / w)) RGD-alginate, which represented the inner compartment. A syringe pump was used to inject the first and second alginate solutions into a glass dish containing 250 mL of 20 mM BaCl2 solution, allowing for crosslinking and formation of hydrogel capsules. The crosslinked hydrogel capsules were then collected in a glass dish, washed with buffer solution (15 times), and then imaged to assess morphology and sphere strength. Bright field microscopy was used to monitor the quality of the hydrogel capsules containing modified polysaccharide polymers and the non-fibrous compound Compound 219, revealing a smooth surface without defects. Further testing of the stability and strength of the hydrogel capsules was performed using texture analysis (e.g., as described in Example 7). The fracture data for hydrogel capsules containing modified polysaccharide polymers with monomers of Compound 219 are shown in Table 4 below. [Table 4]

[0294] Similar fracture analyses were performed on other hydrogel capsules containing different non-fibrous compounds, specifically compound 222, as shown in Table 5 below. [Table 5]

[0295] Example 3: Preparation of Exemplary Cells for Encapsulation in Hydrogels Engineered ARPE-19 cells for encapsulation as single cells. ARPE-19 cells engineered to express a therapeutic agent, such as a clotting factor (e.g., FVIII or FIX protein), can be cultured according to any method known in the art, for example, according to the following protocol.

[0296] 75cm 2 The engineered ARPE-19 cells in the culture flask are aspirated to remove the culture medium, and the cell layer is briefly rinsed with 0.05% (w / v) trypsin / 0.53 mM EDTA solution ("TrypsinEDTA") to remove any residual serum, including trypsin inhibitors. 2-3 mL of TrypsinEDTA solution is added to the flask, and the cells are observed under an inverted microscope until the cell layer is dispersed, usually for 5-15 min. To avoid clumping, handle the cells carefully and minimize tapping or shaking the flask during the dispersion period. If the cells do not detach, leave the flask at 37 °C to facilitate dispersion. Once the cells are dispersed, 6-8 mL of complete growth medium is added, and the cells are aspirated by gentle pipetting. The cell suspension is then transferred to a centrifuge tube and spun down at approximately 125 x g for 5-10 min to remove the TrypsinEDTA. The supernatant is then discarded, and the cells are resuspended in fresh growth medium. Add an appropriate aliquot of the cell suspension to a new culture vessel and incubate it at 37 °C. Change the medium 2-3 times weekly.

[0297] ARPE-19 cells for encapsulation as clusters Prepare spheroid clusters of exemplary cells (e.g., engineered ARPE-19 cells) using AggreWell™ spheroid plates (STEMCELL Technologies) and the protocol outlined herein. On day 1, add rinse solution (4 mL) to each plate and spin down plates in a large centrifuge at 3,000 RPM for 5 minutes. Remove rinse solution with a pipette and add 4 mL of complete growth medium. Seed engineered ARPE-19 cells into plates at desired cell density and pipette immediately to prevent clumping. A general rule of thumb is that 3.9 million cells per well will produce clusters with a diameter of 150 μm. Spin down plates at 800 RPM for 3 minutes and place plates in a 37° C. incubator overnight.

[0298] On day 2, remove the plate from incubation. Using a wide-mouth pipette tip, gently pipette the cells to dislodge the spheroid clusters. Filter the clusters through a 40 μm or 80 μm cell strainer to remove excess detached single cells, then spin down in a centrifuge for 2 × 1 min. Gently resuspend the clusters using a wide-mouth pipette tip and gently agitate to disperse them throughout the medium or another material (such as alginate).

[0299] Alternatively, the following protocol is used to prepare ARPE-19 spheroids: On day 1, remove the AggreWell™ plate from the 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 complete growth medium and add 2 million engineered ARPE-19 cells in 3.9 mL of complete growth medium to each well. Centrifuge the plate at 100 g for 3 minutes and then incubate the cells at 37° C. for 48 hours. On day 3, remove the spheroid clusters using the same protocol as above.

[0300] Alternatively, a PBS MINI bioreactor (PBS Biotec, Inc., Camarillo CA, USA) is used to prepare ARPE19 spheroids using the following protocol: Cell culture medium and 220 million ARPE19 cells are added to a PBS 0.1 L or PBS 0.5 L container, and the container is then inserted into a base unit placed in an incubator. The PBS MINI speed control dial is set to 40 rpm, and the container is incubated at 37°C for at least 48 hours before harvesting the spheroids as described above.

[0301] Example 4: Preparation of cell-containing hydrogel capsules Capsules encapsulating RPE cells as single cells. Immediately prior to encapsulation, single ARPE-19 cells engineered to express a therapeutic protein are centrifuged at 1,400 rpm for 1 min and washed with calcium-free Krebs-Henseleit (KH) buffer (4.7 mM KCl, 25 mM HEPES, 1.2 mM KH2PO4, 1.2 mM MgSO4 x 7H2O, 135 mM NaCl, pH ~7.4, ~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 high molecular weight alginate solution (70:30) to a desired density of suspended single cells per ml of alginate solution.

[0302] Prior to fabricating the one- and two-compartment hydrogel capsules, the buffer and alginate solutions are sterilized by filtration through 0.2 μm filters using an aseptic process.

[0303] To prepare devices configured as two-compartment hydrogel capsules with a diameter of approximately 1.5 mm, the electrostatic droplet generator can be set up as follows: an ES series 0-100-kV, 20-watt high-voltage generator (EQ series, Matsuda, 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 can be connected via a Luer coupling to a second 5 mL syringe that 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 polysaccharide polymer of formula (I) can be placed in the second syringe. For a control two-compartment hydrogel capsule, an alginate solution without the polysaccharide polymer of formula (I) can be used to form the second (outer) compartment. Two syringe pumps move the first and second alginate solutions from the syringes through both lumens of a coaxial needle, and droplets containing both alginate solutions are extruded, drop by drop, from the needle into a glass dish containing the crosslinking solution. The settings of each syringe pump can be adjusted to achieve the optimal flow ratio of the two alginate solutions.

[0304] For the preparation of two-compartment capsules, after extrusion of the desired volume of alginate solution, the alginate droplets are crosslinked for 5 min 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 vessel are collected in a conical tube by pipetting. After the capsules settle in the tube, the crosslinking buffer is removed and the capsules are washed. The cell-free capsules are washed four times with HEPES buffer (15.428 g NaCl, 0.70 g KCl, 0.488 g MgCl2·6H2O, 50 ml HEPES (1 M) buffer solution (Gibco, Life Technologies, California, USA) in 2 liters of deionized water) and stored at 4 °C until use. The capsules encapsulating the cells are washed four times with HEPES buffer, twice with 0.9% saline, and twice with culture medium, and then stored in an incubator at 37°C.

[0305] Example 5. In vivo assays of exemplary compounds The non-fibrotic properties of exemplary compounds of the present disclosure can be analyzed by implanting hydrogel capsules prepared as described in Examples 2 or 4 into the intraperitoneal (IP) space of C57BL / 6J mice according to the following procedure.

[0306] Preparation: Mice are anesthetized under a continuous flow of 1-4% isoflurane with oxygen at 0.5 L / min and prepared for surgery. Preoperatively, all mice receive 0.5 ml of 0.9% saline subcutaneously to prevent dehydration, and may receive buprenorphine subcutaneously at a dose of 0.05-0.1 mg / kg body weight as a preoperative analgesic. Hair is removed using a shaver with a size #40 clipper blade to expose an area approximately 2 cm x 2 cm on the ventral midline of the animal's abdomen. The entire shaved area is aseptically prepared by scrubbing a minimum of three times with Povidine (in a radial direction from the center of the incision site outwards when possible), followed by rinsing with 70% alcohol. A final skin paint with Povidine is also applied. After disinfecting the tabletop surface with 70% ethanol, the surgical site is covered with disposable sterile paper to eliminate surrounding hair from touching the surgical site. Personnel use appropriate PPE, gowns, surgical masks, and surgical gloves.

[0307] Surgical Procedure: Using a sharp scalpel or scissors, make a 0.5-0.75 mm midline incision through the skin and linea alba in the abdomen of the subject mouse. The surgeon strives to keep the incision as small as possible. Using flat sterile forceps, transfer a 0.5 mL aliquot of each capsule composition into the abdominal cavity of each mouse (4 mice per composition). Suture the abdominal muscles closed with 5-0 Ethicon black silk or PDS absorbent 5.0-6.0 monofilament absorbable suture, and close the outer layer of skin using wound clips. Between procedures, remove blood and tissue debris from surgical instruments, and resterilize instruments using a hot bead sterilizer between animals. After surgery, place animals back in their cages on a heat pad or under a heat lamp and monitor until they recover from anesthesia.

[0308] Intraoperative care: Animals are kept warm using a Deltaphase isothermal pad. The animal's eyes are kept hydrated with sterile ophthalmic ointment for the duration of surgery. Care is taken not to over-wet the surgical site to avoid hypothermia. Respiratory rate and characteristics are constantly monitored. If vital signs indicate extreme pain and distress, animals are euthanized by cervical dislocation after placement in a carbon dioxide chamber.

[0309] Post-operative analysis: Four weeks after implantation, the majority of capsules are harvested from the mice and capsule cell counts (one capsule per mouse in duplicate) are measured using the CellTiter Glo® 3D cell viability assay (Promega Corporation, Madison, WI USA). Briefly, one capsule per well is analyzed in duplicate 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 medium, the plate is placed on a shaker at 400 rpm for 15 minutes, and then the luminescence is read on a plate reader. A texture analyzer is also used to measure the mechanical strength (initial fracture) of capsules in aliquots of each composition before implantation and upon harvest after the one-month implantation period.

[0310] Example 6: Conjugation of additional compounds to the polymer Exemplary polymers may be further modified by conjugating additional compounds to one or more monomers at other positions on the monomer, such as free carboxylate.For example, compounds can be conjugated to reactive carboxylic acid groups on alginate polymers.Any moiety that can be coupled to carboxylic acid, such as amines described herein, may be suitable partners for this coupling reaction.

[0311] Exemplary compounds containing free amines can be conjugated to alginates using the methods outlined herein. The alginate polymer is dissolved in water (30 mL / gram 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 is then warmed to 55° C. for 16 hours, cooled to room temperature, concentrated via rotary evaporation, and then dissolved in water. The mixture is then filtered through a bed of cyano-modified silica gel (Silicycle) and the filter cake is washed with water. The resulting solution is then dialyzed (10,000 MWCO membrane) against water for 24 hours, with two changes of water during that time. The resulting solution is concentrated by lyophilization to give the further functionalized alginate.

[0312] Example 7: Particle Analysis Various properties of the particle preparations can be analyzed in vitro or at various times after implantation into subjects such as test animals or human patients. For example, the mechanical strength of the particles (e.g., hydrogel capsules) can be determined by performing a crushing test using a texture analyzer after production but before implantation. Mechanical testing of hydrogel capsules is performed in a TA.XT plus Texture Analyzer (Stable Micro Systems, Surrey, United Kingdom) 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 rate of 0.5 mm / s. Contact between the probe and the capsule is detected when a rebound force of 1 g is measured. The probe continues to move 90% of the distance between the probe contact height and the platform, compressing the capsule until it ruptures. The resistance of the probe to the compression force can be measured and plotted as a function of the probe travel (force vs. displacement curve). Typically, the capsules fracture slightly before completely rupturing, resulting in a small decrease in the force applied to the probe. The analysis macro can be programmed to detect the first time a decrease of 0.25 to 0.5 g occurs in the force versus displacement curve. The force applied by the probe when this occurs is referred to as the initial crush force. In one embodiment, the crush force of a capsule preparation produced using the apparatus described herein is the average of the initial crush forces of at least 10, 20, 30, or 40 capsules.

[0313] The average particle size in a particle preparation can be estimated by determining the average particle size in an aliquot 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 removed from the preparation and examined by optical microscopy, such as bright field imaging.

[0314] Example 8: Preparation and characterization of hydrogel capsules containing modified polysaccharide polymers of compound 101 This example describes the preparation of a two-compartment alginate hydrogel capsule comprising an outer layer made of a modified polysaccharide polymer as described herein and an inner layer made of an unmodified polysaccharide polymer. The modified alginate polymer of Example 1 (0.25 g) was dissolved in 4.75 g saline. The solution was mixed overnight until it was homogenous. A second alginate solution was also prepared by dissolving 0.25 alginate in 8.3 g saline (3% (w / w)) and mixed overnight until it was homogenous. 2.16 g of the 3% (w / w) unmodified alginate solution was added to the 5% (w / w) modified alginate solution and mixed. The modified alginate solution was then loaded into two separate 10 mL syringes.

[0315] A Matsuda high voltage generator was then connected to a coaxial needle (17 gauge) in a needle holder and attached to a ground ring. A Luer lock fitting on the side of the needle was attached to an 8 inch tubing extension connected to a syringe filled with the first (5% (w / w)) alginate solution, which represented the outer compartment. A Luer lock fitting on the top of the needle was also attached to an 8 inch tubing extension connected to a syringe filled with the second (3% (w / w)) unmodified alginate, which represented the inner compartment. A syringe pump was used to inject the first and second alginate solutions into a glass dish containing 250 mL of 20 mM BaCl2 solution to allow crosslinking and formation of hydrogel capsules. The crosslinked hydrogel capsules were then collected in a glass dish, washed with buffer solution (15 times), and then imaged to assess morphology and sphere strength.

[0316] Equivalents and Scope 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 a conflict between any of the incorporated references and this specification, this specification shall control. Also, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are deemed known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0317] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above specification, drawings, or examples, but is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to the specification may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

1. 1. A polysaccharide polymer comprising sugar monomers, the sugar monomers are 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; The glycomonomer has the formula (I-a): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein: X is O, NR ６ or S; R １ is non-existent, 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 )C(O)—, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are each independently selected from one or more R ８ is optionally substituted by R ２ａ , R ２ｂ , R ３ａ , and R ３ｂ are each independently hydrogen, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C(O)R Ｂ , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R ９ and optionally substituted by R ２ａ and R ２ｂ At least one of and R ３ａ and R ３ｂ at least one of is not hydrogen; Each R ４ is non-existent, 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R ８ is optionally substituted by R ５ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 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, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more of R ８ is optionally substituted by R ６ is hydrogen, C １－６ Alkyl, C １－６ Heteroalkyl, or C １－６ haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently one or more R ９ is optionally substituted by R ７ａ and R ７ｂ are each independently hydrogen, C １－６ alkyl, cycloalkyl, or heterocyclyl, where the alkyl, cycloalkyl, or heterocyclyl is selected from one or more R ９ is optionally substituted by Each R ８ is independently 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 selected from 0 to 12 R １０ is replaced by; 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, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R １０ is replaced by; R Ｂ , R Ｃ , and R Ｄ is 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, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R １０ or R Ｂ and R Ｃ together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from one or more R １０ optionally substituted with; Each R ９ is independently １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C １ -C ６ 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 wherein each alkyl, heteroalkyl, and haloalkyl is selected from one or more R １０ is optionally substituted by Each R １０ is independently １－６ The polysaccharide polymer is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

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

3. R １ Is OR Ａ 2. The polysaccharide polymer of claim 1, wherein

4. R ５ is C(O)OR Ａ or C(O)N(R Ｃ ) (R Ｄ 2. The polysaccharide polymer of claim 1 ,

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

7. R ２ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C(O)R Ｂ , aryl, heteroaryl, cycloalkyl, or heterocyclyl.

8. R ３ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C(O)R Ｂ , aryl, heteroaryl, cycloalkyl, or heterocyclyl.

9. R ２ and R ３ One of them is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C(O)R Ｂ and R ２ and R ３ and the other is independently hydrogen.

10. R ４ Is OR Ａ 2. The polysaccharide polymer of claim 1, wherein

11. The glycomonomer has the formula (I-c): 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ５ and each of their subvariables are as defined in claim 1.

12. The glycomonomer has the formula (I-d): 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ５ and each of their subvariables are as defined in claim 1; １ and G ２ 2. The polysaccharide polymer of claim 1, wherein each of is independently hydrogen, a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2), or a peptide.

13. The glycomonomer has the formula (I-e): 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R Ｃ , and R Ｄ and each of their subvariables are as defined in claim 1.

14. The glycomonomer has the formula (If): 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R Ｃ , and R Ｄ and each of their subvariants are as defined in claim 1; １ and G ２ 2. The polysaccharide polymer of claim 1, wherein each of is independently hydrogen, a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2), or a peptide.

15. G １ and G ２ 15. The polysaccharide polymer of claim 14, wherein one of said compounds is independently a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2).

16. G １ and G ２ 15. The polysaccharide polymer of claim 14, wherein both of are independently a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2).

17. The glycomonomer has the formula (I-g): 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ３ａ , R ５ and each of their subvariables are as defined in claim 1; P １ and P ２ are each independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is selected from one or more R １２ is optionally substituted by L １ and L ２ are each independently 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R ８ is optionally substituted by Z １ and Z ２ are each independently hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R ８ is optionally substituted by Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R ７ａ , R ８ , and R １２ The polysaccharide polymer of claim 1, wherein is as defined in claim 1.

18. The glycomonomer has the formula (I-h): 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ３ａ , R Ｃ , R Ｄ and each of their subvariables are as defined in claim 1; P １ and P ２ are each independently aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is selected from one or more R １２ is optionally substituted by L １ and L ２ are each independently 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R ８ is optionally substituted by Z １ and Z ２ are each independently hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R ８ is optionally substituted by Each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R ７ａ , R ８ , and R １２ The polysaccharide polymer of claim 1, wherein is as defined in claim 1.

19. P １ and P ２ is each independently heteroaryl (e.g. triazolyl).

20. P １ and P ２ are each independently 【Chemistry 8】 and R １２ is hydrogen, deuterium, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ 20. The polysaccharide polymer of claim 19, which is haloalkyl, or halo.

21. L １ and L ２ are each independently absent or C １－６ Alkylene (e.g., -CH ２ The polysaccharide according to claim 17 or 18, wherein

22. Z １ and Z ２ is independently aryl, heteroaryl, or heterocyclyl.

23. Z １ and Z ２ is independently heterocyclyl.

24. Z １ and Z ２ are each independently 【Chemistry 9】 24. The polysaccharide polymer of claim 23, wherein

25. The polysaccharide polymer of claim 1 , wherein the non-fibrous compound is selected from the moieties in Table 2.

26. The polysaccharide polymer of claim 1, wherein the non-fibrous compound is selected from compound 218, compound 219, or compound 222.

27. The polysaccharide polymer of claim 1 , wherein the peptide comprises the sequence RGD.

28. The polysaccharide polymer of claim 1 , wherein the polysaccharide polymer is an alginate.

29. 30. The polysaccharide polymer of claim 29, wherein the alginate is a high guluronic acid (G) alginate or a high mannuronic acid (M) alginate.

30. Formula (I-a): 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof, wherein: X is O, NR ６ or S; R １ is non-existent, 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 )C(O)—, where alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene are each independently selected from one or more R ８ is optionally substituted by R ２ａ , R ２ｂ , R ３ａ , and R ３ｂ are each independently hydrogen, C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C(O)R Ｂ , aryl, heteroaryl, cycloalkyl, or heterocyclyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from one or more R ９ and optionally substituted by R ２ａ and R ２ｂ At least one of and R ３ａ and R ３ｂ at least one of is not hydrogen; Each R ４ is non-existent, 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 )C(O)—, where each alkylene, alkenylene, alkynylene, and heteroalkylene is selected from one or more R ８ is optionally substituted by R ５ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 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, azido, aryl, heteroaryl, cycloalkyl, heterocyclyl, a non-fibrous compound, or a peptide, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently selected from one or more of R ８ is optionally substituted by R ６ is hydrogen, C １－６ Alkyl, C １－６ Heteroalkyl, or C １－６ haloalkyl, where alkyl, heteroalkyl, and haloalkyl are each independently one or more R ９ is optionally substituted by R ７ａ and R ７ｂ are each independently hydrogen, C １－６ alkyl, cycloalkyl, or heterocyclyl, where the alkyl, cycloalkyl, or heterocyclyl is selected from one or more R ９ is optionally substituted by Each R ８ is independently 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 selected from 0 to 12 R １０ is replaced by; 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, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is selected from 0 to 12 R １０ is replaced by; R Ｂ , R Ｃ , and R Ｄ is 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, aryl, heteroaryl, cycloalkyl, heterocyclyl, non-fibrous compound, or peptide, where each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, and cycloalkyl is selected from one or more R １０ or R Ｂ and R Ｃ together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl or heteroaryl ring, each of which may be selected from one or more R １０ optionally substituted with; Each R ９ is independently １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C １ -C ６ 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 wherein each alkyl, heteroalkyl, and haloalkyl is selected from one or more R １０ is optionally substituted by Each R １０ is independently １－６ The alginate is alkyl, halogen, oxo, cycloalkyl, or heterocyclyl.

31. 31. The alginate of claim 30, wherein X is O.

32. R １ Is OR Ａ 31. The alginate of claim 30, wherein

33. R ５ is C(O)OR Ａ or C(O)N(R Ｃ ) (R Ｄ 31. The alginate of claim 30, wherein

34. R ５ is C(O)N(R Ｃ ) (R Ｄ ) and R Ｃ and R Ｄ 31. The alginate of claim 30, 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).

35. R Ｃ and R Ｄ is independently hydrogen; Ｃ and R Ｄ The alginate of claim 30, wherein the other is independently a non-fibrous compound (e.g., a non-fibrous compound shown in Table 2) or a peptide (e.g., an RGD peptide).

36. R ２ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C(O)R Ｂ , aryl, heteroaryl, cycloalkyl, or heterocyclyl.

37. R ３ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C(O)R Ｂ , aryl, heteroaryl, cycloalkyl, or heterocyclyl.

38. R ２ and R ３ One of them is independently C １－６ Alkyl, C １－６ Heteroalkyl, C １－６ Haloalkyl, C(O)R Ｂ and R ２ and R ３ The alginate of claim 30, wherein the other is independently hydrogen.

39. R ４ Is OR Ａ 31. The alginate of claim 30, wherein

40. The monomer has the formula (I-c): 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ５ and each of their subvariables are as defined in claim 30.

41. The monomer has the formula (I-d): 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ５ and each of their subvariables is as defined in claim 30; １ and G ２ 31. The alginate of claim 30, wherein each of is independently hydrogen, a non-fibrous compound (e.g., those shown in Table 2), or a peptide.

42. The monomer has the formula (I-e): 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R Ｃ , and R Ｄ and each of their subvariables are as defined in claim 30.

43. The monomer has the formula (If): 【Chemistry 14】 or a pharma- ceutically acceptable salt thereof, wherein R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R Ｃ , and R Ｄ and each of their subvariants is as defined in claim 30; １ and G ２ 31. The alginate of claim 30, wherein each of is independently hydrogen, a non-fibrous compound (e.g., those shown in Table 2), or a peptide.

44. G １ and G ２ 44. The alginate of claim 41 or 43, wherein one of said compounds is, independently, a non-fibrous compound (e.g., one shown in Table 2).

45. The alginate of claim 30, wherein the non-fibrous compound is selected from the sites in Table 2 (e.g., compound 218, compound 219, or compound 222).

46. 31. A hydrogel comprising the polysaccharide polymer of claim 1 or the alginate of claim 30.

47. 47. An implantable component comprising the polysaccharide polymer of claim 1, the alginate of claim 30, or the hydrogel of claim 46.

48. 48. The implantable element of claim 47, further comprising cells (e.g., engineered cells, such as those described herein).

49. 49. The implantable element of claim 48, wherein the cells produce a therapeutic substance (e.g., a protein, such as an enzyme, an antibody, a hormone, or a blood clotting factor).

50. 48. A pharmaceutical composition comprising the polysaccharide polymer of claim 1, the alginate of claim 30, the hydrogel of claim 46, or the implantable element of claim 47, and a pharma- ceutically acceptable excipient.

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