Modified polysaccharide polymers and related compositions and methods

Abstract

Described herein are polysaccharide polymers comprising a sugar moiety modified with a hydroxyl modifier (e.g., a sugar monomer of formula (I)), as well as related compositions, hydrogels, implantable elements, and methods of use thereof.

Description

[0001] Priority declaration

[0002] This application claims priority to U.S. Patent Application No. 63 / 295,297, filed on December 30, 2022, the entire contents of which are incorporated herein by reference in their entirety. Background Art

[0003] The function of implanted devices depends largely on the recipient's biological immune response pathways (Anderson et al., Semin. Immunol. 20:86-100 (2008); Langer, Adv. Mater. 21:3235-3236 (2009)). Modulation of the immune response can have a beneficial effect on the fidelity and function of these devices. Therefore, there is a need in the art for new compounds, compositions and devices to achieve this goal. Summary of the invention

[0004] Polymers containing certain hydroxyl modifications are described herein, as well as compositions and methods related thereto. In one aspect, the disclosure features a polysaccharide polymer comprising a sugar monomer with a hydroxyl moiety, wherein the sugar monomer comprises a hydroxyl modifier covalently bound to the hydroxyl moiety. In one embodiment, the sugar monomer carries a plurality of hydroxyl moieties, wherein the sugar monomer comprises a hydroxyl modifier covalently bound to the hydroxyl moiety. On the other hand, the disclosure features a polysaccharide polymer comprising a sugar monomer with a hydroxyl moiety, wherein the sugar monomer comprises a hydroxyl modifier replacing 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 modifier is a nitrogen-containing hydroxyl modifier. In one embodiment, the hydroxyl modifier comprises an amine or an amide.

[0005] In one aspect, the disclosure features a polysaccharide polymer comprising sugar monomers, wherein the sugar monomers have the structure of formula (I):

[0006] or a pharmaceutically acceptable salt thereof, wherein the variables X, R 1 , R 2 , R 3 , R 4 , R 5a , R 5band its subvariables are defined herein. In some embodiments, the sugar monomer of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (la), (lb), (lc), (Id), (le), or (If) as described herein. In some embodiments, the sugar monomer of formula (I) or a pharmaceutically acceptable salt thereof is shown in Table 1 herein.

[0007] In another aspect, the disclosure features a polysaccharide polymer comprising sugar monomers, wherein the sugar monomers have the structure of formula (Ia):

[0008] or a pharmaceutically acceptable salt thereof, wherein the variables X, R 1 , R 2 , R 3 , R 4 , R 5 and its subvariables are defined herein. In some embodiments, the sugar monomer of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If). In some embodiments, the sugar monomer of formula (I) or a pharmaceutically acceptable salt thereof is shown in Table 1 herein.

[0009] In another aspect, the disclosure features an alginate comprising a sugar monomer, wherein the sugar monomer has the structure of formula (Ia):

[0010] or a pharmaceutically acceptable salt thereof, wherein the variables X, R 1 , R 2 , R 3 , R 4 , R 5 and its subvariables are defined herein. In some embodiments, the sugar monomer of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If). In some embodiments, the sugar monomer of formula (I) or a pharmaceutically acceptable salt thereof is shown in Table 1 herein.

[0011] On the other hand, the feature of the present disclosure is a hydrogel comprising a polysaccharide polymer as described herein (for example, alginate), and an implantable element (for example, device or material) comprising the polysaccharide polymer. In some embodiments, hydrogel or implantable element comprise cells. Exemplary cell types include epithelial cells, endothelial cells, fibroblasts, keratinocytes and stem cells (for example, iPSC or MSC). In some embodiments, hydrogel or implantable element comprise epithelial cells, such as retinal pigment epithelial cells (RPE cells). In some embodiments, hydrogel or implantable element comprise engineered cells (for example, engineered epithelial cells, such as engineered RPE cells).

[0012] In some embodiments, cells (e.g., engineered cells) produce substances, such as therapeutic agents. Exemplary therapeutic agents include nucleic acids (e.g., RNA or DNA), proteins (e.g., hormones, enzymes, antibodies, antibody fragments, antigens or epitopes), small molecules, lipids, drugs, vaccines, or any derivatives thereof. For example, an implantable element may include engineered cells capable of producing proteins (e.g., blood clotting factors (e.g., factor VIII proteins) or hormones (e.g., insulin)).

[0013] On the other hand, the feature of the present disclosure is a method for providing a substance (e.g., a therapeutic agent) to a subject, the method comprising administering a hydrogel or an implantable element to the subject, the hydrogel or implantable element comprising (i) a polysaccharide polymer (e.g., alginate) of a sugar monomer comprising formula (I) as described herein, and (ii) cells capable of producing the substance (e.g., a therapeutic agent). In some embodiments, the substance is a therapeutic agent, such as a protein (e.g., a blood coagulation factor (e.g., a factor VIII protein) or a hormone (e.g., insulin)).

[0014] On the other hand, the present disclosure is characterized by a method for treating a disease, disorder or illness of a subject using a therapeutic agent capable of treating the disease, disorder or illness, the method comprising administering a hydrogel or an implantable element to the subject, the hydrogel or implantable element comprising (i) a polysaccharide polymer (e.g., alginate) of a sugar monomer comprising formula (I) as described herein, and (ii) a cell capable of producing the therapeutic agent. In some embodiments, the disorder is a blood coagulation disorder (e.g., hemophilia A), a lysosomal storage disease (e.g., Fabry disease, MPS I), an endocrine disorder, diabetes or a neurodegenerative disease.

[0015] In some embodiments, methods of providing a substance or methods of treating include reducing a foreign body reaction to an administered implantable element (eg, minimizing the formation of pericranial fibrotic overgrowth (PFO) on the implantable element).

[0016] In any and all aspects of the present disclosure, in some embodiments, the polysaccharide polymer described herein (e.g., comprising a sugar monomer of formula (I)) or a hydrogel or implantable element thereof (e.g., a device or material) is not a polysaccharide polymer, hydrogel or implantable element described in any of WO2012 / 112982, WO2012 / 167223, WO2014 / 153126, WO2016 / 187225, WO2016 / 019391, WO2017 / 075630, WO2017 / 075631, WO 2018 / 067615, WO 2019 / 169333 and US2016-0030359.

[0017] The details of one or more embodiments of the present invention are set forth herein. Other features, objects, and advantages of the present invention will be apparent from the detailed description, drawings, examples, and claims. DETAILED DESCRIPTION

[0018] The present disclosure provides polysaccharide polymers comprising sugar monomers with hydroxyl moieties modified with hydroxyl modifiers, and related compositions, preparation and use methods thereof. In one embodiment, the sugar monomer comprises a hydroxyl modifier covalently bound to the hydroxyl moiety. In one embodiment, a polysaccharide polymer comprising a sugar monomer such as formula (I), and a hydrogel and an implantable element (e.g., a device and material) comprising the polysaccharide polymer, and related compositions and use methods thereof. Specifically, the polysaccharide polymers, hydrogels and implantable elements described herein can be used in methods for preventing and treating diseases, disorders or illnesses of a subject. In some embodiments, a polysaccharide polymer comprising a sugar monomer of formula (I), and a hydrogel and an implantable element comprising the polysaccharide polymer, and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotope-labeled derivatives thereof, can reduce the immune response of a subject.

[0019] definition

[0020] In order to more easily understand the present invention, 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 ordinary technicians in the field to which the present invention belongs.

[0021] As used herein, including the appended claims, singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0022] When "about" is used herein to modify a numerically defined parameter (e.g., a physical description of a polymer or implantable element as described herein, such as diameter, sphericity, the number of cells in a particle (e.g., a hydrogel), the number of particles in a formulation), it means that the parameter can vary up to 15% above and below the stated value of the 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 can have an average diameter of 1.275 to 1.725 mm and can encapsulate about 4.25M to 5.75M cells. In some embodiments, the term "about" means that the parameter can vary up to 10% or 5% above and below the stated value of the parameter.

[0023] As used herein, the term "acquire" or "acquiring" refers to the process of obtaining a value (e.g., a numerical value) or an image or physical entity (e.g., a sample) by "directly obtaining" or "indirectly obtaining" a value or physical entity. "Directly obtaining" means performing a process (e.g., performing an analytical method or protocol) to obtain a value or physical entity. "Indirectly obtaining" refers to receiving a value or physical entity from another party or source (e.g., a third-party laboratory that directly obtains a physical entity or a value). Directly obtaining a value or physical entity includes performing a process that includes a physical change of a physical substance or the use of a machine or device. Examples of directly obtaining a value include obtaining a sample from a human subject. Directly obtaining a value includes performing a process using a machine or device, such as a fluorescence microscope, to obtain fluorescence microscopy data.

[0024] As used herein, "administer," "administering," or "administration" refers to implanting, absorbing, ingesting, injecting, or otherwise introducing an entity described herein (e.g., a polysaccharide polymer described herein, or a hydrogel or implantable element comprising the polysaccharide polymer, including a hydrogel or implantable element encapsulating cells) or a composition comprising the clone) into a subject, or providing the entity to a subject for administration.

[0025] As used herein, "fibrosis-free" refers to at least one aspect of mitigating a foreign body reaction (FBR) to an implant comprising a compound or material, such as a compound or material that minimizes the formation of pericapsular fibrotic overgrowth (PFO) on an implant. For example, the FBR in a biological tissue or tissue fluid induced by implanting a polysaccharide polymer or a device (e.g., a hydrogel or implantable element) comprising a non-fibrotic compound (e.g., a hydrogel comprising a polysaccharide polymer covalently modified with a compound listed in Table 1) into the tissue or tissue fluid occurs at a lower amount or at a later time than the FBR induced by implanting a non-fibrotic reference polymer or device (i.e., lacking any fibrotic compound but having substantially the same composition in other respects) (e.g., a hydrogel capsule formed of the same unmodified polymer and having substantially the same shape and size). In one embodiment, the FBR is induced using an assay known in the art, such as described in WO 2017 / 075630 or using Vegas, A., et al., Nature One or more of the assays / methods described in Biotechnol (supra) (e.g., measurement of subcutaneous tissue proteases of implanted capsules, Masson's trichrome staining (MT), hematoxylin or eosin staining of tissue sections, quantification of collagen density, cell staining and confocal microscopy of macrophages (CD68 or F4 / 80), granulocytes (Siglec-F, Ly-6G), myofibroblasts (α-muscle actin, SMA) or general cell deposition, quantification of 79 RNA sequences for known inflammatory factors and immune cell markers, or FACS analysis of macrophages and neutrophils on the retrieved device (e.g., capsule) after 14 days in the intraperitoneal space of a suitable test subject (e.g., immunocompetent mouse)) are used to assess the extent of FBR through an immune response in tissue or tissue fluid containing an implanted device (e.g., hydrogel capsule), which may include, for example, protein adsorption, macrophages, multinucleated foreign body giant cells, eosinophils, neutrophils, T cells, B cells, fibroblasts, and angiogenesis. In one embodiment, FBR is assessed by measuring the level of one or more biomarkers of immune response (e.g., cathepsin, TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-1, IL-4, IL-5, CCL2, CCL4, TIMP-1) in tissue or tissue fluid containing the implant. In some embodiments, FBR is assessed by checking the amount of PFO on the implant (e.g., hydrogel capsule) at one or more times after administration to a suitable test subject (e.g., immunocompetent mouse); such assessment can be performed using assays known in the art (e.g., any assay described in this definition).In some embodiments, the FBR (e.g., PFO) induced by a modified polymer or device of the invention (e.g., a hydrogel capsule comprising a non-fibrotic compound described herein on its outer surface) is at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% lower than the same FBR induced by a reference polymer or device without non-fibrosis, or occurs at least about 10%, about 20%, about 40%, or about 50% later than the same FBR induced by a reference polymer or device without non-fibrosis. In some embodiments, the FBR (e.g., the level of one or more biomarkers) 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.

[0026] As used herein, "cell" refers to an engineered cell or a non-engineered cell.

[0027] As used herein, "effective amount" refers to an amount of a compound, a modified polymer, or an implantable element, such as one that also includes cells (e.g., engineered cells) or an agent (e.g., a therapeutic agent) produced by cells (e.g., engineered cells) sufficient to reduce or elicit a biological response (e.g., minimize an immune response) or treat a disease, disorder, or condition. As will be appreciated by one of ordinary skill in the art, an effective amount may vary according to 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 both therapeutic and prophylactic treatments. For example, in order to reduce a foreign body reaction (e.g., PFO) caused by an implantable element, a compound as described herein may be disposed on the surface of the implantable element in an amount effective to reduce PFO or prevent the growth or spread of fibrous tissue on or near the implantable element.

[0028] As used herein, "endogenous nucleic acid" is a nucleic acid that naturally occurs in the cells of a subject.

[0029] As used herein, an "endogenous polypeptide" is a polypeptide that naturally occurs in the cells of a subject.

[0030] As used herein, "engineered cells" are cells with non-natural changes and are generally comprised of nucleic acid sequences (e.g., DNA or RNA) or polypeptides that are not present (or present at different levels) in other similar cells under similar conditions of unengineered (exogenous nucleic acid sequences). In one embodiment, the engineered cell comprises an exogenous nucleic acid (e.g., a vector or a changed chromosomal sequence). In one embodiment, the engineered cell comprises an exogenous polypeptide. In one embodiment, the engineered cell comprises an exogenous nucleic acid sequence, such as a sequence that is not present in unengineered similar cells, such as DNA or RNA. In one embodiment, the exogenous nucleic acid sequence is chromosomal, for example, the exogenous nucleic acid sequence is an exogenous sequence placed in an endogenous chromosomal sequence. In one embodiment, the exogenous nucleic acid sequence is chromosomal or extrachromosomal, such as a non-integrated vector. In one embodiment, the exogenous nucleic acid sequence comprises an RNA sequence, such as an mRNA. In one embodiment, the exogenous nucleic acid sequence comprises a chromosomal or extrachromosomal exogenous nucleic acid sequence, and the chromosomal or extrachromosomal exogenous nucleic acid sequence comprises a sequence expressed as RNA, such as an mRNA or a regulatory RNA. In one embodiment, the exogenous nucleic acid sequence comprises a chromosomal or extrachromosomal nucleic acid sequence, and the chromosomal or extrachromosomal nucleic acid sequence comprises a sequence encoding a polypeptide or expressing a polypeptide. In one embodiment, the exogenous nucleic acid sequence comprises a first chromosomal or extrachromosomal exogenous nucleic acid sequence, and the first chromosomal or extrachromosomal exogenous nucleic acid sequence regulates the conformation or expression of the second nucleic acid sequence, wherein the second amino acid sequence can be exogenous or endogenous. For example, the engineered cell may comprise an exogenous nucleic acid that controls the expression of an endogenous sequence. In one embodiment, the engineered cell comprises a polypeptide that exists at a level or distribution different from that found in an unengineered similar cell. In one embodiment, the engineered cell includes a cell engineered to provide RNA or a polypeptide. For example, the engineered cell may comprise an exogenous nucleic acid sequence, and the exogenous nucleic acid sequence comprises a chromosomal or extrachromosomal exogenous nucleic acid sequence, and the chromosomal or extrachromosomal exogenous nucleic acid sequence comprises a sequence expressing RNA, such as mRNA or a regulatory RNA. In one embodiment, the engineered cell comprises an exogenous nucleic acid sequence, and the exogenous nucleic acid sequence comprises a chromosomal or extrachromosomal nucleic acid sequence, and the chromosomal or extrachromosomal nucleic acid sequence comprises a sequence encoding a polypeptide or expressing a polypeptide. In one embodiment, the engineered cell comprises an exogenous nucleic acid sequence that regulates the conformation or expression of an endogenous sequence.In one embodiment, the engineered cell (e.g., RPE cell) is cultured from a colony of stably transfected cells or from a monoclonal cell line.

[0031] As used herein, "exogenous nucleic acid" is a nucleic acid that does not naturally occur in a subject's cells (eg, an engineered cell).

[0032] As used herein, an "exogenous polypeptide" is a polypeptide that does not naturally occur in a subject's cells (eg, an engineered cell).

[0033] As used herein, "implantable element" comprises cells, such as multiple cells, such as cell clusters, wherein one or more cells are placed in a closed part (the closed part is not a cell) in whole or in part, such as the closed part comprises non-cellular components. The term "implantable element" comprises a device or material as described herein. In one embodiment, an implantable element suppresses the influence of an immune attack or an immune attack on one or more closed cells. In one embodiment, an implantable element comprises a semipermeable membrane or a semipermeable polymer matrix or a coating. Implantable elements as described herein comprise polysaccharide polymers (e.g., alginate), which comprise sugar monomers with a structure of formula (I), or a pharmaceutically acceptable salt thereof. Implantable elements as described herein may also comprise polymers (e.g., polysaccharide polymers, such as alginate) or other materials optionally modified with another compound (e.g., without fibrosis compounds or peptides).

[0034] As used herein, "pericapsular fibrotic overgrowth" or "PFO" refers to a fibrotic cell layer that forms over part or all of a hydrogel or implantable element as a result of a foreign body reaction to the implantable element.

[0035] As used herein, "polypeptide" refers to a polymer comprising amino acid residues linked by peptide bonds and having at least two, and in embodiments at least 10, 100 or 200 amino acid residues.

[0036] As used herein, "Prevention," "prevent," and "preventing" refer to treatments that include administering or applying a therapy, such as administering a composition of an implantable element that encapsulates cells (e.g., as described herein), prior to the onset of a disease, disorder, or condition to preclude physical manifestations of the disease, disorder, or condition. In some embodiments, "Prevention," "prevent," and "preventing" require that signs or symptoms of a disease, disorder, or condition have not yet developed or have not been observed.

[0037] "Alternative therapy" or "alternative protein" is a therapeutic protein or its functional fragment that replaces or increases a protein that is reduced, present in insufficient amounts, altered (e.g., mutated) or lacking in a subject suffering from a disease or illness associated with a reduced, altered or lacking protein. Examples are certain blood coagulation factors in certain blood coagulation disorders or certain lysosomal enzymes in certain lysosomal storage diseases. In one embodiment, an alternative therapy or alternative protein provides the function of an endogenous protein. In one embodiment, an alternative therapy or alternative protein has the same amino acid sequence of a naturally occurring variant (e.g., a wild-type allele or an allele unrelated to the disorder) of the replaced protein. In one embodiment, an alternative therapy or alternative protein is different from a naturally occurring variant (e.g., a wild-type allele or an allele unrelated to the disorder, such as an allele carried by a subject) in an amino acid sequence at no more than about 1%, 2%, 3%, 4%, 5%, 10%, 15% or 20% of the amino acid residues.

[0038] As used herein, "subject" refers to humans or non-human animals. In one embodiment, the subject is a human (i.e., male or female), such as a person of any age group, a pediatric subject (e.g., an infant, a child, a teenager) or an adult subject (e.g., a young person, a middle-aged person, or an elderly person). In one embodiment, the subject is a non-human animal, such as a mammal (e.g., a primate (e.g., a cynomolgus monkey or a rhesus monkey)). In one embodiment, the subject is a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog) or a bird (e.g., a commercially relevant bird, such as a chicken, a duck, a goose, or a turkey). In certain embodiments, the animal is a mammal. The animal can be male or female and be at any stage of development. The non-human animal can be a transgenic animal.

[0039] As used herein, the terms "treatment", "treat" and "treating" refer to reducing, reversing, alleviating one or more of the symptoms, manifestations or potential causes of a disease, disorder or illness, delaying its onset or inhibiting its progression. In one embodiment, treatment includes reducing, reversing, alleviating the symptoms of a disease, disorder or illness, delaying its onset or inhibiting its progression. In one embodiment, treatment includes reducing, reversing, alleviating the manifestations of a disease, disorder or illness, delaying its onset or inhibiting its progression. In one embodiment, treatment includes reducing, reversing, alleviating, alleviating the potential causes of a disease, disorder or illness or delaying its onset. In some embodiments, "treatment", "treat" and "treating" require that signs or symptoms of a disease, disorder or illness have developed or have been observed. In other embodiments, treatment may be administered when there are no signs or symptoms of a disease or illness, such as in preventive treatment. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., taking into account symptom history and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have resolved, for example to delay or prevent their recurrence. In some embodiments, treatment includes prevention, and in other embodiments, it does not include prevention.

[0040] Selected chemical definitions

[0041] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th 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, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0042] Abbreviations used herein have their conventional meanings in the chemical and biological arts.The chemical structures and formulae illustrated herein are constructed according to the standard rules of chemical valence known in the chemical arts.

[0043] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C1-C6 alkyl" is intended to encompass 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.

[0044] As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C 12 In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), s-propyl (C4), s-propyl (C5), s-propyl (C6), s-propyl (C7), s-propyl (C8), s-propyl (C9), s-propyl (C10), s-propyl (C11), s-propyl (C12), s-propyl (C13), s-propyl (C14), s-propyl (C15), s-propyl (C16), s-propyl (C17), s-propyl (C18), s-propyl (C19), s-propyl (C21), s-propyl (C22), s-propyl (C23), s-propyl (C24), s-propyl (C25), s-propyl (C26), s-propyl (C27), s-propyl (C28), s-propyl (C29), s-propyl (C31), s-propyl (C32), s-propyl (C33), s-propyl (C34), s-propyl (C35), s-propyl (C36), s-propyl (C37), s-propyl (C38), s-propyl (C39). ), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Additional examples of alkyl include n-heptyl (C7), n-octyl (C8), etc. Each example of alkyl can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl").

[0045] As used herein, "alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C2-C 24 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-C 10The carbon-carbon double bond(s) may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include vinyl (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 aforementioned C 2-4 alkenyl and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Each instance of alkenyl can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl").

[0046] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon triple bonds ("C2-C 24 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2-C 10 The carbon-carbon triple bond(s) may be internal (as in 2-butynyl) or terminal (as in 1-butynyl). -butynyl). Examples of C2-C4 alkynyl include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each example of alkynyl can independently be optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (“substituted alkynyl”).

[0047] As used herein, the term "heteroalkyl" refers to a non-cyclic stable straight or branched chain or a combination thereof comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen atom, phosphorus atom, silicon atom and sulfur atom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. One or more heteroatoms O, N, P, S and Si may be placed 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

[0048] -S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3 and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. When describing "heteroalkyl", the specific heteroalkyl group is described, such as -CH2O, -NR C R D It will be understood that the term heteroalkyl and -CH2O or -NR C R D The terms "heteroalkyl" and "heteroalkyl" are not redundant or mutually exclusive. Instead, specific heteroalkyl groups are described to increase clarity. Therefore, the term "heteroalkyl" should not be interpreted herein to exclude specific heteroalkyl groups, such as -CH2O, -NR C R D wait.

[0049] Unless otherwise indicated, the term "alkylene", "alkenylene", "alkynylene" or "heteroalkylene" alone or as part of another substituent means a divalent group derived from an alkyl, alkenyl, alkynyl or heteroalkylene, respectively. Alkylene, alkenylene, alkynylene or heteroalkylene may be described as, for example, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene or C1-C6 heteroalkylene. In the case of heteroalkylene, heteroatoms may also occupy one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the chemical 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-.

[0050] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) radical having 6-14 ring carbon atoms and zero heteroatoms ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 Aryl is a "group" such as an anthracenyl group. Aryl groups may be described as, for example, C6-C 10 The term "membered" refers to the non-hydrogen ring atoms within the moiety. Aryl includes phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of aryl can independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents.

[0051] As used herein, "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the ring array) having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups, where one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indolyl) or the ring not containing heteroatoms (e.g., 5-indolyl). Heteroaryl groups can be described, for example, as 6-10 membered heteroaryl groups, where the term "membered" refers to non-hydrogen ring atoms within the moiety.

[0052] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of heteroaryl can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.

[0053] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 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, pyridinyl. 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, aza Oxalic acid thia Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0054] As used herein, the terms "arylene" and "heteroarylene" by themselves or as part of another substituent refer to a divalent radical derived from an aryl and heteroaryl group, respectively.

[0055] As used herein, "cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C3-C 10 In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"), or 5 to 10 ring carbon atoms ("C5-C8 cycloalkyl"). 10 Cycloalkyl"). Cycloalkyl can be described, for example, as C4-C7 membered cycloalkyl, where the term "membered" refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyls 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 cycloalkyls include but Not limited to the aforementioned C3-C6 cycloalkyl and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), etc. Exemplary C3-C6 cycloalkyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), etc. 10 Cycloalkyl includes, but is not limited to, the aforementioned C3-C8 cycloalkyl as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As illustrated by the foregoing examples, in certain embodiments, the cycloalkyl is monocyclic ("monocyclic cycloalkyl") or contains a fused, bridged or spiro ring system (such as a bicyclic ring system ("bicyclic cycloalkyl")), and may be saturated or may be partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to refer to the number of carbons in the cycloalkyl ring system. Each example of a cycloalkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents.

[0056] As used herein, "heterocyclyl" refers to a radical of a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. A heterocyclyl may be a monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spirocyclic system, such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. A heterocyclyl bicyclic system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl or heterocyclyl ring; or ring systems in which the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl can be described as, for example, 3-7 membered heterocyclyl, wherein the term "member" refers to the non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl can independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted by one or more substituents ("substituted heterocyclyl"). In certain embodiments, heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, heterocyclyl is a substituted 3-10 membered heterocyclyl.

[0057] In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5-10 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-8 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl”). In some embodiments, 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0058] Exemplary 3-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, aziridine, oxirane and thioethane. Exemplary 4-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetane and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl or thiomorpholinyl-1,1-dioxide. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepane, and thiepanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azocyclooctanyl, oxoctanyl, and thiepanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0059] As used herein, "amino" refers to the group -NR C R D , where R C and R D are independently hydrogen, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 In some embodiments, amino refers to NH2.

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

[0061]

[0043] As used herein, "halo" or "halogen," by itself or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

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

[0063] As used herein, a "hydroxy modifier" is a moiety, such as a substance or compound, that is capable of binding to a material comprising a hydroxyl moiety (i.e., -OH) at the position of the hydroxyl moiety. For example, a hydroxyl modifier can bind to a carbon atom covalently bound to the hydroxyl moiety. Exemplary hydroxyl modifiers include amines, esters, and thiols. In order to achieve covalent binding of a hydroxyl modifier to a material comprising a hydroxyl moiety, for example, as described herein, a sugar moiety comprising a hydroxyl moiety can be subjected to certain reactions to activate atoms around the hydroxyl moiety, such as oxidation, reduction, or amination.

[0064] As defined herein, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups 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). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, such as a substituent that, upon substitution, results in a stable compound, such as a compound that does not spontaneously transform, such as 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 substitution occurs at more than one position in any given structure, the substituent at each position is the same or different. The term "substituted" is intended to include substitution with all permissible substituents of an organic compound, any substituent that produces the formation of a stable compound as described herein. The present invention contemplates any and all such combinations to achieve a stable compound. For purposes of this disclosure, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or any suitable substituent that satisfies the valence of the heteroatom and produces the formation of a stable moiety as described herein.

[0065] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl or heterocyclic radicals. It has been found that such so-called ring-forming substituents are usually but not necessarily connected to the cyclic base structure. In one embodiment, the ring-forming substituent is connected to the adjacent members of the base structure. For example, two ring-forming substituents are connected to the adjacent members of the cyclic base structure, producing a condensed ring structure. In another embodiment, the ring-forming substituent is connected to a single member of the base structure. For example, two ring-forming substituents are connected to a single member of the cyclic base structure, producing a spiro ring structure. In another embodiment, the ring-forming substituent is connected to non-adjacent members of the base structure.

[0066] The compounds of formula (I) described herein may contain one or more asymmetric centers and may therefore exist in a variety of isomeric forms (e.g., 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 stereoisomer mixtures (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELEliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein in the form of individual isomers that are substantially free of other isomers, as well as alternatively in the form of mixtures of different isomers.

[0067] 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 an enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means 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 the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0068] The compounds of formula (I) described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O etc.

[0069] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds used in the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, 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 the like. When the compounds used in the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, etc.; and 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine salts, etc.; and organic acids such as salts of glucuronic acid or galacturonic acid, etc. (see, e.g., Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds used in the present disclosure contain both basic and acidic functionalities, which allow the compounds to be converted into base addition salts or acid addition salts. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are also suitable for use in the present disclosure.

[0070] In addition to salt forms, the present disclosure may also employ compounds of formula (I) in the form of prodrugs. Prodrugs are those compounds that readily undergo chemical changes under physiological conditions to provide compounds useful in the present invention. In addition, prodrugs may be converted into useful compounds of formula (I) by chemical or biochemical methods in an ex vivo environment.

[0071] Some of the compounds of formula (I) described herein can exist in non-solvated form and solvated form (including hydrated form). In general, the solvated form is equivalent to the non-solvated form and is included in the scope of the present invention. Some of the compounds of formula (I) described herein can exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the purposes covered by the present disclosure and are intended to fall within the scope of the present disclosure.

[0072] The term "solvate" refers to a form of a compound that is associated with a solvent, typically by a solvolysis reaction. Such physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 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 stoichiometric solvates and non-stoichiometric solvates.

[0073] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in the hydrate of a compound is in a certain 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 Rx H2O, where R is a compound and where x is a number greater than 0.

[0074] As used herein, the term "tautomer" refers to a compound structure that is an interchangeable form and that varies in hydrogen atom and electron displacement. Thus, by the movement of π electrons and atoms (usually H), the two structures can be in equilibrium. For example, enols and ketones are tautomers because they can be rapidly interconverted by treatment with acid or base. Tautomeric forms can be associated with obtaining optimal chemical reactivity and biological effects of target compounds.

[0075] Symbols used in this article Refers to attachment to a surface of an entity, such as a polysaccharide polymer (eg, a hydrogel-forming polymer such as alginate) or an implantable element (eg, a device or material). The connection represented may refer to direct connection to an entity, such as a polymer or an implantable element, or may refer to connection to an entity through a linking group. As described herein, a "linking group" refers to a portion for connecting a compound of formula (I) to an entity (e.g., a polymer or an implantable element as described herein), and may include any connection chemistry known in the art. A list of exemplary linking groups is summarized in Bioconjugate Techniques (3rd Edition, Greg T. Hermanson, Waltham, MA: Elsevier, Inc, 2013). In some embodiments, the linking group includes alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)-, -OC(O)-, -N(R C )-、-N(R C )C(O)-、-C(O)N(R C )-、-N(R C )N(R D )-、-NCN-、-C(=N(R C )(R D))O-、-S-、-S(O) x -、-OS(O) x -、-N(R C )S(O) x -、-S(O) x N(R C )-、-P(R F ) y -、-Si(OR A )2-、-Si(R G )(OR A )-、-B(OR A )- or metal, where R A , R C , R D , R F , R G Each of x and y is independently as described herein. In some embodiments, the linking group comprises an amine, a ketone, an ester, an amide, an alkyl, an alkenyl, an alkynyl, or a thiol. In some embodiments, the linking group is a crosslinker. In some embodiments, the linking group is -C(O)(C1-C6-alkylene)-, wherein the alkylene is replaced by R 1 Replace, and R 1 As described herein. In some embodiments, the linking group is -C(O)(C1-C6-alkylene)-, wherein 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)-, wherein 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)-.

[0076] Modified sugar monomers

[0077] The invention features a polysaccharide polymer comprising sugar monomers, wherein the sugar monomers comprise a hydroxyl modifier covalently bound to a hydroxyl moiety. In some embodiments, the hydroxyl modifier comprises an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amine, amide, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety. In some embodiments, the hydroxyl modifier comprises an amine.

[0078] Sugar monomer can be any sugar monomer, such as naturally occurring sugar monomer or non-natural sugar monomer. Sugar monomer can contain 1, 2, 3, 4, 5, 6, 7, 8 or more hydroxyl moieties. In one embodiment, sugar monomer is triose, tetrose, pentose, hexose, heptose or octose. . In one embodiment, sugar monomer also comprises additional functional groups, such as carboxylic acid or amine. In one embodiment, sugar monomer also comprises multiple additional functional groups. In one embodiment, 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, sugar monomer is mannuronic acid or guluronic acid.

[0079] In one embodiment, the sugar monomer has the structure of formula (I):

[0080] or a pharmaceutically acceptable salt thereof, wherein X is O, NR 6 or S; R 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein alkylene, alkenylene, alkynylene, heteroalkylene and haloalkylene are optionally substituted by one or more R 8 Replacement; R 2 and R 3 are independently hydrogen, C 1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9, wherein each alkylene or alkenyl group is optionally substituted by one or more R 10 Replace, and R 2 and R 3 Each of R 4 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 Replace; each R 5a and R 5b are independently 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, non-fibrous compounds or peptides, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally replaced by one or more R 8 Replacement; R 6 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl or C 1-6 haloalkyl, wherein alkyl, heteroalkyl and haloalkyl are optionally substituted with one or more R 10 Replacement; R 7a and R 7b are independently hydrogen, C 1-6 alkyl, cycloalkyl or heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R 10 Replace; 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 substituted by 0-12 R 11 Replacement; 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 peptide, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is substituted by 0-12 R 11 Replacement; 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 peptide; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and optionally substituted by one or more R 11 Replace; or R B and R C Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or heteroaryl ring, each of which is optionally substituted by one or more R 10 Replacement; R 9 is a peptide or a non-fibrotic compound; each R 10 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 , wherein each alkyl, heteroalkyl and haloalkyl group is optionally substituted with one or more R 11 Replace; and each R11 Independently for C 1-6 Alkyl, halogen, oxo, cycloalkyl or heterocyclyl.

[0081] In one embodiment, the sugar monomer has the structure of Formula (Ia):

[0082] or a pharmaceutically acceptable salt thereof, wherein X is O, NR 6 or S; R 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein alkylene, alkenylene, alkynylene, heteroalkylene and haloalkylene are optionally substituted by one or more R 8 Replacement; R 2 and R 3 are independently hydrogen, C 1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 , wherein each alkylene or alkenyl group is optionally substituted by one or more R 10 Replace, and R 2 and R 3 Each of R is not hydrogen; each R 4 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 Replacement; R 5 For 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, non-fibrous compounds or peptides, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally replaced by one or more R 8 Replacement; R 6 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl or C 1-6 haloalkyl, wherein alkyl, heteroalkyl and haloalkyl are optionally substituted with one or more R 10 Replacement; R 7a and R 7b are independently hydrogen, C 1-6 alkyl, cycloalkyl or heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R 10 Replace; 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 substituted by 0-12 R 11Replacement; 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 peptide, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is substituted by 0-12 R 11 Replacement; 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 peptide; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and optionally substituted by one or more R 11 Replace; or R B and R C Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or heteroaryl ring, each of which is optionally substituted by one or more R 10 Replacement; R 9 is a peptide or a non-fibrotic compound; each R 10 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 , wherein each alkyl, heteroalkyl and haloalkyl group is optionally substituted with one or more R 11 Replace; and each R 11 Independently for C 1-6 Alkyl, halogen, oxo, cycloalkyl or heterocyclyl.

[0083] In one embodiment, X is O. In one embodiment, R 1 Yes OR A In one embodiment, R 5 It is C(O)OR A or C(O)N(R C )(R D In one embodiment, R 5 It is C(O)OR A In one embodiment, R A is hydrogen. In one embodiment, R 5is C(O)N(R C )(R D In one embodiment, R C and R D Each is independently hydrogen, a non-fibrotic compound (e.g., a non-fibrotic compound provided in Table 2), or a peptide. In one embodiment, R C and R D One of them is hydrogen, and R C and R D The other of the is independently a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2) or a peptide.

[0084] In one embodiment, R 2 It is C 1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 In one embodiment, R 3 It is C 1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 In one embodiment, R 2 is hydrogen and R 3 It is C1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 In one embodiment, R 2 It is C 1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 , and R 3 It's hydrogen.

[0085] In some embodiments, R 1 is O. In some embodiments, R 5 It is C(O)OR A or C(O)N(R C )(R D ). In some embodiments, R 5 is C(O)N(R C )(R D ), and R C and R D Each is independently hydrogen, a non-fibrotic compound (e.g., a non-fibrotic compound provided in Table 2), or a peptide (e.g., an RGD peptide). C and R Done of them is independently hydrogen, and R C and R D The other of R is independently a non-fibrotic compound (e.g., a non-fibrotic compound provided in Table 2) or a peptide (e.g., an RGD peptide). 9 is a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2).

[0086] In one embodiment, the sugar monomer has the structure of Formula (Ib):

[0087] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 5 and each of its subvariables are as defined herein.

[0088] In one embodiment, the sugar monomer has the structure of formula (Ic):

[0089] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 5 , R 9 , n and each of their sub-variables are as defined herein.

[0090] In one embodiment, the sugar monomer has the structure of formula (Id):

[0091] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R C and R D and each of its subvariables are as defined herein.

[0092] In one embodiment, the sugar monomer has the structure of Formula (Ie):

[0093] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 9 , R C , R D , n and each of their sub-variables are as defined herein.

[0094] In one embodiment, R 9 In one embodiment, n is 2.

[0095] In one embodiment, the sugar monomer has the structure of Formula (If):

[0096] or a pharmaceutically acceptable salt thereof, wherein R3 , R 5 and each of its subvariables is as defined herein; P 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 12 Replacement; L 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 Replace; Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 8 Replacement; R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 haloalkyl or halo; each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and R 7a and R 8 As defined herein.

[0097] In one embodiment, the sugar monomer has the structure of formula (Ig):

[0098] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 12 , R C , R D and each of its subvariables is as defined herein; P 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 12 Replacement; L 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Heteroalkylene, C 1-6 Haloalkylene, -N(R 7a )-, -O-, -C(O)-, -C(O)O-, -C(O)N(R C )-or-N(RC )C(O)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 Replace; Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 8 Replacement; R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 haloalkyl or halo; each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and R 7a and R 8 As defined herein. In one embodiment, P 1 and P 2 Each is independently heteroaryl. In one embodiment, P 1 and P 2 Each is independently a monocyclic heteroaryl. 1 and P 2 Each is independently a nitrogen-containing heteroaryl. 1 and P 2 Each is independently a monocyclic nitrogen-containing heteroaryl. 1 and P 2 Each is independently a 5-membered heteroaryl. In some embodiments, P is a 5-membered nitrogen-containing heteroaryl.

[0099] In one embodiment, P 1 is heteroaryl (e.g., triazolyl). In one embodiment, P 1 yes Where R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo.

[0100] In one embodiment, P 1 is one or more R 12 In one embodiment, R 12 is deuterium, alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cyano, azido, -N(R C1 )(R D1 )、-N(R C1 )C(O)R B1 、-C(O)N(R C1 )、-S(O) x R E1 、-N(RC1 )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. In one embodiment, R 12 In one embodiment, P 1 yes Where R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 In one embodiment, P 1 yes

[0101] In one embodiment, L 1 Does not exist or C 1-6 In one embodiment, Z 1 is aryl, heteroaryl or heterocyclyl. In one embodiment, Z 1 In one embodiment, Z 1 yes

[0102] In one embodiment, the sugar moiety is selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[0103] Table 1: Exemplary compounds of formula (I)

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111] In one embodiment, the sugar moiety is selected from compounds 100-127. In one embodiment, the sugar moiety is compound 100. In one embodiment, the sugar moiety is compound 101. In one embodiment, the sugar moiety is compound 102. In one embodiment, the sugar moiety is compound 103. In one embodiment, the sugar moiety is compound 104. In one embodiment, the sugar moiety is compound 105. In one embodiment, the sugar moiety is compound 106. In one embodiment, the sugar moiety is compound 107. In one embodiment, the sugar moiety is compound 108. In one embodiment, the sugar moiety is compound 109. In one embodiment, the sugar moiety is compound 110. In one embodiment, the sugar moiety is compound 111. In one embodiment, the sugar moiety is compound 112. In one embodiment, the sugar moiety is compound 113. In one embodiment, the sugar moiety is compound 114. In one embodiment, the sugar moiety is compound 115. In one embodiment, the sugar moiety is compound 116. In one embodiment, the sugar moiety is compound 117. In one embodiment, the sugar moiety is compound 118. In one embodiment, the sugar moiety is compound 119. In one embodiment, the sugar moiety is compound 120. In one embodiment, the sugar moiety is compound 121. In one embodiment, the sugar moiety is compound 122. In one embodiment, the sugar moiety is compound 123. In one embodiment, the sugar moiety is compound 124. In one embodiment, the sugar moiety is compound 125. In one embodiment, the sugar moiety is compound 126. In one embodiment, the sugar moiety is compound 127. In one embodiment, the sugar moiety is compound 128. In one embodiment, the sugar moiety is compound 129. In one embodiment, the sugar moiety is compound 130. In one embodiment, the sugar moiety is compound 131. In one embodiment, the sugar moiety is compound 132. In one embodiment, the sugar moiety is compound 133. In one embodiment, the sugar moiety is compound 134. In one embodiment, the sugar moiety is compound 135.

[0112] In one embodiment, the sugar moiety further comprises a non-fibrotic compound, eg, covalently bound to another functional group on the sugar moiety. In one embodiment, the non-fibrotic compound is selected from the compounds shown in Table 2.

[0113] Table 2: Exemplary non-fibrotic compounds

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] In one embodiment, the non-fibrosis compound is selected from compounds 200-254 or salts thereof. In one embodiment, the non-fibrosis compound is compound 200. In one embodiment, the non-fibrosis compound is compound 201. In one embodiment, the non-fibrosis compound is compound 202. In one embodiment, the non-fibrosis compound is compound 203. In one embodiment, the non-fibrosis compound is compound 204. In one embodiment, the non-fibrosis compound is compound 205. In one embodiment, the non-fibrosis compound is compound 206. In one embodiment, the non-fibrosis compound is compound 207. In one embodiment, the non-fibrosis compound is compound 208. In one embodiment, the non-fibrosis compound is compound 209. In one embodiment, the non-fibrosis compound is compound 210. In one embodiment, the non-fibrosis compound is compound 211. In one embodiment, the non-fibrosis compound is compound 212. In one embodiment, the non-fibrosis compound is compound 213. In one embodiment, the non-fibrosis compound is compound 214. In one embodiment, the non-fibrosis compound is compound 215. In one embodiment, the non-fibrosis compound is compound 216. In one embodiment, the non-fibrosis compound is compound 200. In one embodiment, the non-fibrosis compound is compound 217. In one embodiment, the non-fibrosis compound is compound 218. In one embodiment, the non-fibrosis compound is compound 219. In one embodiment, the non-fibrosis compound is compound 220. In one embodiment, the non-fibrosis compound is compound 221. In one embodiment, the non-fibrosis compound is compound 222. In one embodiment, the non-fibrosis compound is compound 223. In one embodiment, the non-fibrosis compound is compound 224. In one embodiment, the non-fibrosis compound is compound 225. In one embodiment, the non-fibrosis compound is compound 226. In one embodiment, the non-fibrosis compound is compound 227. In one embodiment, the non-fibrosis compound is compound 228. In one embodiment, the non-fibrosis compound is compound 229. In one embodiment, the non-fibrosis compound is compound 230. In one embodiment, the non-fibrosis compound is compound 231. In one embodiment, the non-fibrosis compound is compound 232. In one embodiment, the non-fibrosis compound is compound 233. In one embodiment, the non-fibrotic compound is Compound 234. In one embodiment, the non-fibrotic compound is Compound 235. In one embodiment, the non-fibrotic compound is Compound 236. In one embodiment, the non-fibrotic compound is Compound 237. In one embodiment, the non-fibrotic compound is Compound 238.In one embodiment, the non-fibrosis compound is compound 239. In one embodiment, the non-fibrosis compound is compound 240. In one embodiment, the non-fibrosis compound is compound 241. In one embodiment, the non-fibrosis compound is compound 242. In one embodiment, the non-fibrosis compound is compound 243. In one embodiment, the non-fibrosis compound is compound 244. In one embodiment, the non-fibrosis compound is compound 245. In one embodiment, the non-fibrosis compound is compound 246. In one embodiment, the non-fibrosis compound is compound 247. In one embodiment, the non-fibrosis compound is compound 248. In one embodiment, the non-fibrosis compound is compound 249. In one embodiment, the non-fibrosis compound is compound 250. In one embodiment, the non-fibrosis compound is compound 251. In one embodiment, the non-fibrosis compound is compound 252. In one embodiment, the non-fibrosis compound is compound 253. In one embodiment, the non-fibrosis compound is compound 254. In one embodiment, the non-fibrosis compound is compound 255. In one embodiment, the non-fibrosis compound is compound 256.

[0122] In one embodiment, the sugar moiety further comprises a peptide covalently bound to another functional group on the sugar moiety (e.g., a sugar moiety of formula (I)). In one embodiment, the peptide is a cell binding peptide. As used herein, "cell binding peptide (CBP)" means a linear or cyclic peptide comprising an amino acid sequence of a cell binding domain derived from a cell adhesion molecule (CAM) (e.g., a cell adhesion molecule that mediates cell-matrix connection or cell-cell connection) ligand. The length of CBP is less than 50, 40, 30, 25, 20, 15 or 10 amino acids. In one embodiment, the length of CBP is between 3 and 12 amino acids, the length is between 4 and 10 amino acids, or the length is 3, 4, 5, 6, 7, 8, 9 or 10 amino acids. The CBP amino acid sequence may be identical to the 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, 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 the cell binding sequences listed in Table 3 below. In one embodiment, the CBP is an RGD peptide, which means that the peptide comprises the amino acid sequence RGD (SEQ ID NO: 20) and optionally comprises one or more additional amino acids located at one or both of the N-terminus and / or the C-terminus. In one embodiment, the peptide is a peptide shown in Table 3.

[0123] Table 3: Exemplary CAM ligand proteins and cell binding sequences

[0124]

[0125]

[0126] 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. In one embodiment, the peptide is a peptide disclosed in WO2020069429A1, which is incorporated herein by reference in its entirety.

[0127] Modified polymer

[0128] Polysaccharide polymers as described herein include sugar moieties modified with hydroxyl modifiers. In one embodiment, polysaccharide polymers can be linear, branched or cross-linked polysaccharide polymers, or polysaccharide polymers with 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, dendrite polymers, graft-copolymers, ladder polymers and dendritic polymers. Polysaccharide polymers can be thermosensitive polymers, such as gels (for example, becoming solid or liquid when exposed to heat or a certain temperature) or photo-crosslinkable polymers. In some embodiments, polysaccharide polymers are composed of a single type of repeating monomer units. In other embodiments, polysaccharide polymers are composed of different types of repeating monomer units (for example, two types of repeating monomer units, three types of repeating monomer units, for example, polymer blends).

[0129] In one embodiment, the polysaccharide polymer is cellulose, such as carboxymethyl cellulose. In one embodiment, the polysaccharide polymer is polylactic acid, polyglycoside or polycaprolactone. In one embodiment, the polysaccharide polymer is hyaluronate, such as sodium hyaluronate. In one embodiment, the polymer is collagen, elastin or gelatin.

[0130] In some embodiments, polysaccharide polymer is a polymer forming a hydrogel. The polymer forming a hydrogel comprises a hydrophilic structure so that it can accommodate a large amount of water in a three-dimensional network. The polymer forming a hydrogel may include a polymer forming a homopolymer hydrogel, a copolymer hydrogel or a polypolymer 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 polymers forming a hydrogel include proteins (e.g., collagen), gelatin, polysaccharides (e.g., starch, alginate, hyaluronate, agarose) and synthetic polysaccharides.

[0131] Exemplary polysaccharides include alginate, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, amylose, chitin, chitosan or its derivatives or variants, for example, as described in Laurienzo (2010), Mar Drugs 9: 2435-65. The polysaccharide polymer may include heparin, chondroitin sulfate, dermatan, dextran or carboxymethyl cellulose. In some embodiments, the polysaccharide polymer is a cross-linked polymer. In some embodiments, the polysaccharide polymer is a cell surface polysaccharide.

[0132] In some embodiments, the polysaccharide polymer is alginate.Alginate is a polysaccharide composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G).In some embodiments, alginate is high guluronic acid (G) alginate, and comprises greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more guluronic acid (G).In some embodiments, alginate is high mannuronic acid (M) alginate, and comprises greater than 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, alginate has an approximate molecular weight of <75kDa and a G:M ratio optionally ≥1.5. In some embodiments, the alginate has an approximate molecular weight of 75 kDa to 150 kDa and optionally a G:M ratio of > 1.5. In some embodiments, the alginate has an approximate molecular weight of 150 to 250 kDa and optionally a G:M ratio of > 1.5.

[0133] The polysaccharide polymer (for example any polymer described herein, for example any alginate described herein) or its pharmaceutically acceptable salt comprising the sugar part with formula (I) structure can be modified on one or more monomeric units. In some embodiments, at least 0.5% of the sugar monomer in the polysaccharide polymer has the structure of formula (I) (for example, at least 1%, 2.5%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more sugar monomer has the structure of formula (I)). In some embodiments, 0.5% to 50%, 10% to 90%, 10% to 50% or 25% to 75% of the sugar monomer of the polysaccharide polymer has the structure of formula (I). In some embodiments, 1% to 20% of the sugar monomer of the polysaccharide polymer has the structure of formula (I). In some embodiments, 1% to 10% of the sugar monomers of the polysaccharide polymer have the structure of formula (I).

[0134] In some embodiments, the polysaccharide polymer (when comprising sugar monomers having a structure of Formula I) comprises (compared to the unmodified polymer) an increase in N% of at least 0.1 wt%, 0.2 wt%, 0.5 wt%, 1.0 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, or 10 wt% N, wherein N% is determined by elemental analysis and corresponds to the amount of compound of Formula (I) in the modified polymer.

[0135] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having a structure of formula (I)) comprises an increase in N% (compared to the unmodified polymer) from 0.1 wt% to 10 wt% N, wherein N% is determined by elemental analysis and corresponds to the amount of compound of formula (I) in the modified polymer.

[0136] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having a structure of formula (I)) comprises an increase in N% (compared to the unmodified polymer) of 0.1 wt% to 2 wt% N, wherein N% is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0137] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having a structure of formula (I)) comprises (compared to the unmodified polymer) an increase in N% of 2 wt% to 4 wt% N, wherein N% is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0138] In some embodiments, the polysaccharide polymer (when comprising a sugar monomer having a structure of formula (I)) comprises (compared to the unmodified polymer) an increase in N% of 4 wt% to 8 wt% N, wherein N% is determined by elemental analysis and corresponds to the amount of the compound of formula (I) in the modified polymer.

[0139] In some embodiments, any polysaccharide polymer described herein (e.g., alginate) comprises a sugar monomer having one or more of formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or a pharmaceutically acceptable salt thereof. In some embodiments, the polymer (e.g., alginate) is modified with the compounds 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, WO 2017 / 075631, WO2018 / 067615, WO 2019 / 169333, and US2016-0030359.

[0140] Implantable components

[0141] The present disclosure also features an implantable element (e.g., device or material) comprising a polysaccharide polymer of formula (I) as described herein or a pharmaceutically acceptable salt thereof. The surface of the implantable element may also include a material modified with a non-fibrotic compound, such as shown in Table 2. In one embodiment, the polysaccharide polymer of formula (I) is present on the surface (e.g., outer surface or inner surface) of the implantable element. The implantable element comprising the polysaccharide polymer of formula (I) may have improved characteristics compared to a reference implantable element (e.g., lacking an otherwise identical implantable element of a polysaccharide polymer of formula (I)). In one embodiment, the improved characteristic is that when the implantable element is applied to a subject, the foreign body reaction to the implantable element is reduced (e.g., lower amount and / or later PFO occurs).

[0142] In some embodiments, implantable element comprises cell.In some embodiments, cell is engineered cell.In some embodiments, cell is arranged in implantable element wholly or partially.Implantable element may comprise closed element, and described closed element partially or completely encapsulates or coats cell.In one embodiment, implantable element comprises closed part, and described closed part is or can be formed in situ on cell (for example, multiple cells, for example, cell cluster) or around cell or microcarrier (for example, bead or the matrix comprising one or more cells).

[0143] Implantable elements can include any material, such as polymer or other materials described herein. In some embodiments, implantable elements are made of a material or multiple types of materials. Implantable elements can include inorganic or metallic components or materials, such as steel (e.g., stainless steel), titanium, other metals or alloys. Implantable elements can include non-metallic components or materials, such as ceramics or hydroxyapatite elements.

[0144] The implantable element may include a component or material made of an electrically conductive material (eg, gold, platinum, palladium, titanium, copper, aluminum, silver, a metal, any combination of these, etc.).

[0145] An implantable element may include more than one component, for example, more than one component disclosed herein, such as more than one of a metal, plastic, ceramic, composite, or hybrid material.

[0146] Exemplary implantable elements include materials such as metals, metal alloys, ceramics, polymers, fibers, inert materials, and combinations thereof. An implantable element may be made entirely of one type of material, or may refer only to the surface or surfaces (e.g., outer or inner surfaces) of an implantable element.

[0147] In some embodiments, the implantable element (e.g., device or material) includes a metal or metal alloy. Exemplary metals or metal alloys include titanium and titanium group alloys (e.g., nitinol, nickel titanium alloys, thermal memory alloy materials), platinum, platinum group 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 316 grade stainless steel (SS 316L) (including 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 the metal-containing implantable element, the amount of metal (e.g., in wt %, actual weight) can be at least 5%, such as at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, such as w / w; less than 20%, such as less than 20%, 15%, 10%, 5%, 1%, 0.5%, 0.1% or less.

[0148] In some embodiments, the implantable element (e.g., device or material) is a 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 silicon dioxide can also be used. In an implantable element containing ceramic, the amount of ceramic (e.g., in % by weight, actual weight) can be at least 5%, such as at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, such as w / w; less than 20%, such as less than 20%, 15%, 10%, 5%, 1%, 0.5%, 0.1% or less.

[0149] In some embodiments, the implantable element includes a polymer (e.g., hydrogel, plastic) component. Exemplary polymers include polyethylene, polypropylene, polystyrene, polyester (e.g., PLA, PLG or PGA, polyhydroxyalkanoate (PHA) or other bioabsorbable plastics), polycarbonate, polyvinyl chloride (PVC), polyethersulfone (PES), polyacrylate (e.g., acrylic acid or PMMA), hydrogel (e.g., acrylic polymer or a blend of acrylic polymer and silicone polymer), polysulfone, polyetheretherketone, thermoplastic elastomer (TPE or TPU), thermosetting elastomer (e.g., silicone (e.g., silicone elastomer)), poly-p-xylylene (poly-p-xylylene (Parylene)), fluoropolymers (e.g., PTFE) and polyacrylates such as poly (acrylic acid) and / or poly (acrylamide) or mixtures thereof. In a polymer-containing implantable element, the amount of polymer (e.g., in wt %, actual weight) can be at least 5%, such as at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, such as w / w; less than 20%, such as less than 20%, 15%, 10%, 5%, 1%, 0.5%, 0.1% or less.

[0150] In some embodiments, the implantable element (e.g., device or material) includes a polymer that 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 can be applied to the implantable element by a variety of techniques in the art, including but not limited to spraying, wetting, immersing, impregnating (e.g., dip coating (e.g., intraoperative dip coating)), painting, or otherwise applying a hydrophobic polymer to the surface of the implantable element.

[0151] In one embodiment, the implantable element comprises a flexible polymer, such as alginate (eg, any of the chemically modified alginates described herein), PLA, PLG, PEG, CMC, or mixtures thereof (referred to herein as a "polymer encapsulated implantable device").

[0152] In some embodiments, implantable element comprises the polymer forming hydrogel.The polymer forming hydrogel comprises hydrophilic structure, enables it to hold a large amount of water in three-dimensional network.The polymer forming hydrogel may include the polymer forming homopolymer hydrogel, copolymer hydrogel or 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 polymers forming hydrogel include protein (for example, collagen), gelatin, polysaccharide (for example, starch, alginate, hyaluronate, agarose) and synthetic polymer.In some embodiments, the polymer forming hydrogel is polysaccharide (for example, alginate).

[0153] In some embodiments, the implantable element comprises a polysaccharide. Exemplary polysaccharides include alginate, agar, agarose, carrageenan, hyaluronate, amylopectin, glycogen, gelatin, cellulose, straight-chain starch, chitin, chitosan or its derivatives or variants, for example, as described in Laurienzo (2010), Mar Drugs 9:2435-65. The implantable element may include a polysaccharide containing heparin, chondroitin sulfate, dermatan, dextran or carboxymethyl cellulose. In some embodiments, the polysaccharide is a cross-linked polymer. In some embodiments, the polysaccharide is a cell surface polysaccharide.

[0154] In some embodiments, the implantable element comprises 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 modified alginate described herein.

[0155] In one embodiment, the implantable element comprises or can be formed in situ on or around cells (eg, a plurality of cells, such as a cell cluster) or on a microcarrier (eg, a bead or a matrix comprising one or more cells).

[0156] In one embodiment, the implantable element is included in a preformed microcarrier (e.g., a bead or a matrix comprising one or more cells) prior to combination with a closed cell (e.g., a plurality of cells, e.g., a cell cluster). The implantable element may include a protein or polypeptide, such as an antibody, protein, enzyme, or growth factor. The implantable element may include an active or inactive fragment of a protein or polypeptide, such as glucose oxidase (e.g., for a glucose sensor), a kinase, a phosphatase, an oxygenase, a hydrogenase, or a reductase.

[0157] The implantable elements included herein include implantable elements configured to have a lumen (e.g., a lumen with one, two or more openings), such as a tubular device, such as a catheter. A typical stent is an example of a device configured to have a lumen and have two openings. Other examples include shunts.

[0158] Implantable elements encompassed herein include, for example, flexible implantable elements configured to conform to the shape of the body.

[0159] Implantable elements contemplated herein include components that stabilize the position of the implantable element, such as an adhesive or a fastener, such as a torque-based or friction-based fastener, such as a screw or a pin.

[0160] Implantable elements included herein can be configured to monitor substances, such as exogenous substances (eg, therapeutic agents or toxins) or endogenous body products (eg, polypeptides (eg, insulin or glucose)). In some embodiments, the implantable element is a diagnostic element.

[0161] The implantable elements included herein can be configured to release substances, such as exogenous substances, such as therapeutic agents described herein. In some embodiments, the therapeutic agent is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is a biomaterial. 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.

[0162] An implantable component herein may be configured to change conformation in response to a signal or movement of the body, such as an artificial joint, such as a knee, hip, or other artificial joint.

[0163] Exemplary implantable elements include stents, shunts, dressings, ocular devices, ports, sensors, orthopedic fixation devices, implants (e.g., dental implants, ocular implants, silicone implants, corneal implants, dermal implants, gastric implants, facial implants, hip implants, bone implants, cochlear implants, penile implants, implants for controlling incontinence), 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), blood vessels, and the like. The invention also includes a device for use in one or more of anesthesiology, cardiology, clinical chemistry, otolaryngology, dentistry, gastroenterology, urology, hematology, immunology, microbiology, neurology, obstetrics / gynecology, ophthalmology, orthopedics, pathology, physical medicine, radiology, general or plastic surgery, veterinary medicine, psychiatry, surgery, and / or clinical toxicology.

[0164] Implantable elements contemplated herein include FDA Class 1, 2, or 3 devices, such as unclassified or not yet classified, or devices classified as humanitarian use devices (HUDs).

[0165] In some embodiments, implantable elements include cells or tissues that are encapsulated or captured. Cells or tissues can be encapsulated or embedded in polymers. In some embodiments, implantable elements include cells, such as cells that are arranged in polymer closed components (e.g., alginate).

[0166] In some embodiments, the implantable element is targeted or designed for a system of the body, such as the nervous system (e.g., peripheral nervous system (PNS) or central nervous system (CNS)), vascular system, skeletal system, respiratory system, endocrine system, lymphatic system, reproductive system, or gastrointestinal tract. In some embodiments, the implantable element is targeted to the CNS. In some embodiments, the implantable element is targeted or designed for 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, muscle, ovary, uterus, vagina, or penis.

[0167] 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., that it minimizes 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 manufacture, 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, for example, while maintaining properties for the intended use of the device), such as heat resistance to autoclave / steam conditions, hydrolytic stability to steam sterilization, chemical resistance to EtO, resistance to high-energy radiation (e.g., electron beam, UV, and gamma rays); or crystal structure.

[0168] Implantable elements can be assembled in vivo (eg, an injectable material that forms a structured shape in vivo at body temperature) or ex vivo.

[0169] The implantable element may have a nanometer size, for example, may include nanoparticles, such as nanoparticles made of polymers described herein (e.g., PLA). The nanoparticles may be chemically modified nanoparticles, for example, modified to prevent uptake by macrophages and Kupffer cells (e.g., a process called opsonization); or to change the circulation half-life of nanoclones. The nanoparticles may 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.

[0170] The implantable element may be configured for implantation, application or administration, implantation or otherwise placement into or on any part of the subject's body, including, but not limited to, 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, kidney, bladder, pancreas, prostate, spleen, lungs), lymphatic system, vascular system, oral cavity, nasal cavity, teeth, gums, gastrointestinal tract, bones, buttocks, adipose tissue (e.g., subcutaneous fat), muscle tissue, breast tissue, circulating blood, eyes, breast, vagina; uterus, joints (e.g., knee, hip or spine): adjacent nerves, and malignant or non-malignant tumors located on, in or near any of the above.

[0171] In some embodiments, the implantable element is configured to be implanted, applied to or implanted or arranged in the IP space, for example, in the peritoneal cavity, the omental sac. The sac (also referred to as the omental sac) refers to a cavity formed by the omentum in the abdomen, and is adjacent 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 gland and the pancreas. Typically, the sac is connected to the greater sac by the greater omental foramen (i.e., the foramen of Winslow). The implantable element can be implanted or applied to the IP space, the peritoneal cavity (e.g., the omentum, such as the sac) or arranged on a surface (e.g., the omentum, such as the sac) in the peritoneal cavity by injection or catheter. Other considerations for implanting, applying or arranging the implantable element in the omentum (e.g., the sac) are provided in M. Pellicciaro et al. (2017) Cell R4 5 (3): e2410.

[0172] In some embodiments, implantable element is configured to implant, use or be implanted, use or otherwise be arranged in CNS, such as brain or spinal cord and its corresponding tissue and cavity, such as back body cavity, including cranial cavity and spinal canal.In some embodiments, implantable element is configured to implant, use or be implanted, use or otherwise be arranged in brain space, such as brain parenchyma space, intraventricular space or subdural space.Implantable element can be implanted in CNS or be arranged on the surface in CNS by the hole formed in skull, and delivered by injection or catheter.

[0173] In some embodiments, the implantable element is configured to be implanted, applied to or implanted, applied to or otherwise disposed in the eye, for example, at one or more of the following: any surface or cavity within the eye, such as the retina, cornea, epithelium, aqueous humor, or vitreous space. The implantable element can be implanted in the eye or disposed on a surface within the eye by incision and / or injection.

[0174] The implantable element may include an electrochemical sensor, such as an electrochemical sensor including a working electrode and a reference electrode. For example, the electrochemical sensor includes a working electrode and a reference electrode that react with an analyte to produce a sensor measurement value related to the concentration of the analyte in the fluid to which the eye-mountable device is exposed. The implantable element may include a window, such as a window of a transparent polymer material having a concave surface and a convex surface; a substrate, such as a substrate at least partially embedded in a transparent polymer material. The implantable element may also include an electronic module, the electronic module including one or more of the following: an antenna; and a controller electrically connected to the electrochemical sensor and the antenna, wherein the controller is configured to control the electrochemical sensor to obtain a sensor measurement value related to the concentration of the analyte in the fluid to which the implantable element (e.g., a mountable implantable element) is exposed and use the antenna to indicate the sensor measurement value.

[0175] The implantable element can adopt any suitable shape, such as spherical, ellipsoidal, elliptical, disc-shaped, cylindrical, donut-shaped, cubic, stadiumoid, conical, pyramidal, triangular, rectangular, square or rod-shaped, or can include curved or flat cross-section. Any shape, curved or flat implantable element can be coated or chemically derivatized with a non-fibrotic compound (e.g., as shown in Table 2), a polymer modified with a non-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the implantable element has a maximum linear dimension (LLD), average diameter or size of 1 millimeter (mm) or less, or in the range of 0.2 mm to 1 mm, such as 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 greater than 0.5 mm, 1 mm or 1.5 mm. In some embodiments, the implantable elements described herein range in size from 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 8 mm, 3 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 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 8 mm. In some embodiments, the implantable element has an LLD, mean diameter or size of 0.5 mm to 1 mm or 1 mm to 4 mm. In some embodiments, the implantable element has a LLD, mean diameter, or size of 1 mm to 2 mm. In some embodiments, the implantable element has a spherical shape and a mean diameter within any of the aforementioned numerical ranges.

[0177] 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 between about 0.1 μm and about 10 μm. For example, the average pore size can be between 0.1 μm and 10 μm, 0.1 μm and 5 μm, 0.1 μm and 2 μm, 0.15 μm and 10 μm, 0.15 μm and 5 μm, 0.15 μm and 2 μm, 0.2 μm and 10 μm, 0.2 μm and 5 μm, 0.25 μm and 10 μm, 0.25 μm and 5 μm, 0.5 μm and 10 μm, 0.75 μm and 10 μm, 1 μm and 10 μm, 1 μm and 5 μm, 1 μm and 2 μm, 2 μm and 10 μm, 2 μm and 5 μm, or 5 μm and 10 μm. In some embodiments, the average pore size of the 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.

[0178] In some embodiments, the implantable element is capable of preventing material exceeding a certain size from passing through the hole or opening. In some embodiments, the implantable element is capable of preventing material greater than 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 from passing through.

[0179] Implantable elements (e.g., implantable elements as described herein) can be provided as preparations or compositions for implantation or administration to a subject. In some embodiments, at least 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the implantable elements in the preparations or compositions have characteristics as described herein, such as average pore size.

[0180] In some embodiments, the implantable element may be configured for or used for different time periods, ranging from minutes to years. For example, the implantable element may be configured for or used for about 1 hour to about 10 years. In some embodiments, the implantable element may be configured for or used for longer than about any of the following time periods: 1 to 24 hours; 1 to 7 days; 1 to 4 weeks; 1 to 24 months; 2 to 10 years, or longer. The implantable element may be configured to function within the expected implantation duration, for example, configured to resist the devitalization caused by the PFO for all or part of the expected duration.

[0181] In some embodiments, the implantable element can be easily removed from the subject, for example, without causing damage to the subject or causing significant damage to surrounding tissue. In one embodiment, the implantable element can be retrieved with minimal or no surgical separation of the implantable element from surrounding tissue, for example, by minimally invasive surgery, incision, removal or excision.

[0182] 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, WO 2017 / 075630, WO 2017 / 075631, WO 2018 / 067615, WO 2019 / 169333, or US2016-0030359.

[0183] 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 in whole or in part within the implantable element.

[0184] In some embodiments, the surface of the implantable element comprising cells (e.g., engineered cells) is chemically modified with a non-fibrotic compound (e.g., as shown in Table 2). In some embodiments, the surface includes the outer surface or inner surface of the implantable element. In some embodiments, the surface (e.g., outer surface) of the implantable element comprising cells (e.g., engineered cells) is chemically modified with a non-fibrotic compound (e.g., as shown in Table 2). In some embodiments, the surface (e.g., outer surface) is covalently linked to a non-fibrotic compound (e.g., as shown in Table 2).

[0185] Implantable element can be coated with non-fibrotic compound (for example, as shown in Table 2) or its pharmaceutically acceptable salt, or coated with polymer containing non-fibrotic compound (for example, as shown in Table 2) or its pharmaceutically acceptable salt. In one embodiment, non-fibrotic compound (for example, as shown in Table 2) is arranged on the surface (for example, inner surface or outer surface) of implantable element. In some embodiments, non-fibrotic compound (for example, as shown in Table 2) is arranged on the surface (for example, inner surface or outer surface) of the closure part associated with implantable element. In one embodiment, non-fibrotic compound (for example, as shown in Table 2) is evenly distributed on the surface. In one embodiment, non-fibrotic compound (for example, as shown in Table 2) is unevenly distributed on the surface.

[0186] In some embodiments, the implantable element (e.g., or its closure component) is coated (e.g., partially or completely covered) with a non-fibrotic compound (e.g., as shown in Table 2) or a polymer modified with a non-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof. In some embodiments, the implantable element (e.g., or its closure component) is coated with a single layer of a non-fibrotic compound (e.g., as shown in Table 2). In some embodiments, the implantable element is coated with multiple layers of a non-fibrotic compound (e.g., as shown in Table 2), for example, at least 2 layers, 3 layers, 4 layers, 5 layers, 10 layers, 20 layers, 50 layers or more layers.

[0187] In one embodiment, a first portion of the surface of the implantable element comprises a non-fibrotic compound (eg, as shown in Table 2), and a second portion of the implantable element lacks the compound, or has a significantly lower density of the compound.

[0188] In some embodiments, the implantable element is coated or chemically derivatized with a non-fibrotic compound (e.g., as shown in Table 2) or a material comprising a non-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof in a symmetrical manner. In some embodiments, the implantable element is coated or chemically derivatized with a non-fibrotic compound (e.g., as shown in Table 2) or a polymer modified with a non-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof in an asymmetrical manner. For example, an exemplary implantable element 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-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof.

[0189] Exemplary implantable elements coated or chemically derivatized with a non-fibrotic compound (e.g., as shown in Table 2) or a polymer modified with a non-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof can be prepared using any method known in the art, such as by self-assembly (e.g., via block copolymers, adsorption (e.g., competitive adsorption), phase separation, microfabrication, or masking).

[0190] In some embodiments, the implantable element comprises a surface that exhibits two or more different physicochemical properties (e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more different physicochemical properties).

[0191] In some embodiments, the coating or chemical derivatization of the surface of an exemplary implantable element with a non-fibrotic compound (e.g., as shown in Table 2), a polymer modified with a non-fibrotic compound (e.g., as shown in Table 2), or a pharmaceutically acceptable salt thereof is described as the average number of compounds attached per given area, such as 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 μm or square mm on or within the surface of the implantable element.

[0192] An implantable element comprising a non-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof may have a reduced immune response (e.g., a marker of immune response) compared to an otherwise identical implantable element that does not comprise a non-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof. The marker of immune response is one or more of: PFO, cathepsin levels, or a marker of immune response such as the level of TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-4, CCL2, or CCL4 as measured, for example, by ELISA. In some embodiments, the immune response to an implantable element comprising a non-fibrotic compound (e.g., as shown in Table 2) or a pharmaceutically acceptable salt thereof is reduced by at least about 1% and up to about 100%, for example, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99%. In some embodiments, the reduced immune response (e.g., a marker of an immune response) is measured after about 30 minutes, 1 hour, 6 hours, 12 hours, about 1 day, 2 days, 3 days or 4 days, about 1 week or 2 weeks, about 1 month, 2 months, 3 months, 6 months or more. In some embodiments, an implantable element comprising a non-fibrotic compound (e.g., as shown in Table 2) is coated with or encapsulated in a layer (e.g., a polymer layer) comprising a non-fibrotic compound (e.g., as shown in Table 2). In some embodiments, an implantable element comprises alginate modified with a non-fibrotic compound (e.g., as shown in Table 2) (e.g., a fibrotic compound described herein (e.g., as shown in Table 2)).

[0193] Implantable element can have smooth surface, or can include projection, depression, hole, slit or hole or its any combination.Described projection, depression, hole, slit or hole can be any size, for example, 10 μm to about 1nm, about 5 μm to about 1nm, about 2.5 μm to about 1nm, 1 μm to about 1nm, 500nm to about 1nm or about 100nm to about 1nm.Smooth surface or projection, depression, hole, slit or hole or its any combination can be coated or chemically derivatized with the polymer modified with no fibrotic compound (for example, as shown in Table 2), no fibrotic compound (for example, as shown in Table 2) or its pharmaceutically acceptable salt.

[0194] In one embodiment, the implantable element includes any of the polymers described herein modified with a non-fibrotic compound (eg, as shown in Table 2) or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, for example, as measured using a quantitative amine assay, the implantable element comprises 5% to 50% of the non-fibrotic compound (e.g., as shown in Table 2). In some embodiments, as measured using a quantitative amine assay, the implantable element comprises 10% to 50% of the non-fibrotic compound (e.g., as shown in Table 2), for example, 15% to 45% of the non-fibrotic compound (e.g., as shown in Table 2), 15% to 40% of the non-fibrotic compound (e.g., as shown in Table 2), 15% to 35% of the non-fibrotic compound (e.g., as shown in Table 2), 15% to 30% of the non-fibrotic compound (e.g., as shown in Table 2), 20% to 45% of the non-fibrotic compound (e.g., as shown in Table 2), 20% to 40% of the non-fibrotic compound (e.g., as shown in Table 2), 20% to 35% of the non-fibrotic compound (e.g., as shown in Table 2), or 20% to 30% of the non-fibrotic compound (e.g., as shown in Table 2).

[0196] In some embodiments, the implantable element comprises an alginate (e.g., any of the alginates described herein) modified with a non-fibrotic compound (e.g., as shown in Table 2).

[0197] In some embodiments, the implantable element comprises alginate modified with a compound shown in Table 2. In some embodiments, the implantable element comprises alginate modified with Compound 200. In some embodiments, the implantable element comprises alginate modified with Compound 218. In some embodiments, the implantable element comprises alginate modified with Compound 219. In some embodiments, the implantable element comprises alginate modified with Compound 224. In some embodiments, the implantable element comprises alginate modified with Compound 222.

[0198] Cells and therapeutic agents

[0199] The implantable element of the present disclosure may include a variety of different cell types (e.g., human cells), including but not limited to: adipocytes, epidermal cells, epithelial cells, endothelial cells, fibroblasts, 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 a mixture of one or more of any of the foregoing. Exemplary cell types include cell types described in WO 2017 / 075631 and WO2019 / 195055. In one embodiment, the implantable element described herein includes a plurality of cells. In one embodiment, a plurality of cells are in the form of a cell suspension before being encapsulated in an implantable element described herein. The cells in the suspension may take the form of a single cell (e.g., from a monolayer cell culture), or may be provided in another form, such as being arranged on a microcarrier (e.g., a bead or matrix) or as a three-dimensional aggregate of cells (e.g., a cell cluster or a spheroid). The cell suspension may include a plurality of cell clusters (e.g., as a spheroid) or a microcarrier. In some embodiments, the device does not contain any pancreatic islet cells, and does not contain any cells capable of producing insulin in a glucose-responsive manner.

[0200] The present disclosure is characterized by a cell that produces or can produce a therapeutic agent for preventing or treating a disease, disorder or illness described herein. In one embodiment, the cell is an engineered cell. In one embodiment, the cell is engineered to sense a stimulus (e.g., a chemical signal) and expresses a therapeutic agent in response to the stimulus. The therapeutic agent can be any biological substance, such as nucleic acid (e.g., nucleotides, DNA or RNA), polypeptide, lipid, sugar (e.g., monosaccharide, disaccharide, oligosaccharide or polysaccharide) or small molecule, each of which is further described in detail below. Exemplary therapeutic agents include those listed in WO 2017 / 075631 and WO2019 / 195055.

[0201] In some embodiments, cells (e.g., engineered cells) produce nucleic acids. The size of nucleic acids produced by cells as described herein may vary, and contain one or more nucleosides or nucleotides, for example, greater than 2, 3, 4, 5, 10, 25, 50 or more nucleosides or nucleotides. In some embodiments, nucleic acids are short fragments such as RNA or DNA, and can be used as reporter genes 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., vector, chromosomal DNA). In some embodiments, 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.

[0202] In some embodiments, the therapeutic agent is a peptide or polypeptide (e.g., protein), such as a hormone, enzyme, cytokine (e.g., proinflammatory cytokine or anti-inflammatory cytokine), growth factor, coagulation factor or lipoprotein. The peptide or polypeptide (e.g., protein, such as a hormone, growth factor, coagulation factor or coagulation factor, antibody molecule, enzyme, cytokine, cytokine receptor, or chimeric protein including cytokine or cytokine receptor) produced by cells in the implantable element may have a naturally occurring amino acid sequence, or may contain a variant of a naturally occurring sequence. The variant may be a naturally occurring or non-natural amino acid substitution, mutation, deletion or addition relative to a reference naturally occurring sequence. The naturally occurring amino acid sequence may be a polymorphic variant. The naturally occurring amino acid sequence may be a human or non-human amino acid sequence. In some embodiments, the naturally occurring amino acid sequence or its naturally occurring variant is a human sequence. In addition, the peptide or polypeptide (e.g., protein) used in the present invention may be modified in some way, such as by chemical or enzymatic modification (e.g., glycosylation, phosphorylation). In some embodiments, the peptide has about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, or 50 amino acids. In some embodiments, the protein has an average molecular weight (kD) of 5, 10, 25, 50, 100, 150, 200, 250, 500 or more.

[0203] In some embodiments, 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, adrenaline, glucagon, insulin, estrogen, progesterone and testosterone. In some embodiments, protein is insulin (e.g., insulin A chain, insulin B chain or proinsulin). In some embodiments, protein is growth hormone, such as human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, methionine-human growth hormone, dephenylalanine human growth hormone and porcine growth hormone. In some embodiments, protein is not insulin (e.g., insulin A chain, insulin B chain or proinsulin).

[0204] 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).

[0205] In some embodiments, the protein is a clotting factor or coagulation factor, such as a blood clotting factor or blood coagulation factor. In some embodiments, the protein is a protein that participates in coagulation, the process by which blood changes from a liquid to a solid or gel. Exemplary coagulation factors and clotting factors include factor I (e.g., fibrinogen), factor II (e.g., prothrombin), factor III (e.g., tissue factor), factor V (e.g., accelerogen, unstable 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., Hagemann factor), factor XIII (e.g., fibrin stabilizing factor), von Willebrand factor, prekallikrein, heparin cofactor II, high molecular weight kininogen (e.g., Fitzgerald factor), antithrombin III, and fibronectin. In some embodiments, the protein is an anticoagulant factor, such as protein C.

[0206] In some embodiments, 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 comprising at least one immunoglobulin variable domain sequence. The term "antibody molecule" includes, for example, a monoclonal antibody (including a full-length antibody with 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 and binds to a single epitope, such as a monospecific antibody molecule with multiple immunoglobulin variable domain sequences, and each immunoglobulin variable domain sequence binds to the same epitope.

[0207] In one embodiment, antibody molecule is a multispecific antibody molecule, for example, it comprises multiple immunoglobulin variable domain sequences, wherein the first immunoglobulin variable domain sequence in the multiple immunoglobulin variable domain sequences has binding specificity to the first epitope, and the second immunoglobulin variable domain sequence in the multiple immunoglobulin variable domain sequences has binding specificity to the second epitope. In one embodiment, the first epitope and the second epitope are in the same antigen, for example, on the same protein (or subunit of a multimeric protein). In one embodiment, the multispecific antibody molecule comprises the 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.

[0208] Various types of antibody molecules can be produced by cells in the implantable elements described herein, including complete immunoglobulins of any class, fragments thereof, and synthetic proteins containing at least the antigen-binding variable domains of antibodies. Antibody molecules can be antibodies, such as IgG antibodies, such as IgG1, IgG2, IgG3, or IgG4. Antibody molecules can be in the form of antigen-binding fragments, including Fab fragments, F(ab')2 fragments, single-chain variable regions, etc. Antibodies can be polyclonal or monoclonal (mAb). Monoclonal antibodies can include "chimeric" antibodies, in which a portion of the heavy chain and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, and the rest of the chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they specifically bind to the target antigen and / or exhibit the desired biological activity. In some embodiments, the antibody molecule is a single domain antibody (e.g., nanobody). Antibodies can also be modified by recombinant means, such as by the deletion, addition, or substitution of amino acids, to increase the efficacy of antibodies in mediating the desired function. Exemplary antibodies include anti-β-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., voranumab, fasitumab, tanezumab).

[0209] In some embodiments, the protein is a cytokine or cytokine receptor, or a chimeric protein comprising a cytokine or its receptor, including, for example, tumor necrosis factor alpha and beta, their receptors and their derivatives, renin; lipoprotein; colchicine; adrenocorticotropic hormone; vasopressin; somatostatin; lysine vasopressin; pancreatin; leuprolide; alpha-1-antitrypsin; atrial natriuretic factor; pulmonary surfactant; plasminogen activators other than tissue-type plasminogen activator (t-PA), such as urokinase; bombesin; thrombin; enkephalin; RANTES (regulatory activated, expressed and secreted by normal T cells); human macrophage inflammatory protein (MIP-1-α); serum albumins, such as human serum albumin; Müllerian inhibitory substance; relaxin A chain; relaxin B chain; prorelaxin; mouse gonadotropin-related peptide; chorionic gonadotropin; microbial proteins, such as beta-lactamase; DNA enzymes; inhibins; activins; receptors for hormones or growth factors; integrins; proteins A or D; rheumatoid factor; platelet-derived growth factor (PDGF); epidermal growth factor (EGF); transforming growth factors (TGF), such as TGF-α and T GF-β, including TGF-β1, TGF-β2, TGF-β3, TGF-β4 or TGF-β5; insulin-like growth factor-I and -II (IGF-I and IGF-II); des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding protein; CD proteins, such as CD-3, CD-4, CD-8 and CD-19; erythropoietin; osteoinductive factors; immunotoxins; interferons, such as interferon-α (e.g., interferon.α.2A), interferon-β, interferon-γ, interferon-λ and complex interferon; colony stimulating factor (CSF), such as M-CSF, GM-CSF and G-CSF; interleukin (IL), such as IL-1 to IL-10; superoxide dismutase; T cell receptor; surface membrane protein; decay accelerating factor; transporter; homing receptor; addressin; fertility inhibitors, such as prostaglandins; fertility promoters; regulatory proteins; antibodies (including fragments thereof) and chimeric proteins, such as immunoadhesins; precursors, derivatives, prodrugs and analogs of these compounds, and pharmaceutically acceptable salts of these compounds or their precursors, derivatives, prodrugs and analogs. Suitable proteins or peptides may be natural or recombinant, and include, for example, fusion proteins.

[0210] 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), CXCL2 (SDF1b), CXCL3 (SDF1c), CXCL4 (SDF1d), CXCL5 (RANTES), CCL6, CCL7, CCL8, CCL9 (CCL10), CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8(IL8), CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, XCL1, XCL2, TNFA, TN FB(LTA), TNFC(LTB), TNFSF4, TNFSF5(CD40LG), TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF13B, EDA, IL2, IL15, IL4, IL13, IL7, IL9, IL 21. IL3, IL5, IL6, IL11, IL27, IL30, IL31, OSM, LIF, CNTF, CTF1, IL12a, IL12b, IL23, IL27, IL35, IL14, IL16, IL32, IL34, IL10, IL22, IL19, IL20, IL24, IL26, IL29, IFNL1, IFNL2, IFNL3, IL28, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21, IFNB1, IF NK, IFNW1, IFNG, IL1A(IL1F1), IL1B(IL1F2), IL1Ra(IL1F3), IL1F5(IL36RN), IL1F6(IL36A), IL1F7(IL37), IL1F8(IL36B), IL1F9(IL36G), IL1F10(IL 38), 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, B mp8a, 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, G df7, Gdf9, Gm12597, Gm13271, Gm13275, Gm13276, Gm13280, Gm13283, Gm256 4. Gpi1, Grem1, Grem2, Grn, Hmgb1, Ifna11, Ifna12, Ifna9, Ifnab, Ifne, Il17a, Il23a, Il25, Il31, Iltifb, Inhba, Lefty1, Lefty2, Mstn, Nampt, Ndp, N odal, 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, adrenaline, melatonin, triiodothyronine, prostaglandins, leukotrienes, prostacyclin, thromboxane, islet amylin, Müllerian inhibitory factor or hormone, adiponectin, adrenocorticotropic hormone, angiotensin II vasopressin, arginine vasopressin, atrial natriuretic peptide, 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, 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 polypeptide, androgen, alpha-glucosidase (also known as acid maltase),Glycogen phosphorylase, glycogen debranching enzyme, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, carnitine palmitoyltransferase, carnitine and myoadenylate deaminase.

[0211] In some embodiments, the protein is a replacement therapy or a replacement protein. In some embodiments, the replacement therapy or replacement protein is a coagulation factor or a 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).

[0212] In some embodiments, the cell is engineered to express factor VIII, e.g., recombinant factor VIII. In some embodiments, the cell is derived from human tissue and is engineered to express factor VIII, e.g., recombinant factor VIII. In some embodiments, the recombinant factor VIII is a recombinant factor VIII with a B domain deletion (FVIII-BDD).

[0213] In some embodiments, the cell is derived from human tissue and is engineered to express factor IX, such as recombinant factor IX. In some embodiments, the cell is engineered to express factor IX, such as wild-type human factor IX (FIX) or a polymorphic variant thereof. In some embodiments, the cell is engineered to express a gain-of-function (GIF) variant of a wild-type FIX protein (FIX-GIF), wherein the GIF variant has a higher specific activity than the corresponding wild-type FIX.

[0214] In some embodiments, the replacement therapy or replacement protein is an enzyme, such as α-galactosidase, α-L-iduronidase (IDUA), or N-sulfoglucosamine sulfohydrolase (SGSH). In some embodiments, the replacement therapy or replacement protein is an enzyme, such as α-galactosidase A (e.g., comprising a naturally occurring human α-galactosidase A amino acid sequence or a variant thereof). In some embodiments, the replacement therapy or replacement protein is a cytokine or an antibody.

[0215] In some embodiments, the therapeutic agent is a sugar, such as a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide. In some embodiments, sugar includes triose, tetrose, pentose, hexose or heptose moieties. In some embodiments, sugar includes linear monosaccharides or cyclized monosaccharides. In some embodiments, sugar includes glucose, galactose, fructose, rhamnose, mannose, arabinose, glucosamine, galactosamine, sialic acid, mannosamine, glucuronic acid, galacturonic acid, mannuronic acid or guluronic acid moieties. In some embodiments, sugar is attached to protein (e.g., N-linked polysaccharides or O-linked polysaccharides). Exemplary sugars include glucose, galactose, fructose, mannose, rhamnose, sucrose, ribose, xylose, sialic acid, maltose, straight-chain starch, inulin, oligofructose, oligogalactose, mannan, lectin, pectin, starch, cellulose, heparin, hyaluronic acid, chitin, amylopectin or glycogen. In some embodiments, the therapeutic agent is a sugar alcohol.

[0216] In some embodiments, the therapeutic agent is a lipid. The lipid can be hydrophobic or amphipathic, and can form a tertiary structure (such as liposomes, vesicles or membranes) or be inserted into liposomes, vesicles or membranes. The lipid can include fatty acids, glycerolipids, glycerophospholipids, sterol lipids, isopentenol lipids, sphingolipids, glycolipids, polyketides or sphingolipids. The example of the lipid produced by cells as described herein includes anandamide, docosahexaenoic acid, prostaglandins, leukotrienes, thromboxanes, eicosanoids, triglycerides, cannabinoids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, ceramide, sphingomyelin, cerebrosides, gangliosides, estrogen, androsterone, testosterone, cholesterol, carotenoids, quinones, hydroquinone or ubiquinone.

[0217] In some embodiments, the therapeutic agent is a small molecule. Small molecules may include natural products produced by cells. In some embodiments, small molecules have poor availability or do not meet the Lipinski five rules (a set of guidelines for estimating whether small molecules may become human oral active drugs; see, for example, Lipinski, CA et al. (2001) Adv Drug Deliv 46: 2-36). Exemplary small molecule natural products include antibacterial drugs (e.g., calumonan, daptomycin, fidaxomycin, fosfomycin, ipamycin, sulphomemycin, mikamycin, mopicin, netilmicin sulfate, teicoplanin, thiomycin, rifamycin, erythromycin, vancomycin), antiparasitic drugs (e.g., artemisinin, ivermectin), anticancer drugs (e.g., doxorubicin, aclarubicin, aminolevulinic acid, arglabin, homoharringtonine, paclitaxel, pentostatin, peplomycin, romidepsin , trabectin, actinomycin D, bleomycin, chromomycin A, daunorubicin, leucovorin, neocarcinogen, streptozotocin, trabectin, vinblastine, vincristine), antidiabetic drugs (e.g., voglibose), central nervous system drugs (e.g., levodopa, galantamine, zicontide), statins (e.g., mevastatin), antifungal drugs (e.g., fumagillin, cyclosporin), 1-deoxynojirimycin and theophylline, sterols (cholesterol, estrogen, testosterone). Other small molecule natural products are described in Newman, DJ And and Cragg, M. (2016) J Nat Prod 79: 629-661 and Butler, MS et al. (2014) Nat Prod Rep 31: 1612-1661.

[0218] In some embodiments, the cell is engineered to synthesize a non-protein or non-peptide small molecule. For example, in one embodiment, the cell can produce a statin (e.g., taurostatin, pravastatin, fluvastatin, or atorvastatin).

[0219] 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 considered by those skilled in the art to have an immunostimulatory effect, that is, they can stimulate an immune response or provide effective immunity to the organism or molecule from which they are derived. Antigens can be nucleic acids, peptides, proteins, sugars, lipids, or combinations thereof.

[0220] Cells (e.g., engineered cells, such as engineered cells described herein) can produce a single therapeutic agent or multiple therapeutic agents. In some embodiments, cells produce a single therapeutic agent. In some embodiments, cell clusters include cells that produce a single therapeutic agent. In some embodiments, at least about 1% or about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% of cells in a cluster produce a single therapeutic agent (e.g., a therapeutic agent described herein). In some embodiments, cells produce multiple therapeutic agents, such as at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 therapeutic agents. In some embodiments, cell clusters include cells that produce multiple therapeutic agents. In some embodiments, at least about 1%, or about 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the cells in a cluster produce a plurality of therapeutic agents (e.g., a therapeutic agent described herein).

[0221] The therapeutic agent may be related 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 (e.g., as a prodrug). In the latter case, the therapeutic agent can be activated by a downstream agent (e.g., an enzyme). In some embodiments, the therapeutic agent is not secreted or released from the cell, but is maintained in the cell. For example, the therapeutic agent can be an enzyme that participates in the detoxification or metabolism of an unwanted substance, and the detoxification or metabolism of an unwanted substance occurs in the cell.

[0222] Treatment

[0223] Described herein are methods of 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 pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of a disease, disorder, or condition. In some embodiments, the methods described herein prevent or mitigate the occurrence of a disease, disorder, or condition. In some embodiments, the subject is a human.

[0224] In some embodiments, the disease, disorder, or condition affects a body system, such as the nervous system (e.g., peripheral or central nervous system), vascular system, skeletal system, respiratory system, endocrine system, lymphatic system, reproductive system, or 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, muscle, ovaries, uterus, vagina, or penis.

[0225] In some embodiments, the disease, disorder or condition is a neurodegenerative disease, diabetes (type 1 or type 2), heart disease, an autoimmune disease, cancer, liver disease, a lysosomal storage disease, a blood coagulation disorder or a coagulation disorder, an orthopedic disorder, an amino acid metabolism disorder.

[0226] In some embodiments, the disease, disorder or condition is a neurodegenerative disease. Exemplary neurodegenerative diseases include Alzheimer's disease, Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and cerebral palsy (CP), dentatorubral nucleus-globus pallidus Lewy body atrophy (DRPLA), neuronal intranuclear hyaline inclusion disease (NIHID), Lewy body dementia, Down syndrome, Hallervorden-Spatz disease, prion disease, argyrophilic grain dementia, corticobasal degeneration, dementia pugilistica, diffuse neurofibrillary tangles, Gerstmann-Strauss-Scheinker disease, Jacob-Kreutzfeldt disease, Niemann-Pick disease type 3, progressive supranuclear palsy, subacute sclerosing panencephalitis, spinocerebellar ataxia, Pick's disease and dentatorubral nucleus-globus pallidus Lewy body atrophy.

[0227] In some embodiments, the disease, disorder, or condition is an autoimmune disease, such as scleroderma, multiple sclerosis, lupus, or allergy.

[0228] In some embodiments, the disease is a liver disease, such as hepatitis B, hepatitis C, cirrhosis, NASH.

[0229] 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.

[0230] In some embodiments, the disease, disorder, or condition is an orthopedic condition. Exemplary orthopedic conditions include osteoporosis, osteonecrosis, Paget's disease, or a bone fracture.

[0231] 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, sialic acid storage disease, Sanfilippo syndrome (also known as mucopolysaccharidosis type IIIA (MPS3A)), multiple sulfatase deficiency, Mara-La syndrome, metachromatic leukodystrophy, Krabbe disease, Scheher-Ellison syndrome, Hurler-Schwein syndrome, Sly syndrome, hyaluronidase deficiency, Pompe disease, Danon disease, gangliosidosis, or Morquio syndrome.

[0232] In some embodiments, the disease, disorder or condition is a blood coagulation disorder or coagulation disorder. Exemplary blood coagulation 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 afibrinogenemia.

[0233] In some embodiments, the disease, condition, or disorder is an amino acid metabolism disorder, such as phenylketonuria, tyrosinemia (eg, type 1 or type 2), alkaptonuria, homocystinuria, hyperhomocysteinemia, maple syrup urine disease.

[0234] In some embodiments, the disease, disorder or condition is a fatty acid metabolism disorder, such as hyperlipidemia, hypercholesterolemia, galactosemia.

[0235] In some embodiments, the disease, disorder, or condition is a disorder of purine or pyrimidine metabolism, such as Lesch-Nyhan syndrome.

[0236] In some embodiments, the disease, disorder, or condition is not type I diabetes and / or is not type II diabetes.

[0237] The invention further includes methods for identifying a subject having or suspected of having a disease, disorder or condition as described herein, and after such identification, administering to the subject an implantable element comprising cells (e.g., optionally encapsulated by a closure member and optionally modified with a compound of formula (I) as described herein, or a composition thereof). In one embodiment, the subject is a human.

[0238] List of implementation plans

[0239] 1. A polysaccharide polymer comprising a sugar monomer, wherein the sugar monomer comprises a hydroxyl-modifying agent covalently bound to a hydroxyl moiety.

[0240] 2. A polysaccharide polymer as described in embodiment 1, wherein the hydroxyl modifier comprises an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amine, amide, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl or heterocyclyl moiety.

[0241] 3. The polysaccharide polymer of any one of embodiments 1-2, wherein the polysaccharide polymer is selected from the group consisting of hyaluronate, alginate, cellulose, chitosan, chitin, amylose, dextran, starch, glycogen, chondroitin and pectin.

[0242] 4. A polysaccharide polymer as described in any one of embodiments 1-3, wherein 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.

[0243] 5. The polysaccharide polymer of any one of embodiments 1-4, wherein the sugar monomer is mannuronic acid or guluronic acid.

[0244] 6. The polysaccharide polymer of any one of embodiments 1-5, wherein the sugar monomer has a structure of formula (I):

[0245] 6. The polysaccharide polymer of any one of embodiments 1-5, wherein the sugar monomer has a structure of formula (Ia):

[0246]

[0247] or a pharmaceutically acceptable salt thereof, wherein:

[0248] X is O, NR 6 or S;

[0249] R 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein alkylene, alkenylene, alkynylene, heteroalkylene and haloalkylene are optionally substituted by one or more R 8 replace;

[0250] R 2 and R 3 are independently hydrogen, C1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 , wherein each alkylene or alkenyl group is optionally substituted by one or more R 10 Replace, and R 2 and R 3 Not every one of them is hydrogen;

[0251] Each R 4 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace;

[0252] R 5 It 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, non-fibrous compounds or peptides, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally replaced by one or more R 8 replace;

[0253] R 6 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl or C 1-6 haloalkyl, wherein alkyl, heteroalkyl and haloalkyl are optionally substituted with one or more R 10 replace;

[0254] R 7a and R 7b are independently hydrogen, C 1-6 alkyl, cycloalkyl or heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R 10 replace;

[0255] 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 substituted by 0-12 R 11 replace;

[0256] 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 peptide, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is substituted by 0-12 R 11 replace;

[0257] 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 peptide; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and optionally substituted by one or more R 11 replace;

[0258] or R B and R C Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or heteroaryl ring, each of which is optionally substituted by one or more R 10 replace;

[0259] R 9 are peptides or non-fibrotic compounds;

[0260] Each R 10 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 , wherein each alkyl, heteroalkyl and haloalkyl group is optionally substituted with one or more R 11 replace; and

[0261] Each R 11 Independently for C 1-6 Alkyl, halogen, oxo, cycloalkyl or heterocyclyl.

[0262] 7. The polysaccharide polymer of embodiment 6, wherein X is O.

[0263] 8. A polysaccharide polymer as described in any one of embodiments 6-7, wherein R 1 It's O.

[0264] 9. A polysaccharide polymer as described in any one of embodiments 6-8, wherein R 5 It is C(O)OR A or C(O)N(R C )(R D ).

[0265] 10. The polysaccharide polymer according to embodiment 9, wherein R 5 is C(O)N(R C )(R D), and R C and R D Each is independently hydrogen, a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2), or a peptide (eg, an RGD peptide).

[0266] 11. The polysaccharide polymer according to embodiment 10, wherein R C and R D one of is independently hydrogen, and R C and R D The other of the is independently a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2) or a peptide (eg, an RGD peptide).

[0267] 12. A polysaccharide polymer as described in any one of embodiments 6-11, wherein R 2 is hydrogen or C(O)-C 1-6 Alkylene-R 9 .

[0268] 13. A polysaccharide polymer as described in any one of embodiments 6-12, wherein R 3 is hydrogen or C(O)-C 1-6 Alkylene-R 9 .

[0269] 14. A polysaccharide polymer as described in any one of embodiments 6-13, wherein R 2 and R 3 One of them is independently C(O)-C 1-6 Alkylene-R 9 , and R 2 and R 3 The other of the R is independently hydrogen.

[0270] 15. A polysaccharide polymer as described in any one of embodiments 6-14, wherein R 9 It is a non-fibrotic compound.

[0271] 16. The polysaccharide polymer of any one of embodiments 1-15, wherein the sugar monomer has a structure of formula (Ia):

[0272]

[0273] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 5 and each of its subvariables are as defined in Embodiment 6.

[0274] 17. The polysaccharide polymer of any one of embodiments 1-16, wherein the sugar monomer has a structure of formula (Ib):

[0275]

[0276] or a pharmaceutically acceptable salt thereof, wherein R 9 and its subvariants as defined in claim 6, and R 3a is hydrogen, and n is 1, 2, 3, 4 or 5.

[0277] 18. The polysaccharide polymer of any one of embodiments 1-17, wherein the sugar monomer has a structure of formula (Ic):

[0278]

[0279] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R C , R D and each of its subvariables are as defined in Embodiment 6.

[0280] 19. The polysaccharide polymer of any one of embodiments 1-18, wherein the sugar monomer has the structure of formula (Id):

[0281]

[0282] or a pharmaceutically acceptable salt thereof, wherein R 9 , R C , R D and each of its subvariables is as defined in Embodiment 6, and R 3a is hydrogen, and n is 1, 2, 3, 4 or 5.

[0283] 20. The polysaccharide polymer according to embodiment 17 or 19, wherein R 9 It is a non-fibrotic compound.

[0284] 21. The polysaccharide polymer of embodiment 17 or 19, wherein n is 2.

[0285] 22. The polysaccharide polymer of any one of embodiments 1-21, wherein the sugar monomer has a structure of formula (Ie):

[0286]

[0287] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 5 and each of its subvariables is as defined in Embodiment 6;

[0288] P 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R12 replace;

[0289] L 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace;

[0290] Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace;

[0291] R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo;

[0292] each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0293] R 7a and R 8 As defined in embodiment 6.

[0294] 23. The polysaccharide polymer of any one of embodiments 1-22, wherein the sugar monomer has a structure of formula (If):

[0295]

[0296] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 12 , R C , R D and each of its subvariables is as defined in Embodiment 6;

[0297] P 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 12 replace;

[0298] L 1 does not exist, C 1-6 Alkylene, C2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace;

[0299] Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace;

[0300] R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo;

[0301] each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0302] R 7a and R 8 As defined in embodiment 6.

[0303] 24. The polysaccharide of embodiment 22 or 23, wherein P 1 is a heteroaryl group (eg, a triazolyl group).

[0304] 25. The polysaccharide polymer of embodiment 24, wherein P 1 yes Where R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo.

[0305] 26. A polysaccharide polymer as described in any one of embodiments 22-25, wherein L 1 Does not exist or C 1-6 Alkylene (e.g., -CH2-).

[0306] 27. A polysaccharide polymer as described in any one of embodiments 22-26, wherein Z 1 is an aryl group, a heteroaryl group or a heterocyclic group.

[0307] 28. The polysaccharide polymer of embodiment 22 or 23, wherein Z1 It is a heterocyclic group.

[0308] 29. The polysaccharide polymer according to embodiment 28, wherein Z 1 yes

[0309] 30. The polysaccharide polymer of any one of embodiments 1-29, wherein the non-fibrotic compound is selected from the moieties in Table 2.

[0310] 31. The polysaccharide polymer of any one of embodiments 1-30, wherein the peptide comprises the sequence RGD.

[0311] 32. The polysaccharide of any one of embodiments 1-31, wherein the polysaccharide polymer is alginate.

[0312] 33. The polysaccharide of embodiment 32, wherein the alginate is high guluronic acid (G) alginate or high mannuronic acid (M) alginate.

[0313] 34. The polysaccharide of any one of embodiments 32-33, wherein the alginate comprises an increase in N% (compared to the unmodified polymer) from 0.1 wt% to 10 wt% N, wherein N% is determined by elemental analysis.

[0314] 35. The polysaccharide of any one of embodiments 32-34, wherein the alginate comprises an increase in N% (compared to the unmodified polymer) of 1 wt% to 10 wt% N, wherein N% is determined by elemental analysis.

[0315] 36. A polysaccharide as described in any of embodiments 32-35, wherein the alginate comprises an increase in N% (compared to the unmodified polymer) from 2 wt% to 8 wt% N, wherein N% is determined by elemental analysis and corresponds to the amount of compound of formula (I) in the modified alginate.

[0316] 37. The polysaccharide of any one of embodiments 1-36, wherein the polysaccharide comprises a plurality of sugar monomers comprising a hydroxyl-modifying agent covalently bound to a hydroxyl moiety.

[0317] 38. An alginate comprising mannuronic acid or guluronic acid monomers, wherein the mannuronic acid or guluronic acid monomers comprise a hydroxyl modifying agent covalently bound to the hydroxyl moiety.

[0318] 39. The alginate of embodiment 38, wherein the hydroxyl modifier comprises an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, haloalkoxy, ester, ether, carbamate, aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety.

[0319] 40. The alginate of any one of embodiments 38-39, wherein the alginate comprises a monomer having a structure of formula (I):

[0320]

[0321] or a pharmaceutically acceptable salt thereof, wherein:

[0322] X is O, NR 6 or S;

[0323] R 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein alkylene, alkenylene, alkynylene, heteroalkylene and haloalkylene are optionally substituted by one or more R 8 replace;

[0324] R 2 and R 3 are independently hydrogen, C 1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 , wherein each alkylene or alkenyl group is optionally substituted by one or more R 10 Replace, and R 2 and R 3 Not every one of them is hydrogen;

[0325] Each R 4 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace;

[0326] R 5 It 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, non-fibrous compounds or peptides, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally replaced by one or more R 8 replace;

[0327] R 6 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl or C 1-6 haloalkyl, wherein alkyl, heteroalkyl and haloalkyl are optionally substituted with one or more R 10 replace;

[0328] R 7a and R 7b are independently hydrogen, C 1-6 alkyl, cycloalkyl or heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R 10 replace;

[0329] 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 )(RD )、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 substituted by 0-12 R 11 replace;

[0330] 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 peptide, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is substituted by 0-12 R 11 replace;

[0331] 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 peptide; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and optionally substituted by one or more R 11 replace; or

[0332] R B and R C Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or heteroaryl ring, each of which is optionally substituted by one or more R 10 replace;

[0333] R 9 are peptides or non-fibrotic compounds;

[0334] Each R 10 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 , wherein each alkyl, heteroalkyl and haloalkyl group is optionally substituted with one or more R 11replace; and

[0335] Each R 11 Independently for C 1-6 Alkyl, halogen, oxo, cycloalkyl or heterocyclyl.

[0336] 41. The alginate of embodiment 40, wherein X is O.

[0337] 42. The alginate of any one of embodiments 40-41, wherein R 1 It's O.

[0338] 43. The alginate of any one of embodiments 40-42, wherein R 5 It is C(O)OR A or C(O)N(R C )(R D ).

[0339] 44. The alginate of any one of embodiments 40-43, wherein R 5 is C(O)N(R C )(R D ), and R C and R D Each is independently hydrogen, a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2), or a peptide (eg, a peptide provided in Table X).

[0340] 45. The alginate of any one of embodiments 40-44, wherein R C and R D one of is independently hydrogen, and R C and R D The other of the is independently a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2) or a peptide (eg, a peptide provided in Table X).

[0341] 46. ​​The alginate of any one of embodiments 40-45, wherein R 2 is hydrogen or C 1-6 Alkylene-S(O)2-R 9 .

[0342] 47. The alginate of any one of embodiments 40-46, wherein R 3 is hydrogen or C 1-6 Alkylene-S(O)2-R 9 .

[0343] 48. The alginate of any one of embodiments 40-47, wherein R 2 and R 3 One of them is independently C 1-6Alkylene-S(O)2-R 9 , and R 2 and R 3 The other of the R is independently hydrogen.

[0344] 49. The alginate of any one of embodiments 40-48, wherein R 9 It is a non-fibrotic compound.

[0345] 50. The alginate of any one of embodiments 40-49, wherein the monomer has a structure of formula (Ia):

[0346]

[0347] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 5 and each of its subvariables is as defined in Embodiment 40.

[0348] 51. The alginate of any one of embodiments 40-50, wherein the monomer has a structure of formula (Ib):

[0349]

[0350] or a pharmaceutically acceptable salt thereof, wherein R 9 and its subvariables are as defined in Embodiment 40, and R 3a is hydrogen, and n is 1, 2, 3, 4 or 5.

[0351] 52. The alginate of any one of embodiments 40-51, wherein the monomer has a structure of formula (Ic):

[0352]

[0353] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R C , R D and each of its subvariables is as defined in Embodiment 40.

[0354] 53. The alginate of any one of embodiments 40-52, wherein the monomer has the structure of formula (Id):

[0355]

[0356] or a pharmaceutically acceptable salt thereof, wherein R 9 , R C , R Dand each of its subvariables is as defined in Embodiment 40, and R 3a is hydrogen, and n is 1, 2, 3, 4 or 5.

[0357] 54. A salt as claimed in claim 51 or 53, wherein R 9 It is a non-fibrotic compound.

[0358] 55. An alginate as claimed in claim 51 or 53 wherein n is 2 and m is 1.

[0359] 56. The alginate of any one of embodiments 40-55, wherein the monomer has a structure of formula (Ie):

[0360]

[0361] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 5 and each of its subvariables is as defined in Embodiment 40;

[0362] P 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 12 replace;

[0363] L 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace;

[0364] Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace;

[0365] R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo;

[0366] p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

[0367] R 7a and R 8 As defined in embodiment 40.

[0368] 57. The alginate of any one of embodiments 40-56, wherein the monomer has a structure of formula (If):

[0369]

[0370] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 12 , R C , R D and each of its subvariables is as defined in Embodiment 40;

[0371] P 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 12 replace;

[0372] L 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace;

[0373] Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace;

[0374] R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo;

[0375] p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

[0376] R 7a and R 8 As defined in embodiment 40.

[0377] 58. The alginate of embodiment 56 or 57, wherein P 1 is a heteroaryl group (eg, a triazolyl group).

[0378] 59. The alginate of embodiment 58, wherein P 1 yes Where R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo.

[0379] 60. The alginate of any one of embodiments 57-58, wherein L 1 Does not exist or C 1-6 Alkylene (e.g., -CH2-).

[0380] 61. The alginate of any one of embodiments 57-60, wherein Z 1 is an aryl group, a heteroaryl group or a heterocyclic group.

[0381] 62. The alginate of embodiment 61, wherein Z 1 It is a heterocyclic group.

[0382] 63. A salt as claimed in claim 62, wherein Z 1 yes

[0383] 64. The alginate of any one of embodiments 40-65, wherein the non-fibrotic compound is selected from the group consisting of those in Table 1.

[0384] 65. A hydrogel comprising the polysaccharide polymer of any one of embodiments 1-39 or the alginate of any one of embodiments 40-64.

[0385] 66. An implantable element comprising the polysaccharide polymer of any one of embodiments 1-39, the alginate of any one of embodiments 40-64, or the hydrogel of embodiment 65.

[0386] 67. A pharmaceutical composition comprising the polysaccharide polymer of any one of embodiments 1-39, the alginate of any one of embodiments 40-64 or the hydrogel of claim 65, and a pharmaceutically acceptable excipient.

[0387] Example

[0388] In order to more fully understand the invention described herein, 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 the examples should not be interpreted in any way as limiting their scope.

[0389] The compounds provided herein, modified polymers, implantable elements and compositions thereof can be prepared from readily available starting materials using modifications of the specific synthetic schemes well known to those skilled in the art as described below. It should be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary according to the specific reactants or solvents used, but such conditions may be determined by those skilled in the art through conventional optimization procedures.

[0390] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from reacting undesirably. The selection of protecting groups suitable for specific functional groups and suitable conditions for protection and deprotection is well known in the art. For example, many protecting groups and their introduction and removal are described in Greene et al., Protecting Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991 and in the references cited therein.

[0391] Any of the strategies described below may be used to prepare the exemplary compounds, modified polymers, implantable devices, and compositions of the invention.

[0392] Example 1: Synthesis of Exemplary Compounds

[0393] General solution

[0394] The following procedures describe methods for preparing exemplary compounds of chemically modified implantable elements. The compounds provided herein can be prepared from readily available starting materials using modifications of the specific synthetic schemes well known to those skilled in the art as described below. It should be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary according to the specific reactants or solvents used, but such conditions may be determined by those skilled in the art by conventional optimization procedures.

[0395] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from reacting undesirably. The selection of protecting groups suitable for specific functional groups and suitable conditions for protection and deprotection is well known in the art. For example, many protecting groups and their introduction and removal are described in Greene et al., Protecting Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991 and in the references cited therein.

[0396] Synthesis of compound 100

[0397]

[0398] To TBA-alginate (0.89g, 1.47mmol) and anhydrous DMF (15mL) in 100mL round-bottomed flask, add TBAF 1M in THF (2mL), stir until evenly.Add triethylamine (615uL, 4.41mmol), then add (methyl) acryloyl chloride (1.76mmol).Mixture was stirred at room temperature for 3 hours.In another 40mL glass vial, a certain nucleophilic reagent (3mmol) without fibrosis compound amine was dissolved in dimethylformamide (8mL).Amine solution is added in main mixture and stirred overnight at room temperature, then transferred to the flask containing 150mL EtOAc.Gained suspension is stirred for a while, then filtered by 60mL disposable filter, and washed with acetone (50mL x 4), solid is obtained.

[0399] The 1:1 mixture (15mL) of EtOH:0.6M HCl is then used to process wet solid, and at room temperature stirred for 4 hours.Suspension is filtered on 60mL disposable filter, and washed with acetone (50mL x 4), then at room temperature in 1N NaHCO (15mL) in stirring 1-4 hour.The reaction solution is diluted to about 100mL with saline, purified by tangential flow filtration system (MWCO 10K) with saline (about 1L), pure water (about 1L) subsequently, and finally freeze drying obtains the product in solid.By ultimate analysis, final modified alginate is analyzed, indicating 5.0% nitrogen, 36.3% carbon and 1.9% sulphur.

[0400] Synthesis of compound 102

[0401]

[0402] The reaction was performed using the conditions outlined for compound 100. The final modified alginate was analyzed by elemental analysis indicating 3.8% nitrogen, 36.4% carbon and 1.4% sulfur.

[0403] Synthesis of compound 104

[0404]

[0405] The reaction was performed using the conditions outlined for compound 100. The final modified alginate was analyzed by elemental analysis indicating 4.7% nitrogen, 35.6% carbon and 2.1% sulfur.

[0406] Synthesis of compound 106

[0407]

[0408] The reaction was performed using the conditions outlined for compound 100. The final modified alginate was analyzed by elemental analysis indicating 4.3% nitrogen, 36.2% carbon and 1.7% sulfur.

[0409] Synthesis of compound 108

[0410]

[0411] The reaction was performed using the conditions outlined for compound 100. The final modified alginate was analyzed by elemental analysis indicating 5.1% nitrogen, 37.1% carbon, and 0% sulfur.

[0412] Synthesis of compound 110

[0413]

[0414] The reaction was performed using the conditions outlined for compound 108. The final modified alginate was analyzed by elemental analysis indicating 4.7% nitrogen, 39.0% carbon, and 0% sulfur.

[0415] Synthesis of compound 112

[0416]

[0417] To TBA-alginate (0.89g, about 1.47mmol / monomer) and DMSO (15mL) in 100mL round bottom, add TBAF 1M in THF (about 2mL), and at room temperature stir until evenly.Add triethylamine (615uL, 4.41mmol), then dropwise add activator (1.76mmol).Solution was stirred at room temperature for 30 minutes, then heated to 55 ℃ and kept for 10 minutes.Amine (3mmol) is dissolved in DMSO (5mL) separately, then added in main mixture at 55 ℃ and stirred 4 hours, cooled to room temperature and spent the night.Mixture is poured in 150mL EtOAc, then gained suspension is stirred for a while, filtered on 60mL disposable filter, and washed with acetone (50mL x 4), solid is obtained.Then solid is processed with 1:1 mixture (15mL) of EtOH:0.6M HCl, and at room temperature stirred 4 hours. The suspension is filtered on 60mL disposable filter, and washed with acetone (50mL x 4). Gained solid is stirred at room temperature for 0.5-1 hour in 1N NaHCO (15mL). The solution is diluted to about 100mL with saline, purified by tangential flow filtration system (MWCO 10K) with saline (about 1L), pure water (about 1L) subsequently, and finally freeze-dried to obtain the final product in solid. By elemental analysis, the final modified alginate is analyzed, indicating 1.2% nitrogen, 32.3% carbon and 0.5% sulphur.

[0418] Synthesis of compound 116

[0419]

[0420] The reaction was performed using the conditions outlined for compound 112. The final modified alginate was analyzed by elemental analysis indicating 1.1% nitrogen, 32.7% carbon, and 0.9% sulfur.

[0421] Synthesis of compound 118

[0422]

[0423] The reaction was performed using the conditions outlined for compound 112. The final modified alginate was analyzed by elemental analysis indicating 1.7% nitrogen, 32.5% carbon, and 0.9% sulfur.

[0424] Synthesis of compound 120

[0425]

[0426] The reaction was performed using the conditions outlined for compound 112. The final modified alginate was analyzed by elemental analysis indicating 1.6% nitrogen, 31.9% carbon, and 0.7% sulfur.

[0427] Synthesis of compound 124

[0428]

[0429] The reaction was performed using the conditions outlined for compound 112. The final modified alginate was analyzed by elemental analysis indicating 2.8% nitrogen, 40.5% carbon and 1.5% sulfur.

[0430] Synthesis of compound 128

[0431]

[0432] The reaction was performed using the conditions outlined for compound 112. The final modified alginate was analyzed by elemental analysis indicating 1.4% nitrogen, 32.7% carbon, and 0.0% sulfur.

[0433] Synthesis of compound 130

[0434]

[0435] The reaction was performed using the conditions outlined for compound 112. The final modified alginate was analyzed using elemental analysis indicating 0.31% nitrogen, 32.31% carbon, and 0.31% sulfur.

[0436] Example 2: Preparation of hydrogel capsules containing modified polysaccharide polymers

[0437] The present embodiment describes the preparation of a two-compartment hydrogel capsule comprising a modified polysaccharide polymer as described herein. The first 5% (w / w) alginate solution comprising compound 100 is prepared by dissolving 0.25g of modified alginate in 4.75g of saline. The solution is mixed overnight until the solution is uniform. The second alginate solution (3% (w / w)) modified with RGD peptide is also prepared by dissolving 0.25g of RGD alginate in 8.3g of saline and mixing overnight until uniform. 2.16g of 3% (w / w) RGD alginate solution is added to 5% (w / w) modified alginate solution and mixed. The modified alginate solution is then loaded into two separate 10mL syringes.

[0438] The Matsusada high voltage generator was then connected to a coaxial needle (No. 17) in a needle holder and to a grounding ring. The Luer lock connector on the side of the needle was connected to an 8-inch tube extension, which was connected to a syringe loaded with a first (5% (w / w)) alginate solution, which was intended to be an outer compartment. The Luer lock connector at the top was also connected to an 8-inch tube extension, which was connected to a syringe loaded with a second (3% (w / w)) RGD alginate, which was intended to be an inner compartment. Using a syringe pump, the first and second alginate solutions were pumped into a glass dish containing 250mL20mM BaCl2 solution for crosslinking and hydrogel capsule formation. The crosslinked hydrogel capsules were then collected in a glass dish, washed with a buffer solution (15 times), and then imaged to assess morphology and spheroid strength. The quality of the hydrogel capsules containing modified polysaccharide polymers and non-fibrotic compound 219 was monitored using a bright field microscope, which revealed a smooth surface and no defects. The stability and strength of the hydrogel capsules were further tested using texture analysis (eg, as described in Example 7). The fracture data of the hydrogel capsules comprising the modified polysaccharide polymer composed of monomers of Compound 219 are shown in Table 4 below.

[0439] Table 4. Fragmentation data of hydrogels modified with compound 219

[0440] Sphere batch number Initial breaking strength (g) Crispness(mm) 1 20.61 0.47 2 14.83 0.42 3 17.28 0.41 4 15.05 0.36 5 20.48 0.49 6 16.75 0.37 7 21.00 0.46 8 14.15 0.37 9 28.08 0.51 10 11.52 0.34 11 15.13 0.39 12 15.65 0.40 13 15.50 0.39 14 7.38 0.29 15 14.24 0.36 16 19.82 0.41 17 12.22 0.43 18 20.09 0.41 19 19.32 0.41 20 19.10 0.41

[0441] Example 3: Preparation of exemplary cells for encapsulation in hydrogel capsules

[0442] Engineered ARPE-19 cells for encapsulation as single cells.

[0443] ARPE-19 cells engineered to express a therapeutic agent, such as a blood clotting factor (eg, FVIII or FIX protein), can be cultured according to any method known in the art, such as according to the following protocol.

[0444] 75cm 2The 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 / 0.53mM EDTA solution ("trypsin EDTA") to remove all traces of serum containing trypsin inhibitors. 2-3mL of trypsin EDTA solution is added to the flask, and the cells are observed under an inverted microscope until the cell layer is dispersed, usually between 5-15 minutes. In order to avoid agglomeration, cells are carefully handled, and the knocking or shaking flask during dispersion is minimized. If the cells are not separated, the flask is placed at 37°C to promote dispersion. Once the cells are dispersed, 6-8mL of complete growth medium is added, and the cells are aspirated by gently pipetting. The cell suspension is then transferred to a centrifuge tube and spun at about 125x g for 5-10 minutes to remove trypsin EDTA. The supernatant is then discarded, and the cells are resuspended in fresh growth medium. An appropriate aliquot of the cell suspension is added to a new culture container, which is incubated at 37°C. Renew the culture medium 2-3 times a week.

[0445] ARPE-19 cells for cluster encapsulation

[0446] Using AggreWell TM Spheroid plates (STEMCELL Technologies) and the protocols outlined herein were used to prepare spheroid clusters of exemplary cells (e.g., engineered ARPE-19 cells). On day 1, a rinse solution (4 mL) was added to each plate and the plate was then spun in a large centrifuge at 3,000 RPM for 5 minutes. The rinse solution was aspirated by pipette and 4 mL of complete growth medium was added. Engineered ARPE-19 cells were seeded into the plate at the desired cell density and immediately aspirated to prevent aggregation, with a general rule of thumb that 3.9 million cells per well will produce clusters of 150 μm in diameter. The plate was spun at 800 RPM for 3 minutes and then placed in an incubator at 37° C. overnight.

[0447] The next day, remove the dish from incubation. Using a wide-bore 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 and spin 2x 1 minute in a centrifuge. Gently resuspend the clusters using a wide-bore pipette tip and gently stir to distribute them throughout the culture medium or another material (e.g., alginate).

[0448] Alternatively, use the following protocol to prepare ARPE-19 spheroids. TM Remove the plate from its packaging and place it in a sterile tissue culture hood. Add 2 mL of Aggrewell to each well. TMRinse solution. Centrifuge the plate at 2,000 g for 5 minutes to remove air bubbles and remove the AggreWell from the wells. TM Rinse solution. 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 described above.

[0449] Alternatively, ARPE19 spheroids were prepared using a PBS MINI bioreactor (PBS Biotec, Inc., Camarillo CA, USA) according to the following protocol. Cell culture medium and 220 million ARPE19 cells were added to a PBS 0.1L or PBS 0.5L container, which was then inserted into the base unit placed in an incubator. The PBS MINI speed adjustment dial was set to 40 rpm, and the container was incubated at 37°C for at least 48 hours, and then the spheroids were collected as described above.

[0450] Example 4: Preparation of hydrogel capsules containing cells

[0451] RPE cells are used as capsules for single cell encapsulation. Just before encapsulation, single ARPE-19 cells engineered to express therapeutic proteins are centrifuged at 1,400 rpm for 1 minute and washed with calcium-free Krebs-Henseleit (KH) buffer (4.7 mM KCl, 25 mM HEPES, 1.2 mM KH2PO4, 1.2 mM MgSO4 × 7H2O, 135 mM NaCl, pH ≈ 7.4, ≈ 290 mOsm). After washing, the cells are centrifuged again and all supernatants are aspirated. In some experiments, the cell pellet is resuspended in a high molecular weight alginate solution (70: 30) with a suspended single cell at a desired density per milliliter of alginate solution.

[0452] Prior to fabrication of single-compartment and two-compartment hydrogel capsules, the buffer and alginate solutions were sterilized by filtration through a 0.2 μm filter using an aseptic process.

[0453] In order to prepare a device configured as a two-compartment hydrogel capsule of about 1.5mm in diameter, an electrostatic droplet generator can be arranged as follows: ES series 0-100kV, 20 watts of high voltage generators (EQ series, Matsusada, NC, USA) are connected to the top and bottom of a coaxial needle (22G inner cavity, 18G outer cavity, Ramé-Hart Instrument Co., Succasunna, NJ, USA). The inner cavity will be connected to the first 5-mL syringe with a Luer lock, and the syringe is connected to a vertically oriented syringe pump. The outer cavity is connected to the second 5-mL syringe by a Luer connector, and the syringe is connected to the second horizontally oriented syringe pump. In order to encapsulate cells only in the first (inner) compartment, the first alginate solution comprising cells (as a single cell suspension) can be placed in the first syringe, and the second acellular alginate solution comprising formula (I) compound is placed in the second syringe. For comparison of 2 compartment hydrogel capsules, the second (outer) compartment can be formed using an alginate solution not comprising formula (I) compound. Two syringe pumps move the first and second alginate solutions from syringes through the two lumens of the coaxial needle, and a single droplet containing both alginate solutions is extruded 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 rate ratio of the two alginate solutions.

[0454] For the manufacture of two-compartment capsules, after extruding the required volume of alginate solution, the alginate droplets were cross-linked in a cross-linking solution containing 25mM HEPES buffer, 20mM BaCl2, 0.2M mannitol and poloxamer 188 for 5 minutes. The capsules that fell to the bottom of the cross-linking container were collected by pipetting into a conical tube. After the capsules settled in the tube, the cross-linking buffer was removed and the capsules were washed. The cell-free capsules were washed four times with HEPES buffer (NaCl 15.428g, KCl0.70g, MgCl2·6H2O0.488g, 50ml of HEPES (1M) buffer solution (Gibco, Life Technologies, California, USA) in 2 liters of deionized water) and stored at 4°C until use. The cell-encapsulated capsules were washed four times in HEPES buffer, twice in 0.9% saline, and twice in culture medium, and stored in an incubator at 37°C.

[0455] Example 5. In vivo assays of exemplary compounds

[0456] The non-fibrogenic properties of exemplary compounds of the present disclosure can be explored by implanting hydrogel capsules prepared as described in Example 2 or 4 into the intraperitoneal (IP) space of C57BL / 6J mice according to the following procedure.

[0457] Preparation: Mice were prepared for surgery by being placed under anesthesia with a continuous flow of 1%-4% isoflurane and oxygen at 0.5 L / min. Preoperatively, all mice received 0.05-0.1 mg / kg body weight of buprenorphine as a preoperative analgesic subcutaneously, while receiving 0.5 ml of 0.9% saline subcutaneously to prevent dehydration. A razor with a size of #40 scissor blade will be used to remove hair to reveal an area of ​​approximately 2 cm×2 cm on the ventral midline of the animal's abdomen. The entire shaved area was prepared under sterile conditions, accompanied by at least 3 cycles of washing with povidone (where possible, in a centrifugal direction from the center of the incision site outward), followed by rinsing with 70% alcohol. A final skin paint containing povidone was also applied. After disinfecting the workbench top surface with 70% ethanol, the surgical site was covered with sterile disposable paper to exclude surrounding hair from contacting the surgical site. Personnel will use appropriate PPE, gowning, surgical masks, and surgical gloves.

[0458] Surgical procedure: Use sharp surgical blades or scissors to cut a 0.5-0.75mm midline incision through the skin and cut the white line into the abdomen of the test mouse. The surgeon will try to keep the incision as small as possible. Use flat sterile tweezers to transfer a 0.5mL aliquot of each capsule composition into the abdominal cavity of each mouse (4 mice for each composition). The abdominal muscles are closed by suturing with 5-0 Ethicon black silk or PDS absorbable 5.0-6.0 monofilament absorbable sutures, and the outer skin layer is closed using wound clips. Blood and tissue debris are removed from surgical instruments between procedures, and these instruments are also sterilized again between animals using a hot bead sterilizer. After surgery, the animals are placed back on a hot plate or in a cage under a heat lamp and monitored until they recover from anesthesia.

[0459] Intraoperative Care: Animals were kept warm using a Deltaphase isothermal pad. During surgery, the animal's eyes were hydrated with sterile ophthalmic ointment. Care was taken to avoid overwetting the surgical site to avoid hypothermia. Respiratory rate and characteristics were continuously monitored. If vital signs indicated extreme pain and distress, the animal was euthanized in a carbon dioxide chamber followed by cervical dislocation.

[0460] Postoperative analysis: 4 weeks after implantation, most of the capsules were removed from the mice and analyzed using CellTiter The number of cells in the capsules was measured using the 3D cell viability assay (Promega Corporation, Madison, WI USA) (one capsule per mouse, in duplicate). Briefly, one capsule per well was analyzed in duplicate and compared to a standard curve of plated cells. 100 μl of CellTiter 3D reagent was added to each well containing 100 μl of medium, the plate was placed on a shaker at 400 rpm for 15 minutes, and then the luminescence value was read on a plate reader. In addition, a texture analyzer was used to measure the mechanical strength (initial break) of capsules in aliquots of each composition before implantation and when removed after a 1-month implantation period.

[0461] Example 6: Conjugation of additional compounds to polymers

[0462] Exemplary polymers can be further modified by conjugating additional compounds to one or more monomers at another position of the monomer (such as at a free carboxylate). For example, the compound can be conjugated to an active carboxylic acid group on an alginate polymer. Any component (such as an amine as described herein) that can be coupled to a carboxylic acid can be a suitable partner for this coupling reaction.

[0463] The exemplary compounds containing free amines can be conjugated with alginate 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 equivalent) and N-methylmorpholine (1 equivalent). The amine-containing compound of interest is then dissolved in acetonitrile (0.3 M) and added to the alginate solution. The reactant is then warmed to 55 ° C for 16 hours, then cooled to room temperature, concentrated by rotary evaporation, and then dissolved in water. The mixture is then filtered through a cyano-modified silica gel bed (Silicycle), and the filter cake is washed with water. The resulting solution is then dialyzed with water (10,000 MWCO membrane) for 24 hours, and water is changed twice. The resulting solution is concentrated by freeze drying to obtain additional functionalized alginate.

[0464] Example 7: Particle Analysis

[0465] Various properties of the particle formulations can be analyzed in vitro or at various times after implantation in a subject (eg, an experimental animal or a human patient).

[0466] For example, the mechanical strength of particles (e.g., hydrogel capsules) can be determined by fracture testing using a texture analyzer after manufacture but before implantation. In one embodiment, a 5mm probe connected to a 5kg load cell is used to mechanically test hydrogel capsules on a TA.XTplus texture analyzer (Stable Micro Systems, Surrey, United Kingdom). A single capsule is placed on a platform and compressed from above by a probe at a fixed rate of 0.5mm / sec. When a repulsive force of 1g is measured, contact between the probe and the capsule is detected. The probe continues to travel 90% of the distance between the contact height of the probe and the platform, compressing the capsule to the rupture point. The resistance of the probe to the compression force is measured and plotted as a function of the probe stroke (force versus displacement curve). Typically, before the capsule is completely broken, the capsule will be slightly broken, and the force applied to the probe will be slightly reduced. The analysis macro can be programmed to detect the first reduction of 0.25-0.5g in the force versus displacement curve. The force applied by the probe when this happens is called the initial rupture force. In one embodiment, the breaking force of a capsule formulation manufactured using the apparatus described herein is the average of the initial breaking forces of at least 10, 20, 30, or 40 capsules.

[0467] The average particle size in a particle preparation can be estimated by measuring 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, e.g., by bright field imaging.

[0468] Example 8: Preparation and characterization of hydrogel capsules containing modified polysaccharide polymers

[0469] The present embodiment describes the preparation of two-compartment hydrogel capsules, and the hydrogel capsules include an outer layer composed of the polysaccharide polymers of modification described herein and an inner layer composed of unmodified polysaccharide polymers. The first 5% (w / w) alginate solution comprising compound 101 is prepared by dissolving 0.25g modified alginate in 4.75g saline. The solution is mixed overnight until the solution is uniform. Also by dissolving 0.25g alginate in 8.3g saline and mixing overnight until uniformly preparing the second alginate solution (3% (w / w)). 2.16g of 3% (w / w) unmodified alginate solution is added to 5% (w / w) modified alginate solution and mixed. Then modified alginate solution is loaded into two separate 10mL syringes.

[0470] The Matsusada high voltage generator is then connected to the coaxial needle (No. 17) in the needle holder and to the grounding ring. The Luer lock connector on the side of the needle is connected to an 8-inch tube extension, which is connected to a syringe loaded with the first (5% (w / w)) alginate solution, which is intended to be an outer compartment. The Luer lock connector at the top is also connected to an 8-inch tube extension, which is connected to a syringe loaded with the second (3% (w / w)) unmodified alginate, which is intended to be an inner compartment. Using a syringe pump, the first and second alginate solutions are pumped into a glass dish containing 250mL 20mM BaCl2 solution for cross-linking and hydrogel capsule formation. The cross-linked hydrogel capsules are then collected in a glass dish, washed with a buffer solution (15 times), and then imaged to assess morphology and spheroid strength.

[0471] Equivalents and scope

[0472] The present application mentions various issued patents, published patent applications, magazine articles and other publications, which are all incorporated herein by reference. If there is a conflict between any incorporated reference and this specification, the specification shall prevail. In addition, any specific embodiment of the present invention belonging to the prior art can be explicitly excluded from any one or more of the claims. Because such embodiments are considered to be known to those of ordinary skill in the art, even if exclusion is not explicitly stated herein, they can also be excluded. Any specific embodiment of the present invention can be excluded from any claim for any reason, whether or not related to the existence of the prior art.

[0473] Those skilled in the art will recognize or be able to determine using only routine experimentation many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, drawings or examples, but is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications may be made to this specification without departing from the spirit or scope of the invention, as defined in the following claims.

Claims

1. A polysaccharide polymer comprising sugar monomers, wherein the sugar monomers have a structure of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X is O, NR 6 or S; R 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein alkylene, alkenylene, alkynylene, heteroalkylene and haloalkylene are optionally substituted by one or more R 8 replace; R 2 and R 3 are independently hydrogen, C 1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 , wherein each alkylene or alkenyl group is optionally substituted by one or more R 10 Replace, and R 2 and R 3 Not every one of them is hydrogen; Each R 4 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace; R 5 It 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, non-fibrous compounds or peptides, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally replaced by one or more R 8 replace; R 6 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl or C 1-6 haloalkyl, wherein alkyl, heteroalkyl and haloalkyl are optionally substituted with one or more R 10 replace; R 7a and R 7b are independently hydrogen, C 1-6 alkyl, cycloalkyl or heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R 10 replace; 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 substituted by 0-12 R 11 replace; 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 peptide, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is substituted by 0-12 R 11 replace; 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 peptide; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and optionally substituted by one or more R 11 replace; or R B and R C Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or heteroaryl ring, each of which is optionally substituted by one or more R 10 replace; R 9 are peptides or non-fibrotic compounds; Each R 10 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 , wherein each alkyl, heteroalkyl and haloalkyl group is optionally substituted with one or more R 11 replace; and Each R 11 Independently for C 1-6 Alkyl, halogen, oxo, cycloalkyl or heterocyclyl.

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

3. The polysaccharide polymer according to claim 1, wherein R 1 It's O.

4. The polysaccharide polymer according to claim 1, wherein R 5 It is C(O)OR A or C(O)N(R C )(R D ).

5. The polysaccharide polymer according to claim 1, wherein R 5 is C(O)N(R C )(R D ), and R C and R D Each is independently hydrogen, a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2), or a peptide (eg, an RGD peptide).

6. The polysaccharide polymer according to claim 5, wherein R C and R D one of them is independently hydrogen, and R C and R D The other of the is independently a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2) or a peptide (eg, an RGD peptide).

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

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

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

10. The polysaccharide polymer according to claim 1, wherein R 9 It is a non-fibrotic compound.

11. The polysaccharide polymer of claim 1, wherein the sugar monomer has a structure of formula (Ib): or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 5 and each of its sub-variants as defined in claim 1.

12. The polysaccharide polymer of claim 1, wherein the sugar monomer has the structure of formula (Ic): or a pharmaceutically acceptable salt thereof, wherein R 9 and its subvariants as defined in claim 1, and R 3a is hydrogen, and n is 1, 2, 3, 4 or 5.

13. The polysaccharide polymer of claim 1, wherein the sugar monomer has the structure of formula (Id): or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R C , R D and each of its sub-variants as defined in claim 1.

14. The polysaccharide polymer of claim 1, wherein the sugar monomer has a structure of formula (Ie): or a pharmaceutically acceptable salt thereof, wherein R 9 , R C , R D and each of its subvariants as defined in claim 1, and R 3a is hydrogen, and n is 1, 2, 3, 4 or 5.

15. The polysaccharide polymer according to claim 1, wherein R 9 It is a non-fibrotic compound.

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

17. The polysaccharide polymer of claim 1, wherein the sugar monomer has a structure of formula (If): or a pharmaceutically acceptable salt thereof, wherein R 3 , R 5 and each of its subvariants as defined in claim 1; P 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 12 replace; L 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace; Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace; R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo; each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and R 7a and R 8 As defined in claim 6.

18. The polysaccharide polymer of claim 1, wherein the sugar monomer has the structure of formula (Ig): or a pharmaceutically acceptable salt thereof, wherein R 3 , R 12 , R C , R D and each of its subvariants as defined in claim 1; P 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 12 replace; L 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace; Z 1 is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace; R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo; each of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and R 7a and R 8 As defined in claim 1.

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

20. The polysaccharide polymer of claim 17 or 18, wherein P 1 yes Where R 12 It is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl or halo.

21. The polysaccharide polymer according to claim 17 or 18, wherein L 1 Does not exist or C 1-6 Alkylene (e.g., -CH2-).

22. The polysaccharide polymer of claim 17 or 18, wherein Z 1 is an aryl group, a heteroaryl group or a heterocyclic group.

23. The polysaccharide polymer of claim 22, wherein Z 1 It is a heterocyclic group.

24. The polysaccharide polymer of claim 23, wherein Z 1 yes 25. The polysaccharide polymer of claim 1, wherein the non-fibrotic compound is selected from the group consisting of those listed in Table 2.

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

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

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

29. An alginate comprising mannuronate or guluronate monomers, wherein the mannuronate or guluronate monomers have the structure of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X is O, NR 6 or S; R 1 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein alkylene, alkenylene, alkynylene, heteroalkylene and haloalkylene are optionally substituted by one or more R 8 replace; R 2 and R 3 are independently hydrogen, C 1-6 Alkylene-R 9 , C 1-6 Heteroalkylene-R 9 、C(O)-C 1-6 Alkylene-R 9 、C(O)-C 1-6 Heteroalkylene-R 9 , C 1-6 Alkylene-C(O)-R 9 , C 1-6 Heteroalkylene-C(O)-R 9 , C 1-6 Alkylene-N(R 7a )-R 9 or C 1-6 Heteroalkylene-N(R 7a )-R 9 , wherein each alkylene or alkenyl group is optionally substituted by one or more R 10 Replace, and R 2 and R 3 Not every one of them is hydrogen; Each R 4 does not exist, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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)-, wherein each alkylene, alkenylene, alkynylene, heteroalkylene and optionally substituted by one or more R 8 replace; R 5 It 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, non-fibrous compounds or peptides, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally replaced by one or more R 8 replace; R 6 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl or C 1-6 haloalkyl, wherein alkyl, heteroalkyl and haloalkyl are optionally substituted with one or more R 10 replace; R 7a and R 7b are independently hydrogen, C 1-6 alkyl, cycloalkyl or heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R 10 replace; 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 substituted by 0-12 R 11 replace; 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 peptide, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is substituted by 0-12 R 11 replace; 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 peptide; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and optionally substituted by one or more R 11 replace; or R B and R C Together with the atoms to which they are attached, they form a 3-10 membered heterocyclyl or heteroaryl ring, each of which is optionally substituted by one or more R 10 replace; R 9 are peptides or non-fibrotic compounds; Each R 10 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 , wherein each alkyl, heteroalkyl and haloalkyl group is optionally substituted with one or more R 11 replace; and Each R 11 Independently for C 1-6 Alkyl, halogen, oxo, cycloalkyl or heterocyclyl.

30. The alginate of claim 29, wherein X is O.

31. The alginate of claim 29, wherein R 1 It's O.

32. The alginate of claim 29, wherein R 5 It is C(O)OR A or C(O)N(R C )(R D ).

33. The alginate of claim 29, wherein R 5 is C(O)N(R C )(R D ), and R C and R D Each is independently hydrogen, a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2), or a peptide (eg, a peptide provided in Table 3).

34. A salt of alginate as claimed in claim 29, wherein R C and R D one of them is independently hydrogen, and R C and R D The other of the is independently a non-fibrotic compound (eg, a non-fibrotic compound provided in Table 2) or a peptide (eg, a peptide provided in Table X).

35. A salt as claimed in claim 39, wherein R 2 is hydrogen or C 1-6 Alkylene-S(O)2-R 9 .

36. A salt as claimed in claim 29, wherein R 3 is hydrogen or C 1-6 Alkylene-S(O)2-R 9 .

37. A salt of alginate as claimed in claim 29, wherein R 2 and R 3 One of them is independently C 1-6 Alkylene-S(O)2-R 9 , and R 2 and R 3 The other of the R is independently hydrogen.

38. A salt of alginate as claimed in claim 29, wherein R 9 is a non-fibrotic compound (eg, as shown in Table 2).

39. The alginate of claim 29, wherein the monomer has the structure of formula (Ib): or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 5 and each of its sub-variables as defined in claim 29.

40. The alginate of claim 29, wherein the monomer has the structure of formula (Ic): or a pharmaceutically acceptable salt thereof, wherein R 9 and its subvariants as defined in claim 29, and R 3a is hydrogen, and n is 1, 2, 3, 4 or 5.

41. The alginate of claim 29, wherein the monomer has the structure of formula (Id): or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R C , R D and each of its sub-variables as defined in claim 29.

42. The alginate of claim 29, wherein the monomer has the structure of formula (Ie): or a pharmaceutically acceptable salt thereof, wherein R 9 , R C , R D and each of its subvariants as defined in claim 29, and R 3a is hydrogen, and n is 1, 2, 3, 4 or 5.

43. An alginate as described in claim 29, wherein the non-fibrotic compound is selected from the group consisting of those in Table 2.

44. A hydrogel comprising the polysaccharide polymer of any one of claims 1-28 or the alginate of any one of claims 29-43.

45. An implantable element comprising the polysaccharide polymer of any one of claims 1-39, the alginate of any one of claims 40-64, or the hydrogel of claim 65.

46. ​​The implantable element of claim 45, further comprising cells (eg, engineered cells).

47. The implantable element of claim 46, wherein the cells produce a therapeutic substance (eg, an enzyme, an antibody, a hormone, or a blood clotting factor).

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

49. A method of treating a disease, disorder or condition in a subject, e.g., a subject in need thereof, by administering to the subject an implantable element of any one of embodiments 45-47 or a pharmaceutical composition of embodiment 48, thereby treating the disease, disorder or condition in the subject.

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