EP4724107A2 - Ophthalmic films - Google Patents

Abstract

The present application describes the synthesis, formulation and uses of systems comprising conjugates or materials prepared therefrom, capable of retaining systems on the ocular surface.

Description

Attorney Docket No.: 2013105-0050 OPHTHALMIC FILMS Priority Claim [0001] The benefit of priority is claimed to the United States Provisional Application Number 63/507,099, filed 8 June 2023 (8.6.2023), the entire contents of which are included herein and incorporated herein by reference in accordance with PCT Rule 20.6. Background [0002] Dry eye disease and other ophthalmic conditions cause significant discomfort and can result in serious damage to ocular tissues. Prevalence of dry eye disease has been reported to be above 50%, and to increase with age; at least one study has reported a prevalence greater than 65% among study participants aged 71 years and above. See, for example, Shah & Jani Oman J. Ophthalmol 8:151, 2015. Summary [0003] The present disclosure provides a variety of insights relating to providing benefits to ocular tissues. For example, in some embodiments, the present disclosure provides technologies for improving one or more of moisturization, lubricity and barrier function of ocular tissues such as, for example, the cornea, the sclera, conjunctival surfaces, etc., and/or combinations thereof. [0004] Among other things, the present disclosure provides certain conjugates, and systems and materials that comprise them and/or are formed from them. [0005] In certain embodiments, conjugates (and/or materials, such as films, generated from them, and/or systems that include them), as described herein, can complex either with the tear film and/or with ophthalmic tissue surfaces. Without wishing to be bound by any particular theory, the present disclosure proposes that such complexation (which may include, for example, non-covalent association and/or covalent bonding – e.g., cross-linking), may enhance persistence of HA (e.g., of the HA moiety in the conjugate) on or in the eye (e.g., on the cornea). 1 11991680v1 Attorney Docket No.: 2013105-0050 [0006] In some embodiments, the present disclosure provides populations of conjugates comprising a glycopolymer moiety conjugated to a retention moiety, wherein, for example, the molecular weight of the glycopolymer moieties in the population is about 10 kDa or more; and the retention moiety includes a reactive group that associates with an ocular moiety such that the conjugate is retained in or on the eye for an extended period of time relative to that for which unconjugated glycopolymer moiety is retained. Those skilled in the art, reading the present disclosure, will appreciate the scope and extent of “in or on” the eye, for example, including association with the cornea, conjunctiva of the eyelid, tear(s), tear film, tear duct, sclera, conjunctival surface, etc. [0007] In some such embodiments, the molecular weight of the glycopolymer moiety is between 10 kDa and 2500 kDa, or between 10 kDa and 1000 kDa, or between 10 kDa and 500 kDa, or between 500kDa and 2500 kDa, or between 750 kDa and 2500 kDa, or between 1000 kDa and 2500 kDa or about 1000 kDa. Alternatively or additionally, in some such embodiments, the glycopolymer moiety is hyaluronic acid (HA) or a therapeutically equivalent variant thereof, and/or the retention moiety has a structure that is or comprises formula (I): wherein 1 R is independently –H, substituted C_1-6 aliphatic, optionally substituted 5-10-membered heterocyclyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5-10-membered heteroaryl; R² is –H, halogen, –CN, optionally substituted C_1-6 aliphatic, optionally substituted 5- 10-membered heterocyclyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5-10-membered heteroaryl; and m is 1-4. [0008] In certain particular such embodiments, the binding moiety is (I-a): 2 11991680v1 Attorney Docket No.: 2013105-0050 or pharmaceutically or : (I-b), or pharmaceutically acceptable salt thereof, wherein A is a polymer moiety. Still further alternatively or additionally, in some embodiments, the mol% of binding moiety relative to glycopolymer is between 0.01 – 100%, or between 1 – 50%, or between 2-10%. Yet further alternatively or additionally, in some such embodiments, the glycopolymer moiety and retention moiety are covalently bound through a link. [0009] In some embodiments, the present disclosure provides populations of glycopolymer conjugates prepared by a process comprising steps of: conjugating a glycopolymer preparation characterized by a molecular weight of 10 kDa or more with a reaction partner, under conditions and for a time sufficient in amount that a glycopolymer conjugate as recited herein (e.g., hereinabove) is generated. [0010] In some embodiments, the present disclosure provides methods of preparing glycopolymers of molecular weight 5000 kDa or more, the method comprising steps of, for example, (i) functionalizing a glycopolymer with molecular about 500 kDa or more with a reactive moiety; (ii) adding a cross-linker to a solution of said functionalized glycopolymer; and (iii) purifying the product via chromatographic methods; in certain such embodiments, the glycopolymer is an HA. [0011] In some embodiments, the present disclosure provides systems comprising a population of glycopolymers (e.g., as described herein); and a cross-linking agent. In certain such embodiments, the cross-linking agent is bifunctional. Alternatively or additionally, in 3 11991680v1 Attorney Docket No.: 2013105-0050 certain such embodiments, the system is prepared prior to and/or substantially contemporaneously with application to a subject. [0012] In some embodiments, the present disclosure provides formulations for use in administration to a patient to treat an ocular disease, which formulation comprising a glycopolymer conjugate as recited herein, for example a formulation that is or comprises a preparation of conjugates comprising a glycopolymer moiety conjugated to a retention moiety. In some such embodiments, the glycopolymer moiety has a molecular weight of about 10 kDa or more. Alternatively or additionally, in some such embodiments, the formulation is characterized as a gel (e.g., a hydrogel), powder, aerosol, or liquid. Alternatively or additionally, in some such embodiments the formulation comprises saline, is or comprises a contact lens solution, and/or comprises one or more pharmaceutically acceptable ophthalmic excipients (e.g., hydrogen peroxide, boric acid, ascorbic acid, or more broadly, disinfectants, preservatives, surfactants, and wetting solutions). Further alternatively or additionally, in some such embodiments concentration of conjugate within a formulation is 0.1-0.5% w/v. In many embodiments, a glycopolymer in a conjugate included in such a formulation is HA or a variant of HA. In many embodiments, a formulation is sterile. [0013] In some embodiments, the present disclosure provides films (e.g., monolayers), for example that are prepared from conjugates as described herein (e.g., via crosslinking). In some embodiments, a film is dimensioned and constructed for application to an ocular surface. In some embodiments, a film includes one or more moieties as described herein available to interact with an element of an ocular surface; in some embodiments, such one or more moieties include one or more retention moieties as described herein. In some embodiments, such one or more moieties include one or more moieties on a polymer moiety. In some embodiments, interaction(s) between a film and an ocular surface are or comprise non-covalent interactions. Alternatively or additionally, in some embodiments, such interaction(s) include one or more covalent bonds (e.g., cross-links, for example with cysteine(s) that may in some embodiments be endogenous to the eye). In some embodiments, a retention moiety of a film interacts covalently with an element of an ocular surface. Alternatively or additionally, in some embodiments, a retention moiety of a film interacts non-covalently with an element of an ocular surface. In some embodiments, a film is characterized by improved retention to the ocular surface (e.g., relative to a suitable reference 4 11991680v1 Attorney Docket No.: 2013105-0050 film lacking or not prepared from conjugate(s) as described herein). In some embodiments, a film has a thickness of 40 μm or less, or a thickness between 0.1 μm to 40.01 μm. In some embodiments, the film has a thickness of 2 μm or less when assessed by confocal laser scanning microscopy (CLSM). In some embodiments a film is characterized as a non-Newtonian fluid. In some embodiments, a film is transparent and/or non-refractive. In some embodiments, a film is characterized by an oxygen permeability between 25 Dk/t to 50 Dk/t. [0014] In some embodiments, the present disclosure provides improvements to a system comprising a hyaluronic acid component formulated for topical application to an eye, the improvement, for example by utilizing as the hyaluronic acid component a conjugate preparation, or material (e.g., film such as a monolayer) prepared therefrom, as described herein. In some such embodiments, the improvement achieves improved retention (e.g., in or on the eye, such as on surface(s) thereof). [0015] In some embodiments (including, for example, in improvements provided hereby), a composition (e.g., a composition that is or comprises a preparation of conjugates described herein, a material (e.g., a film such as a monolayer) and/or a formulation of one of the foregoing, is topically applied to the eye 2 or fewer times per day. In some embodiments, administering occurs 3 or fewer times a day. In some embodiments, administering occurs 4 or fewer times a day. In some embodiments, administering occurs 5 or fewer times a day. In some embodiments, administering occurs 6 or fewer times a day. In some embodiments, administering occurs 10 or fewer times a day. [0016] In some embodiments, the present disclosure provides methods of reducing one or more (and, in some embodiments, substantially all or all) signs and symptoms of dry eye disease (DED) and/or one or more related ophthalmic conditions, for example comprising steps of: (i) functionalizing a glycopolymer with a reactive moiety, or providing a preparation of glycopolymers so functionalized, or of a material (e.g., a film such as a monolayer) prepared therefrom; and (ii) administering one or more doses of a formulation of such a preparation to the eye. In some embodiments, such providing and/or administering are performed so as to establish a conjugated glycopolymer-containing film on or near the ocular surface. In some such embodiments, the administering involves 2 or fewer applications per day. In some embodiments, administering occurs 3 or fewer times a day. In some embodiments, administering occurs 4 or 5 11991680v1 Attorney Docket No.: 2013105-0050 fewer times a day. In some embodiments, administering occurs 5 or fewer times a day. In some embodiments, administering occurs 6 or fewer times a day. In some embodiments, administering occurs 10 or fewer times a day. In some embodiments, a subsequent application is performed before a prior application is cleared. In some embodiments, frequency of application (e.g., of dose administration) decreases over time. [0017] In some embodiments, the present disclosure provides methods of modulating one or more (and in some embodiments, substantially all or all) effects of a hyaluronic acid treatment comprising, comprising steps of (i) functionalizing an enzyme with a reactive moiety, or providing a preparation of an enzyme so functionalized; and (ii) administering one or more doses of a formulation of reactive moiety-conjugated enzyme to an ocular surface. In some such embodiments, the enzyme is hyaluronidase. [0018] In some embodiments, the present disclosure provides methods of imparting a benefit to the eye, for example by administering a composition that is or comprises a glycopolymer moiety associated with a retention moiety, or a material (e.g., a film such as a monolayer) prepared therefrom. In some embodiments of such methods, the glycopolymer moiety is or comprises an HA moiety or a variant thereof. Brief Description of the Drawing [0019] Figure 1 presents a representative GPC figure of a preparation of a 500 kDa HA conjugate with 10 mole% gly-CBT loading. [0020] Figure 2 presents a representative ¹H NMR spectrum of a preparation of a 500 kDa HA conjugate with 10 mole% gly-CBT loading. [0021] Figure 3 presents a representative histological image of an untreated rabbit eye stained with colloidal iron. [0022] Figure 4 presents a representative histological image of a rabbit eye treated with a preparation of 10 kDa HA with 10 mole% gly-CBT on Days 1-5 and then stained with colloidal iron on Day 8. 6 11991680v1 Attorney Docket No.: 2013105-0050 [0023] Figure 5 presents a representative histological image of a rabbit eye treated with a preparation of 250 kDa HA with 5 mole% gly-CBT on Days 1-5 and then stained with colloidal iron on Day 8. [0024] Figure 6 presents a representative histological image of a rabbit eye treated with a preparation of 1000 kDa HA with 5 mole% gly-CBT on Days 1-5 and then stained with colloidal iron on Day 8. [0025] Figure 7 presents a histogram of colloidal iron staining between untreated and treated eyes of different rabbits with various formulations of prepared conjugates. [0026] Figure 8 presents a representative histogram of colloidal iron staining between untreated eyes and eyes treated with a formulation of 1000 kDa HA with 5 mole% gly-CBT. [0027] Figure 9 presents a visualization of the HA layer on mouse cornea when treated with conventional unmodified HA or with an HA-CBT derivative of the same molecular weight. [0028] Figure 10 presents a visualization of the HA layer on mouse cornea treated with 1000 kDa HA with 13.6 mole% gly-CBT and 0.038% fluorescent dye. [0029] Figure 11 presents a visualization of the HA layer on mouse cornea treated once by sequential application of 1000 kDa HA with 13.6 mole% gly-CBT and 0.038% fluorescent dye, followed by addition of crosslinker (cysteine-ethylene diamine-cysteine), and additionally followed by 1000 kDa HA with 13.6 mole% gly-CBT and 0.038% fluorescent dye. [0030] Figure 12 presents a visualization of the HA layer on mouse cornea treated twice by sequential application of 1000 kDa HA with 13.6 mole% gly-CBT and 0.038% fluorescent dye, followed by addition of crosslinker (cysteine-ethylene diamine-cysteine), and additionally followed by 1000 kDa HA with 13.6 mole% gly-CBT and 0.038% fluorescent dye. Definitions [0031] About: The term “about”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a 7 11991680v1 Attorney Docket No.: 2013105-0050 range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value. [0032] Administration: As used herein, the term “administration” typically refers to the administration of a composition to a subject or system to achieve delivery of an agent that is, or is included in, the composition. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g. intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. [0033] Affinity: As is known in the art, “affinity” is a measure of the tightness with which two or more binding partners associate with one another. Those skilled in the art are aware of a variety of assays that can be used to assess affinity, and will furthermore be aware of appropriate controls for such assays. In some embodiments, affinity is assessed in a quantitative assay. In some embodiments, affinity is assessed over a plurality of concentrations (e.g., of one binding partner at a time). In some embodiments, affinity is assessed in the presence of one or more potential competitor entities (e.g., that might be present in a relevant – e.g., physiological – setting). In some embodiments, affinity is assessed relative to a reference (e.g., that has a known affinity above a particular threshold [a “positive control” reference] or that has a known affinity below a particular threshold [a “negative control” reference”]. In some embodiments, affinity may be assessed relative to a contemporaneous reference; in some embodiments, affinity may be 8 11991680v1 Attorney Docket No.: 2013105-0050 assessed relative to a historical reference. Typically, when affinity is assessed relative to a reference, it is assessed under comparable conditions. [0034] Agent: In general, the term “agent”, as used herein, may be used to refer to a compound or entity of any chemical class including, for example, a polypeptide, nucleic acid, saccharide, lipid, small molecule, metal, or combination or complex thereof. In appropriate circumstances, as will be clear from context to those skilled in the art, the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof. Alternatively or additionally, as context will make clear, the term may be used to refer to a natural product in that it is found in and/or is obtained from nature. In some instances, again as will be clear from context, the term may be used to refer to one or more entities that is man-made in that it is designed, engineered, and/or produced through action of the hand of man and/or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form; in some embodiments, an agent may be utilized in crude form. In some embodiments, potential agents may be provided as collections or libraries, for example that may be screened to identify or characterize active agents within them. In some cases, the term “agent” may refer to a compound or entity that is or comprises a polymer; in some cases, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound or entity that is not a polymer and/or is substantially free of any polymer and/or of one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety. [0035] Aliphatic: The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 carbon atoms. In some embodiments, aliphatic groups contain 1-4 carbon atoms. In some embodiments, aliphatic groups contain 1-3 9 11991680v1 Attorney Docket No.: 2013105-0050 carbon atoms, and in some embodiments, aliphatic groups contain 1-2 carbon atoms. In some embodiments, “carbocyclic” (or “cycloaliphatic” or “carbocycle” or “cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0036] Alkyl: As used herein, the term "alkyl" is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched- chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, alkyl has 1-100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C₁-C₂₀ for straight chain, C₂-C₂₀ for branched chain), and alternatively, about 1- 10. In some embodiments, a cycloalkyl ring has from about 3-10 carbon atoms in their ring structure where such rings are monocyclic or bicyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C₁-C₄ for straight chain lower alkyls). [0037] Alkylene: The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH₂)_n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0038] Alkynyl: As used herein, the term “alkynyl” refers to an alkyl group, as defined herein, having one or more triple bonds. [0039] Amino acid: in its broadest sense, as used herein, the term “amino acid” refers to a compound and/or substance that can be, is, or has been incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H₂N–C(H)(R)–COOH. In some embodiments, an amino acid is a naturally- occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some 10 11991680v1 Attorney Docket No.: 2013105-0050 embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L- amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and/or amino- terminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and/or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and/or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide. [0040] Analog: As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance. [0041] Animal: As used herein refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans, of either sex and at any stage of development. In some embodiments, "animal" refers to non-human animals, at any stage of development. In certain 11 11991680v1 Attorney Docket No.: 2013105-0050 embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms. In some embodiments, an animal may be a transgenic animal, genetically engineered animal, and/or a clone. [0042] Aryl: The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system and exemplary groups include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. [0043] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and/or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and/or form correlates with incidence of and/or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof. [0044] Binding: It will be understood that the term “binding”, as used herein, typically refers to a non-covalent association between or among two or more entities. “Direct” binding involves physical contact between entities or moieties; indirect binding involves physical 12 11991680v1 Attorney Docket No.: 2013105-0050 interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts – including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a retention entity and/or in a biological system or cell). Binding between two entities may be considered “specific” if, under the conditions assessed, the relevant entities are more likely to associate with one another than with other available binding partners. [0045] Binding agent: In general, the term “binding agent” is used herein to refer to any entity that binds to a target of interest as described herein. In many embodiments, a binding agent of interest is one that binds specifically with its target in that it discriminates its target from other potential binding partners in a particular interaction context. In general, a binding agent may be or comprise an entity of any chemical class (e.g., polymer, non-polymer, small molecule, polypeptide, carbohydrate, lipid, nucleic acid, etc.). In some embodiments, a binding agent is a single chemical entity. In some embodiments, a binding agent is a complex of two or more discrete chemical entities associated with one another under relevant conditions by non-covalent interactions. For example, those skilled in the art will appreciate that in some embodiments, a binding agent may comprise a “generic” binding moiety (e.g., one of biotin/avidin/streptavidin and/or a class-specific antibody) and a “specific” binding moiety (e.g., an antibody or aptamers with a particular molecular target) that is linked to the partner of the generic biding moiety. In some embodiments, such an approach can permit modular assembly of multiple binding agents through linkage of different specific binding moieties with the same generic binding moiety partner. In some embodiments, binding agents are or comprise polypeptides (including, e.g., antibodies or antibody fragments). In some embodiments, binding agents are or comprise small molecules. In some embodiments, binding agents are or comprise nucleic acids. In some embodiments, binding agents are aptamers. In some embodiments, binding agents are polymers; in some embodiments, binding agents are not polymers. In some embodiments, binding agents are non-polymeric in that they lack polymeric moieties. In some embodiments, binding agents are or comprise carbohydrates. In some embodiments, binding agents are or comprise lectins. In some embodiments, binding agents are or comprise peptidomimetics. In some embodiments, binding agents are or comprise scaffold proteins. In some embodiments, binding agents are or 13 11991680v1 Attorney Docket No.: 2013105-0050 comprise mimotopes. In some embodiments, binding agents are or comprise stapled peptides. In certain embodiments, binding agents are or comprise nucleic acids, such as DNA or RNA. [0046] Biocompatible: The term “biocompatible”, as used herein, refers to materials that do not cause significant harm to living tissue when placed in contact with such tissue, e.g., in vivo. In certain embodiments, materials are “biocompatible” if they are not toxic to cells. In certain embodiments, materials are “biocompatible” if their addition to cells in vitro results in less than or equal to 20% cell death, and/or their administration in vivo does not induce significant inflammation or other such adverse effects. [0047] Biodegradable: As used herein, the term “biodegradable” refers to materials that, when introduced into cells, are broken down (e.g., by cellular machinery, such as by enzymatic degradation, by hydrolysis, and/or by combinations thereof) into components that cells can either reuse or dispose of without significant toxic effects on the cells. In certain embodiments, components generated by breakdown of a biodegradable material are biocompatible and therefore do not induce significant inflammation and/or other adverse effects in vivo. In some embodiments, biodegradable polymer materials break down into their component monomers. In some embodiments, breakdown of biodegradable materials (including, for example, biodegradable polymer materials) involves hydrolysis of ester bonds. Alternatively or additionally, in some embodiments, breakdown of biodegradable materials (including, for example, biodegradable polymer materials) involves cleavage of urethane linkages. Exemplary biodegradable polymers include, for example, polymers of hydroxy acids such as lactic acid and glycolic acid, including but not limited to poly(hydroxyl acids), poly(lactic acid)(PLA), poly(glycolic acid)(PGA), poly(lactic-co-glycolic acid)(PLGA), and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates, poly(lactide-co-caprolactone), blends and copolymers thereof. Many naturally occurring polymers are also biodegradable, including, for example, proteins such as albumin, collagen, gelatin and prolamines, for example, zein, and polysaccharides such as alginate, cellulose derivatives and polyhydroxyalkanoates, for example, polyhydroxybutyrate blends and copolymers thereof. Those of ordinary skill in the art will appreciate or be able to determine when such polymers are biocompatible and/or biodegradable 14 11991680v1 Attorney Docket No.: 2013105-0050 derivatives thereof (e.g., related to a parent polymer by substantially identical structure that differs only in substitution or addition of particular chemical groups as is known in the art). [0048] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied. [0049] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity, or in some embodiments, as will be clear from context, a set or collection of discrete physical entities in association with one another (e.g., in a shared common packaging, such as in a kit), that comprises one or more specified components. The term “composition”, in principle, can relate to materials in any physical state or form – such as gas, gel, liquid, solid, etc.; those skilled in the art, reading the present disclosure will appreciate from context if any particular such form is necessarily included or excluded in a particular circumstance. [0050] Corresponding to: As used herein in the context of polypeptides, nucleic acids, and chemical compounds, the term “corresponding to”, designates the position/identity of a structural element, e.g., of an amino acid residue, a nucleotide residue, or a chemical moiety, in a compound or composition through comparison with an appropriate reference compound or composition. For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be 15 11991680v1 Attorney Docket No.: 2013105-0050 identified as “corresponding to” a residue in an appropriate reference polymer. For example, those of ordinary skill will appreciate that, for purposes of simplicity, residues in a polymer may be designated using a canonical numbering system based on a reference related polymer, so that a residue “corresponding to” one at position 190 of a reference polymer, for example, need not actually be the 190^th residue in a polymer of interest, but rather refers to the residue that corresponds to the residue found at position 190 in the reference polymer; those of ordinary skill in the art readily appreciate how to identify “corresponding” residues in polymers (e.g., using commercially available sequence comparison software for polypeptide and nucleic acid polymers; optionally manually for other polymers). [0051] Designed: As used herein, the term “designed” refers to an agent (i) whose structure is or was selected by the hand of man; (ii) that is produced by a process requiring the hand of man; and/or (iii) that is distinct from natural substances and other known agents. [0052] Detectable entity: The term “detectable entity” as used herein refers to any element, molecule, functional group, compound, fragment or moiety that is detectable. In some embodiments, a detectable entity is provided or utilized alone. In some embodiments, a detectable entity is provided and/or utilized in association with (e.g., joined to) another agent. Examples of detectable entities include, but are not limited to: various ligands, radionuclides (e.g., ³H, ¹⁴C, ¹⁸F, ¹⁹F, ³²P, ³⁵S, ¹³⁵I, ¹²⁵I, ¹²³I, ⁶⁴Cu, ¹⁸⁷Re, ¹¹¹In, ⁹⁰Y, ^99mTc, 1⁷⁷Lu, ⁸⁹Zr etc.), fluorescent dyes (for specific exemplary fluorescent dyes, see below), chemiluminescent agents (such as, for example, acridinum esters, stabilized dioxetanes, and the like), bioluminescent agents, spectrally resolvable inorganic fluorescent semiconductors nanocrystals (i.e., quantum dots), metal nanoparticles (e.g., gold, silver, copper, platinum, etc.) nanoclusters, paramagnetic metal ions, enzymes (for specific examples of enzymes, see below), colorimetric labels (such as, for example, dyes, colloidal gold, and the like), biotin, dioxigenin, haptens, and proteins for which antisera or monoclonal antibodies are available. [0053] Domain: The term “domain” as used herein refers to a section or portion of an entity. In some embodiments, a “domain” is associated with a particular structural and/or functional feature of the entity so that, when the domain is physically separated from the rest of its parent entity, it substantially or entirely retains the particular structural and/or functional feature. Alternatively or additionally, a domain may be or include a portion of an entity that, 16 11991680v1 Attorney Docket No.: 2013105-0050 when separated from that (parent) entity and linked with a different (recipient) entity, substantially retains and/or imparts on the recipient entity one or more structural and/or functional features that characterized it in the parent entity. In some embodiments, a domain is a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a section of a polypeptide; in some such embodiments, a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, α-helix character, β-sheet character, coiled-coil character, random coil character, etc.), and/or by a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.). [0054] Dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an agent (e.g., a therapeutic, diagnostic or cosmetic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial (e.g., therapeutic and/or cosmetic) outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a regimen that has been determined to correlate with a desired or beneficial cosmetic outcome (e.g., provides visible and/or tactile improvement to skin) when administered to a relevant population. Those of ordinary skill in the art appreciate that the total amount of a composition or agent administered to a particular subject is determined by one or more attending professionals (e.g., physicians, nurses, or other licensed professionals) and may involve administration of multiple dosage forms. In some embodiments, a dosage form may be provided in a formulation that is or comprises a cream, gel, liquid, lotion, mist, mask, matrix, particle, paste, patch, powder, serum, solid, spray (or collection thereof), or a combination thereof. [0055] Dosing regimen: Those skilled in the art will appreciate that the term “dosing regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given agent has a recommended dosing regimen, which may involve one or 17 11991680v1 Attorney Docket No.: 2013105-0050 more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population. [0056] Engineered: In general, the term “engineered” refers to the aspect of having been manipulated by the hand of man. For example, a polynucleotide is considered to be “engineered” when two or more sequences that are not linked together in that order in nature are manipulated by the hand of man to be directly linked to one another in the engineered polynucleotide and/or when a particular residue in a polynucleotide is non-naturally occurring and/or is caused through action of the hand of man to be linked with an entity or moiety with which it is not linked in nature. For example, in some embodiments described and/or utilized herein, an engineered polynucleotide comprises a regulatory sequence that is found in nature in operative association with a first coding sequence but not in operative association with a second coding sequence, is linked by the hand of man so that it is operatively associated with the second coding sequence. Comparably, a polypeptide may be considered to be “engineered” if encoded by or expressed from an engineered polynucleotide, and/or if produced other than natural expression in a cell. Analogously, a cell or organism is considered to be “engineered” if it has been subjected to a manipulation, so that it’s genetic, epigenetic, and/or phenotypic identity is altered relative to an appropriate reference cell such as otherwise identical cell that has not been so manipulated. In some embodiments, the manipulation is or comprises a genetic manipulation, so that its genetic information is altered (e.g., new genetic material not previously present has been introduced, for example by transformation, mating, somatic hybridization, transfection, transduction, or other 18 11991680v1 Attorney Docket No.: 2013105-0050 mechanism, or previously present genetic material is altered or removed, for example by substitution or deletion mutation, or by mating protocols). In some embodiments, an engineered cell is one that has been manipulated so that it contains and/or expresses a particular agent of interest (e.g., a protein, a nucleic acid, and/or a particular form thereof) in an altered amount and/or according to altered timing relative to such an appropriate reference cell. As is common practice and is understood by those in the art, progeny of an engineered polynucleotide or cell are typically still referred to as “engineered” even though the actual manipulation was performed on a prior entity. [0057] Excipient: As used herein, the term “excipient” refers to an inactive (e.g., not a therapeutic active such as a cosmetic active) agent that may be included in a pharmaceutical composition, for example to provide or contribute to a desired consistency or stabilizing effect. [0058] Fragment: A “fragment” of a material or entity as described herein has a structure that includes a discrete portion of the whole, but lacks one or more moieties found in the whole. In some embodiments, a fragment consists of such a discrete portion. In some embodiments, a fragment consists of or comprises a characteristic structural element or moiety found in the whole. In some embodiments, a polymer fragment comprises or consists of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomeric units (e.g., residues) as found in the whole polymer. In some embodiments, a polymer fragment comprises or consists of at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of the monomeric units (e.g., residues) found in the whole polymer. The whole material or entity may in some embodiments be referred to as the “parent” of the fragment. [0059] Gel: As used herein, the term “gel” refers to viscoelastic materials whose rheological properties distinguish them from solutions, solids, etc. In some embodiments, a composition is considered to be a gel if its storage modulus (G’) is larger than its modulus (G”). In some embodiments, a composition is considered to be a gel if there are chemical or physical cross-linked networks in solution, which is distinguished from entangled molecules in viscous solution. 19 11991680v1 Attorney Docket No.: 2013105-0050 [0060] Halogen: The term “halogen” means F, Cl, Br, or I. [0061] Heteroaryl: The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and/or having, in addition to carbon atoms, from one to five heteroatoms wherein the term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Examplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]– 1,4–oxazin–3(4H)–one. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0062] Heteroatom: The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N- substituted pyrrolidinyl)). [0063] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, 20 11991680v1 Attorney Docket No.: 2013105-0050 preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in N– substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [0064] High affinity binding: The term “high affinity binding”, as used herein refers to a high degree of tightness with which a particular ligand binds to its partner. Those skilled in the art will appreciate that various technologies are available for assessing affinity. In some embodiments, binding is considered to be high affinity if the K_d is about 500 pM or less (e.g., below about 400 pM, about 300 pM, about 200 pM, about 100 pM, about 90 pM, about 80 pM, about 70 pM, about 60 pM, about 50 pM, about 40 pM, about 30 pM, about 20 pM, about 10 pM, about 5 pM, about 4 pM, about 3 pM, about 2 pM, etc.) in binding assays. In some embodiments, binding is considered to be high affinity if the affinity is stronger (e.g., the K_d is lower) for a binding partner of interest than for a selected reference binding partner. In some embodiments, binding is considered to be high affinity if the ratio of the Kd for a binding partner of interest to the K_d for a selected reference binding partner is 1:1 or less (e.g., 0.9:1, 0.8:1, 0.7:1, 0.6:1, 0.5:1.0.4:1, 0.3:1, 0.2:1, 0.1:1, 0.05:1, 0.01:1, or less). In some embodiments, binding is considered to be high affinity if the K_d for a binding partner of interest is about 100% or less 21 11991680v1 Attorney Docket No.: 2013105-0050 (e.g., about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, about 1% or less) of the K_d for a selected reference binding partner. [0065] Hydrophilic: As used herein, the term “hydrophilic” and/or “polar” refers to a tendency to mix with, or dissolve easily in, water. [0066] Hydrophobic: As used herein, the term “hydrophobic” and/or “non-polar”, refers to a tendency to repel, not combine with, or an inability to dissolve easily in, water. [0067] “Improve,” “increase”, “inhibit” or “reduce”: As used herein, the terms “improve”, “increase”, “inhibit’, “reduce”, or grammatical equivalents thereof, indicate values that are relative to a baseline or other reference measurement. In some embodiments, an appropriate reference measurement may be or comprise a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions absent presence of (e.g., prior to and/or after) a particular agent or treatment, or in presence of an appropriate comparable reference agent. In some embodiments, an appropriate reference measurement may be or comprise a measurement in comparable system known or expected to respond in a particular way, in presence of the relevant agent or treatment. [0068] In vitro: The term “in vitro” as used herein refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism. [0069] In vivo: as used herein refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems). [0070] Isolated: as used herein, refers to a substance and/or entity that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature and/or in an experimental setting), and/or (2) designed, produced, prepared, and/or manufactured by the hand of man. Isolated substances and/or entities may be separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 22 11991680v1 Attorney Docket No.: 2013105-0050 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% of the other components with which they were initially associated. In some embodiments, isolated agents are about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. In some embodiments, as will be understood by those skilled in the art, a substance may still be considered "isolated" or even "pure", after having been combined with certain other components such as, for example, one or more carriers or excipients (e.g., buffer, solvent, water, etc.); in such embodiments, percent isolation or purity of the substance is calculated without including such carriers or excipients. [0071] K_D: as used herein, refers to the dissociation constant of a binding agent (e.g., an antibody or binding component thereof) from a complex with its partner (e.g., the epitope to which the antibody or binding component thereof binds). [0072] K_off: as used herein, refers to the off rate constant for dissociation of a binding agent (e.g., an antibody or binding component thereof) from a complex with its partner (e.g., the epitope to which the antibody or binding component thereof binds). [0073] K_on: as used herein, refers to the on rate constant for association of a binding agent (e.g., an antibody or binding component thereof) with its partner (e.g., the epitope to which the antibody or binding component thereof binds). [0074] Linker: as used herein, is used to refer to that portion of a multi-element agent that connects different elements to one another. [0075] Low affinity binding: The term “low affinity binding”, as used herein refers to a low degree of tightness with which a particular ligand binds to its partner. As described herein, affinities can be measured by any available method, including methods known in the art. In some embodiments, binding is considered to be low affinity if the K_d is about 100 pM or more (e.g., above about 200 pM, 300 pM, 400 pM, 500 pM, 600 pM, 700 pM, 800 pM, 900 pM, 1 nM, 1.1 nM, 1.2 nM, 1.3 nM, 1.4 nM, 1.5 nM, etc.) In some embodiments, binding is considered to be low affinity if the affinity is the same or lower (e.g., the K_d is about the same or higher) for a binding partner of interest than for a selected reference binding partner. In some embodiments, 23 11991680v1 Attorney Docket No.: 2013105-0050 binding is considered to be low affinity if the ratio of the K_d for a binding partner of interest to the K_d for a selected reference binding partner is 1:1 or more (e.g., 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1.1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 3:1, 4:1, 5:1, 10:1 or more). In some embodiments, binding is considered to be low affinity if the K_d for a polypeptide of interest is 100% or more (e.g., 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 300%, 400%, 500%, 1000%, or more) of the K_d for a selected reference polypeptide. [0076] Marker: A marker, as used herein, refers to an entity or moiety whose presence or level is a characteristic of a particular state or event. In some embodiments, presence or level of a particular marker may be characteristic of presence, state, or stage of a disease, disorder, or condition. [0077] Moiety: Those skilled in the art will appreciate that a “moiety” is a defined chemical group or entity with a particular structure and/or or activity, as described herein. [0078] Nucleic acid: As used herein, in its broadest sense, refers to any compound and/or substance that is or can be incorporated into an oligonucleotide chain. In some embodiments, a nucleic acid is a compound and/or substance that is or can be incorporated into an oligonucleotide chain via a phosphodiester linkage. As will be clear from context, in some embodiments, "nucleic acid" refers to an individual nucleic acid residue (e.g., a nucleotide and/or nucleoside); in some embodiments, "nucleic acid" refers to an oligonucleotide chain comprising individual nucleic acid residues. In some embodiments, a "nucleic acid" is or comprises RNA; in some embodiments, a "nucleic acid" is or comprises DNA. In some embodiments, a nucleic acid is, comprises, or consists of one or more natural nucleic acid residues. In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleic acid analogs. In some embodiments, a nucleic acid analog differs from a nucleic acid in that it does not utilize a phosphodiester backbone. For example, in some embodiments, a nucleic acid is, comprises, or consists of one or more "peptide nucleic acids", which are known in the art and have peptide bonds instead of phosphodiester bonds in the backbone, are considered within the scope of the present invention. Alternatively or additionally, in some embodiments, a nucleic acid has one or more phosphorothioate and/or 5'-N-phosphoramidite linkages rather than phosphodiester bonds. In some embodiments, a nucleic acid is, comprises, or consists of one or more natural 24 11991680v1 Attorney Docket No.: 2013105-0050 nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxy guanosine, and deoxycytidine). In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleoside analogs (e.g., 2-aminoadenosine, 2- thiothymidine, inosine, pyrrolo-pyrimidine, 3 -methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5 -propynyl-cytidine, C5-methylcytidine, 2- aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)- methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a nucleic acid comprises one or more modified sugars (e.g., 2'- fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) as compared with those in natural nucleic acids. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or protein. In some embodiments, a nucleic acid includes one or more introns. In some embodiments, nucleic acids are prepared by one or more of isolation from a natural source, enzymatic synthesis by polymerization based on a complementary template (in vivo or in vitro), reproduction in a recombinant cell or system, and chemical synthesis. In some embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues long. In some embodiments, a nucleic acid is partly or wholly single stranded; in some embodiments, a nucleic acid is partly or wholly double stranded. In some embodiments a nucleic acid has a nucleotide sequence comprising at least one element that encodes, or is the complement of a sequence that encodes, a polypeptide. In some embodiments, a nucleic acid has enzymatic activity. [0079] Ocular Moiety: An ocular moiety, as described herein, in its broadest sense, refers to any moiety that exists in, on, around, or otherwise may be associated with the eye. An ocular moiety may refer to one moiety or a combination of moieties, which may be the same or different. In some embodiments, an ocular moiety is or comprises components of the eye. In some embodiments, an ocular moiety is the cornea. In some embodiments, an ocular moiety is the conjunctiva of the eyelid. In some embodiments, and ocular moiety refers to tear(s). In some embodiments, an ocular moiety is the tear film. In some embodiments, an ocular moiety is or 25 11991680v1 Attorney Docket No.: 2013105-0050 comprises components of the tear film. In some embodiments, an ocular moiety is the tear duct. In some embodiments, an ocular moiety is the sclera. In some embodiments, an ocular moiety is a conjunctival surface. [0080] Optionally Substituted: As described herein, compounds may sometimes contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH₂)_0–4Rq; –(CH₂)_0–4ORq; -O(CH₂)_0-4R^o, –O– (CH₂)_0–4C(O)OR°; –(CH₂)_0–4CH(ORq)₂; –(CH₂)_0–4SRq; –(CH₂)_0–4Ph, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°; –NO₂; –CN; –N₃; -(CH₂)_0–4N(Rq)₂; –(CH₂)_0–4N(Rq)C(O)Rq; –N(Rq)C(S)Rq; –(CH₂)_{0– 4}N(Rq)C(O)NRq₂; -N(Rq)C(S)NRq₂; –(CH₂)_0–4N(Rq)C(O)ORq; – N(Rq)N(Rq)C(O)Rq; -N(Rq)N(Rq)C(O)NRq₂; -N(Rq)N(Rq)C(O)ORq; –(CH₂)_0–4C(O)Rq; – C(S)Rq; –(CH₂)_0–4C(O)ORq; –(CH₂)_0–4C(O)SRq; -(CH₂)_0–4C(O)OSiRq₃; –(CH₂)_0–4OC(O)Rq; – 26 11991680v1 Attorney Docket No.: 2013105-0050 OC(O)(CH₂)_0–4SR–, SC(S)SR°; –(CH₂)_0–4SC(O)Rq; –(CH₂)_0–4C(O)NRq₂; –C(S)NRq₂; – C(S)SR°; –SC(S)SR°, -(CH₂)_0–4OC(O)NRq₂; -C(O)N(ORq)Rq; –C(O)C(O)Rq; – - – – – (CH₂)_0–4OS(O)₂Rq; –S(O)₂NRq₂; -(CH₂)_0–4S(O)Rq; -N(Rq)S(O)₂NRq₂; –N(Rq)S(O)₂Rq; – N(ORq)Rq; –C(NH)NRq₂; –P(O)₂Rq; -P(O)Rq₂; -OP(O)Rq₂; –OP(O)(ORq)₂; SiRq₃; –(C_1–4 straight or branched alkylene)O–N(Rq)₂; or –(C_1–4 straight or branched alkylene)C(O)O–N(Rq)₂, wherein each Rq may be substituted as defined below and is independently hydrogen, C_{1– 6} aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, -CH₂-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rq, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. Suitable monovalent substituents on Rq (or the ring formed by taking two independent occurrences of Rq together with their intervening atoms), are independently halogen, –(CH₂)_{0– 2}R^z, –(haloR^z), –(CH₂)_0–2OH, –(CH₂)_0–2OR^z, –(CH₂)_0–2CH(OR^z)₂; -O(haloR^z), –CN, –N₃, – 0_– branched alkylene)C(O)OR^z, or –SSR^z wherein each R^z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C_{1– 4} aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of Rq include =O and =S. Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR^* 2, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)₂R^*, =NR^*, =NOR^*, –O(C(R^* 2))_2–3O–, or –S(C(R^* 2))_2–3S–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group 27 11991680v1 Attorney Docket No.: 2013105-0050 include: –O(CR^* 2)_2–3O–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on the aliphatic group of R^* include halogen, – R^z, -(haloR^z), -OH, –OR^z, –O(haloR^z), –CN, –C(O)OH, –C(O)OR^z, –NH₂, –NHR^z, –NR^z 2, or –NO₂, wherein each R^z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R^†, –NR^† 2, –C(O)R^†, –C(O)OR^†, –C(O)C(O)R^†, – C(O)CH₂C(O)R^†, -S(O)₂R^†, -S(O) wherein below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on the aliphatic group of R^† are independently halogen, – R^z, -(haloR^z), –OH, –OR^z, –O(haloR^z), –CN, –C(O)OH, –C(O)OR^z, –NH₂, –NHR^z, –NR^z 2, with one or more or a membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0081] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, an active agent is present in a unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. 28 11991680v1 Attorney Docket No.: 2013105-0050 [0082] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings (and/or animals, where relevant, as will be clear to those skilled in the art) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0083] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary 29 11991680v1 Attorney Docket No.: 2013105-0050 ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. [0084] Physiological conditions: as used herein, has its art-understood meaning referencing conditions under which cells or organisms live and/or reproduce. In some embodiments, the term refers to conditions of the external or internal milieu that may occur in nature for an organism or cell system. In some embodiments, physiological conditions are those conditions present within the body of a human or non-human animal, especially those conditions present at and/or within a target site of interest. Physiological conditions typically include one or more of, e.g., a temperature within the range of 20 – 40 °C (and specifically about 37 °C), atmospheric pressure of 1, pH of 6-8, glucose concentration of 1-20 mM, oxygen concentration at atmospheric levels, and gravity as it is encountered on earth. [0085] Prodrug: As used herein, the term “prodrug” refers to a compound that is a drug precursor which, following administration, releases (e.g., is converted into) the drug in vivo via a chemical or physiological process (e.g., via cleavage as a result of exposure to a particular pH or through action of a particular enzyme or enzymes). [0086] Reference: As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and/or comparison to a particular possible reference or control. [0087] Small molecule: As used herein, the term “small molecule” typically refers to a low molecular weight organic and/or inorganic compound; in many circumstances (as will be clear from context to those skilled in the art), to a low molecular weight organic compound. 30 11991680v1 Attorney Docket No.: 2013105-0050 Typically, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, a small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer. In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid. In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting/inhibitory agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent. [0088] Subject: As used herein, the term “subject” refers to an organism to which a provided conjugate, material, or system is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. In many embodiments, subjects are animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In embodiments of particular interest, a subject is a human. In some embodiments, a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a subject displays one or more symptoms of a disorder or condition. In some embodiments, a subject has been diagnosed with one or more disorders or conditions. In some embodiments, the subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition. In some particular embodiments, a subject is suffering from or susceptible to an ophthalmic disease, disorder or condition. [0089] Symptoms are reduced: According to the present disclosure, “symptoms are reduced” when one or more symptoms of a particular disease, disorder or condition is reduced in 31 11991680v1 Attorney Docket No.: 2013105-0050 magnitude (e.g., intensity, severity, etc.) and/or frequency. For purposes of clarity, a delay in the onset of a particular symptom is considered one form of reducing the frequency of that symptom. [0090] Therapeutic agent: As used herein, the phrase “therapeutic agent” is used to refer to an agent that elicits a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to exhibit an effect (e.g., to be a therapeutic agent) if it demonstrates a statistically significant effect across an appropriate population (i.e., when administered to such population). In some embodiments, an appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by particular criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc., or combination thereof. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. [0091] Treat: As used herein, the terms “treat,” “treatment,” or “treating” are used to refer to partial or complete alleviation, amelioration, delay of onset of, inhibition, prevention, relief, and/or reduction in incidence and/or severity of one or more symptoms or features of a disease, disorder, and/or condition, or achievement of another desired physiological effect. In some embodiments, treatment comprises administration of an agent which results in a physiological effect. In some embodiments, treatment may be administered to a subject who does not exhibit signs or features of a disease, disorder, and/or condition (e.g., may be prophylactic). In some embodiments, treatment may be administered to a subject who exhibits only early or mild signs or features of the disease, disorder, and/or condition, for example for the purpose of decreasing the risk of developing pathology associated with a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits established, severe, and/or late-stage signs of a disease, disorder, or condition. Detailed Description of Certain Embodiments [0092] As described herein, the present disclosure provides certain technologies relating to treatment of ophthalmic conditions and/or improvement of one or more features of ophthalmic tissue or a condition or feature thereof. 32 11991680v1 Attorney Docket No.: 2013105-0050 [0093] Among other things, the present disclosure provides conjugates of a polymer moiety (e.g., a glycopolymer moiety such as a glycosaminoglycan moiety and specifically a hyaluronic acid moiety) with a retention moiety as described herein. The present disclosure further provides various uses of such conjugates and/or materials and/or systems created from or by them (e.g., by cross-linking). In some embodiments, provided conjugates are applied to eyes (e.g., to corneas), e.g., without prior cross-linking and/or without application of an exogenous cross-linker. In some embodiments, provided conjugates are cross-linked (to some degree) prior to application (e.g., to eyes, such as to cornea), and/or are applied together with (e.g., reasonably contemporaneously with, including simultaneously or sequentially – such as before and/or after) a cross-linker. In some embodiments, provided conjugates and/or materials (e.g., films) generated therefrom, interact with (e.g., bind to and/or cross-link with) one or more sites (e.g., chemical moieties) in or on the eye (e.g., on the cornea, such as on surfaces thereof, in proximity to or on tissue surfaces such as the conjunctiva of the eyelid, in tears or in or on the tear film, etc.). [0094] For example, the present disclosure teaches that certain HA conjugates – e.g., those with HA of at least 10 kDa, at least 100 kDa, at least 250 kDa, at least 500 kDa, at least 1000 kDa or even more, such as at least 1500 kDa, at least 2000 kDa, at least 2500 kDa, etc. are particularly well retained and/or otherwise provide particular advantages when applied to ophthalmic tissue (e.g., to corneas). [0095] The present disclosure also teaches that a CBT moiety as described herein may be particularly useful as a retention moiety. Without wishing to be bound by any particular theory, the present disclosure proposes that ability of CBT (and analogs thereof) to form cross-links, for example with cysteines in or on the eye such as on the cornea surface) may contribute to improved retention of HA (e.g., of HA in the conjugate) as described herein. In some embodiments, a cysteine may be an endogenous cysteine. Alternatively or additionally, in some embodiments, a cysteine may be present in a crosslinking agent and/or a crosslink partner such as another HA conjugate (e.g., so that a crosslinked HA material such as a film is formed). In many embodiments, a retention moiety for use in accordance with the present disclosure, is or comprises CBT or an analog thereof. 33 11991680v1 Attorney Docket No.: 2013105-0050 Ophthalmic Conditions [0096] Ophthalmic conditions such as dry eye and dry eye disease are common. Approximately 20M people in the US, and >100M people worldwide, have Dry Eye Disease (DED); a chronic condition related to defective tear film production and/or impaired tear film function. Symptoms of DED include one or more of the following: a stinging or burning sensation of the eyes, an unpleasant sensation of having something in the eye, sensitivity to light, eye redness, difficulty wearing contact lenses, blurred vision, eye redness and eye fatigue. The etiology of dry eye disease is complex and can involve dysregulation of a potentially large number of underlying biological pathways including inflammation. Consequences of this dysregulation may result, for example, in insufficient production of tear film and/or in a tear film that has an altered composition, which impairs its ability to provide moisture or lubricity to the eye. For example, an impaired tear film may result in premature tear film breakup or evaporation. [0097] Healthy ophthalmic function requires that surface tissues of the eye, such as, for example, corneal epithelium, mucosal layer, sclera layers of the eye and/or conjunctival surfaces of the inner eyelids remain moist and lubricious. Signs and symptoms of dry eyes appear, for example, when the quantity and/or quality of tear film components produced is insufficient to wet and lubricate the outer surface of the eye. Defective tear composition may produce unstable tear films that do not persist on the surface of the eye, either through rapid evaporation or premature tear film “breakup”, so that the surface of the eye may dry between sequential blinks of the eyelid. [0098] The tear film consists of a complex of aqueous and lipid components that provide a protective and lubricious layer that overlies the cornea. Components of the tear film are produced by the lacrimal and Meibomian glands. They are distributed over the surfaces of the eye by the eyelid by the process of blinking. Impaired function of the lacrimal and Meibomian glands in dry eye disease results in tear films that either become unstable and undergo premature “breakup” or rapid evaporation resulting in exposure of the cornea to air during the interval between blinks. In addition to serving to maintain adequate moisture and lubricity, the tear film must maintain optical transparency and be present as a uniformly thin layer to avoid refractive anomalies. Proper tear film function is also important to the maintenance of visual acuity. 34 11991680v1 Attorney Docket No.: 2013105-0050 Premature tear film break up or evaporation results in changes that impair the optics of the eye and thus impair vision. [0099] Signs and/or symptoms of dry eye may occur as a result of environmental factors (dry atmospheric conditions) or behavioral factors (staring at computer screens over prolonged periods of time). The condition may be temporary or chronic and due to underlying pathology. Chronic conditions that result in Dry Eye Disease (DED), include diabetes and Sjögrens Disease. [0100] The present disclosure appreciates that, as a chronic condition, dry eye disease requires medical treatments that ameliorate signs and symptoms over a long duration. The present disclosure specifically appreciates the need for safe and effective treatments that can be administered conveniently and with a dosing schedule that supports patient compliance. [0101] Conventional approaches to addressing dry eye disease, or symptoms thereof, include: over-the-counter “Artificial Tear” type products (ATs)– ATs provide temporary relief of dry eye symptoms by introducing viscoelastic polymers onto the surface of the eye that provide lubrication and maintain moisture to improve tear film stability. Many ATs generally consist of aqueous formulations containing glycopolymers (such as HA) that temporarily moisten and lubricate the eyes. They are topically applied in drop form using a squeeze dispenser that delivers a consistent dose to surface of eyes. Resultant drops create a temporary tear like coating on the eye to hydrate and lubricate. [0102] The present disclosure identifies the source of a problem with various conventional technologies, including for example undesirable side effect profiles, poor efficacy, and/or inconvenient dosing. In particular, the present disclosure identifies that many conventional approaches, including specifically approaches that utilize and/or administer viscoelastic polymers require inconvenient dosing. The present disclosure provides an insight that there is a need for technologies that can improve efficacy and/or the durability of administered therapies, including specifically that there is a need for technologies that can improve retention of certain polymer agents when administered to an eye. [0103] The present disclosure teaches that most or all over-the-counter AT therapeutics share a common limitation regarding the durability of relief of symptoms. They typically provide 2-3 hours of symptomatic relief and therefore need to be reapplied frequently to achieve 35 11991680v1 Attorney Docket No.: 2013105-0050 sustained symptomatic relief. For the many individuals with chronic conditions such as DED and Sjögrens Syndrome, this is a major inconvenience, requiring a potentially life-long commitment to frequent reapplication of ATs. The present disclosure provides an insight that the temporary nature of such products may be due, at least in part, to rapid wash out of glycopolymers from the tear film milieu, potentially exacerbated by mechanical forces such as blinking and/or endogenous tear production. The present disclosure provides a solution to this problem – e.g., providing conjugates of relevant polymers (e.g., glycopolymers such as hyaluronic acid polymers) with a retention moiety (e.g., such as CBT or an analog thereof) that, for example, may improve retention of HA in or on the eye. Without wishing to be bound by any particular theory, the present disclosure proposes that interactions (e.g., non-covalent associations and/or covalent bonds such as cross-links) between a retention moiety and eye surfaces (e.g., sites or moieties thereon) can achieve desirable retention of polymer moieties (e.g., glycopolymer moieties such as hyaluronic acid moieties). The present disclosure particularly teaches that agents or entities capable of creating or participating in such interactions may be particularly useful as retention moieties as described herein. Alternatively or additionally, the present disclosure teaches that conjugates, or materials (e.g., films), or systems, formed therefrom that include reactive moieties such as may be capable of binding, and/or specifically of cross-linking, with such sites or moieties on eye surfaces (e.g., corneal surfaces), may be particularly useful in applications as described herein (e.g., for treatment of dry eye disorder, and/or other ophthalmic diseases, disorders or conditions.) [0104] Teachings of the present disclosure are not limited to treatment of dry eye disease. Without wishing to be bound by any particularly theory, the present disclosure proposes that technologies provided herein may be useful, for example, in treatment of one or more diseases, disorders or conditions such as, for example, abrasions (e.g., epithelial/corneal abrasions), blepharitis, corneal ulcers, immunological ocular surface disease, keratitis, neurotrophic corneal defects, and/or thyroid eye disease. Additionally or alternatively, in some embodiments, provided technologies may be useful, for example, as a surgical aid for cataract surgery and/or as treatment for foreign body discomfort and/or general ophthalmic pain relief. In some embodiments, provided technologies may facilitate ophthalmic surgery, for example by coating the ocular surface to enhance visualization. In some embodiments, provided technologies may 36 11991680v1 Attorney Docket No.: 2013105-0050 facilitate surgical treatment of glaucoma, for example, by enhancing aqueous outflow following injection into Schlemm’s Canal. In some embodiments, provided technologies may facilitate tear duct surgery, for example, by coating tear drainage tubular system to enhance tear egress. [0105] Teachings of the present disclosure may be particularly useful when used in conjunction with a contact lens (e.g., when applied to an ocular moiety before the application of a contact lens). The present disclosure provides methods for tuning the thickness of the provided technology. Additionally or alternatively, the present disclosure provides conjugates, materials (e.g., films), and/or systems which are uniform. Without wishing to be bound by any particular theory, conjugates having material properties of being thin and/or uniform may provide particular benefit to the provided technology when used in conjunction with a contact lens. In some embodiments, benefits may include comfort and/or ability to see (e.g., a thick and/or non- uniform layer may produce foreign body sensations, introduce visual anomalies, and/or prevent sufficient gas permeability needed to maintain corneal health). Conjugates [0106] The present disclosure provides technologies that utilize conjugate entities (and/or materials, such as films, generated from them, and/or systems that include them), for example to provide benefit to ocular tissues, including in ophthalmic applications. In many embodiments, a conjugate provided and/or utilized in accordance with the present disclosure includes a polymer moiety, such as a glycopolymer moiety (e.g., a glycosaminoglycan moiety which, in many embodiments, may be a hyaluronic acid moiety) and a retention moiety, covalently linked to one another, optionally via a linker. [0107] Without wishing to be bound by any particular theory, the present disclosure teaches that, in some embodiments, retention may be achieved by virtue of retention moiety contributions and/or contributions from polymer moiety (e.g., through “entanglement” or “interweaving” with endogenous entities or features). [0108] Without wishing to be bound by any particular theory, the present disclosure proposes that retention moieties which include a reactive center capable of interacting (e.g., binding and/or becoming covalently linked) to an ocular structure (e.g., a reactive group) may be particularly useful in accordance with the present disclosure. For example, the present disclosure 37 11991680v1 Attorney Docket No.: 2013105-0050 proposes that, in some embodiments, conjugates (and/or materials, e.g., films formed from them) utilized as described herein may associate (e.g., bind, complex, mix with, integrate into and/or become linked) with tear film and/or ophthalmic tissue surfaces. In some embodiments, such association may permit or achieve persistent association of such conjugates (and/or materials, e.g., films formed from them) with the eye. [0109] In some embodiments, a conjugate as described herein (and/or a material, e.g., a film, which may, in some embodiments, be a monolayer, formed from such conjugate) may be characterized by improved retention at an ocular site as compared, for example, with an appropriate reference, for example, an unconjugated HA (e.g., with a reasonably comparable HA preparation, such as a preparation of the same HA that is present as the HA moiety in the conjugate and/or of the HA that was used to prepare the conjugate, that is not conjugated to, and in some embodiments does not include the retention moiety). [0110] In some embodiments, a conjugate utilized as described herein may include a glycopolymer moiety directly or indirectly (e.g., via a linker) linked to two or more retention moieties; in some such embodiments, a single polymer moiety may be linked with two or more instances of the same retention moiety. Alternatively or additionally, in some embodiments, a single polymer moiety may be linked with two or more different retention moieties. [0111] Analogously, in some embodiments, a polymer moiety that is linked with two or more retention moieties (whether two or more instances of the same retention moiety or two or more different retention moieties, or both) may by indirectly linked (i.e., via a linker) to at least one such retention moiety, more than one such retention moiety, or all such retention moieties. In some embodiments, the same linker is utilized for some or all indirect linkages; in some embodiments at least two different linkers are utilized or a different linker is used for each such indirect linkage. In some embodiments, each instance of the same retention moiety is linked the same way (e.g., is directly linked or is linked via the same linker) to the polymer moiety. In some embodiments, different instances of the same retention moiety may be linked in different ways (e.g., directly vs indirectly and/or indirectly via different linkers) to the polymer moiety. In some embodiments, different retention moieties are linked the same way (e.g., are directly linked or are linked via the same linker) to the polymer moiety. In some embodiments, different 38 11991680v1 Attorney Docket No.: 2013105-0050 retention moieties may be linked in different ways (e.g., directly vs indirectly and/or indirectly via different linkers) to the polymer moiety. [0112] The present disclosure teaches that conjugates (or materials generated from or by them – e.g., films, which may in some embodiments be monolayers, generated from them) particularly useful in accordance with the present disclosure are those that include available reactive group(s) (typically on a retention moiety) capable of interacting (e.g., binding, and particularly, in some embodiments, forming a covalent bond, e.g., via a click chemistry reaction) with one or more sites or entities on or in an eye to which such conjugates or materials are applied. [0113] Thus, for example, in embodiments in which a polymer may be cross-linked before being applied, or substantially contemporaneously with being applied, to an eye, it may be desirable to ensure that, notwithstanding such crosslinking, sufficient reactive groups remain available for in situ interaction with the site of application (e.g., with the eye such as with the cornea, e.g., with the surface thereof) and /or for interaction with other reactive groups which may be sequentially applied to the ocular moiety (e.g., to build up a conjugate layer/ tune thickness of a layer). Those skilled in the art, reading the present disclosure, will appreciate how conditions of crosslinking performed prior to or substantially simultaneously with such application may be adjusted to maintain a desirable level of reactive groups. [0114] The present disclosure teaches that particularly useful retention moieties for use in accordance with the present disclosure may be or be derived from CBT or analogs thereof. [0115] The present disclosure particularly teaches that certain HA conjugates – e.g., those with HA of (e.g., prepared from preparations of HA of) at least 10 kDa, at least 100 kDa, at least 250 kDa, at least 500 kDa, at least 1000 kDa or even more, such as at least 1500 kDa, at least 2000 kDa, at least 2500 kDa, etc. are particularly well retained and/or otherwise provide particular advantages when applied to ophthalmic tissue (e.g., to corneas). In some embodiments, the present disclosure teaches that conjugates with HA of (e.g., prepared from preparations of HA of) molecular weight within a range of about 10 to about 2500 kDa, or about 10 to about 2000 kDa, or about 10 kDa to about 1500 kDa, or about 10 kDa to about 1000 kDa, or about 10 kDa to about 500 kDa, or about 10 kDa to about 250 kDa, or about 250 kDa to about 39 11991680v1 Attorney Docket No.: 2013105-0050 2500 kDa, or about 250 kDa to about 2000 kDa, or about 250 kDa to about 1500 kDa, or about 250 kDa to about 1000 kDa, or about 250 kDa to about 500 kDa, or about 500 kDa to about 2500 kDa, or about 500 kDa to about 2000 kDa, or about 500 kDa to about 1500 kDa, or about 500 kDa to about 1000 kDa, or about 1000 kDa to about 2500 kDa, or about 1000 kDa to about 2000 kDa, or about 1000 kDa to about 1500 kDa, or about 1000 kDa, may be particularly well retained and/or otherwise provide particular advantages when applied to ophthalmic tissue (e.g., to corneas). In particular embodiments, especially useful conjugates include such HA conjugated to a CBT moiety as described herein. [0116] In some embodiments, higher molecular weight (e.g., 1000 kDa) and/or lower molecular weight (e.g., 10 kDa) HAs may be useful, for example, if cross-linked, e.g., prior to or substantially contemporaneously with application to the eye as described herein. In some embodiments, higher molecular weight (e.g., 1000 kDa) HAs may be useful. In some embodiments, lower molecular weight (e.g., 10 kDa) HAs may be useful. In some embodiments, a prepared conjugate as described herein has a structure as generally set out in formula (II), which may be utilized in a pharmaceutically acceptable salt form: wherein A is a polymer moiety; B is a retention moiety; L is an optional linker; and n is any value such that the mole% of B relative to A is between 0.1-100%. [0117] In some embodiments, the mole% of B relative to A is 1%. In some embodiments, the mole% of B relative to A is 2%. In some embodiments, the mole% of B relative to A is 5%. In some embodiments, the mole% of B relative to A is 10%. In some embodiments, the mole% of B relative to A is 20%. In some embodiments, the mole% of B relative to A is 50%. In some embodiments, the mole% of B relative to A is between 1 and 2%. In some embodiments, the mole% of B relative to A is between 1 and 5%. In some embodiments, the mole% of B relative to 40 11991680v1 Attorney Docket No.: 2013105-0050 A is between 1 and 10%. In some embodiments, the mole% of B relative to A is between 5 and 10%. In some embodiments, the mole% of B relative to A is between 1 and 50%. [0118] In many embodiments, a conjugate as described herein may possess all the elements of formula II, but absent any optional linker (I.e., A is directly linked to B). [0119] In some embodiments, a conjugate has a structure as set forth in formula (II-a), which may be utilized in a pharmaceutically acceptable salt form: wherein A is a polymer moiety; L is an optional linker; R¹ is independently at each occurrence –H, halogen, –CN, optionally substituted C_1-6 aliphatic, optionally substituted 5-10-membered heterocyclyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5-10-membered heteroaryl; R² is –H, halogen, –CN, optionally substituted C_1-6 aliphatic, optionally substituted 5- 10-membered heterocyclyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5-10-membered heteroaryl; and m is 1-4. [0120] In some embodiments, a conjugate has a structure as set forth in formula (II-b), which may be utilized in a pharmaceutically acceptable salt form: wherein A, L, R¹, R², and m are defined herein. 41 11991680v1 Attorney Docket No.: 2013105-0050 [0121] In some embodiments, a conjugate has a structure as set forth in formula (II-c), which may be utilized in a pharmaceutically acceptable salt form: wherein A is defined [0122] In some embodiments, a conjugate has a structure as set forth in formula (II-d), which may be utilized in a pharmaceutically acceptable salt form: wherein A is defined herein. [0123] In some embodiments, a conjugate has a structure as set forth in formula (II-e), which may be utilized in a pharmaceutically acceptable salt form: (II-e), wherein A is defined herein. [0124] In some embodiments, a conjugate has a structure as set forth in formula (III), which may be utilized in a pharmaceutically acceptable salt form: 11991680v1 Attorney Docket No.: 2013105-0050 wherein A is a polymer moiety; B is a retention moiety; L is an optional linker; and n is 1-100, wherein each of A, B, L, and n may be defined as set forth elsewhere herein. [0125] In many embodiments, a conjugate as described herein may possess all the elements of formula III, but absent any optional linker (I.e., A is directly linked to B). [0126] In some embodiments of any one of formulas (II) (including formula (II-a), formula (II-b), formula (II-c), formula (II-d) and formula (II-e)), or formula (III), a polymer moiety may be, for example, a glycopolymer moiety such as a glycosaminoglycan moiety, and specifically a hyaluronic acid moiety as described herein. [0127] Without wishing to be bound by any particular theory, the present disclosure proposes that conjugates as described herein may include polymer moieties (e.g., hyaluronic acid or other glycopolymer moieties) that may impart benefits when delivered and/or administered to an ocular site and/or retention moieties that may be characterized as capable of interaction, for example, with certain endogenous components present at or on a surface of an ocular site. For example, in some particular embodiments, it is proposed that conjugates as described herein may include retention moieties that associate (e.g., non-covalently, and in some embodiments, covalently) with site(s) on or in the eye (e.g., on or in the cornea). Again without wishing to be bound by any particular theory, the present disclosure proposes that provided conjugates may be retained (e.g., by virtue of interaction, for example covalent interaction, between retention moiety(ies) and endogenous group(s)) at or on a surface of an ocular site, thereby retaining the conjugate on the eye, and, for example, extending the period over which a benefit provided by a polymer moiety is conferred. Without wishing to be bound by any particular theory, the present disclosure proposes that conjugate layers may be built on top of one another using the method described herein, which may impart certain beneficial properties to the conjugate (e.g., thickness, smoothness, strength, etc.). As noted above and elsewhere herein, in some embodiments, polymer and retention moiety(ies) may be directly associated with one another (e.g., directly linked via a covalent bond); in some embodiments, polymer and retention moiety(ies) may be 43 11991680v1 Attorney Docket No.: 2013105-0050 indirectly associated with one another (e.g., covalently linked via a linker). Those of ordinary skill in the art will appreciate that, in many embodiments, association (e.g., covalent linkage) between a polymer moiety and a retention moiety is such that interaction of such retention moiety with an ocular surface serves to retain its covalently linked polymer moiety at or on such surface. In some embodiments, a conjugate as described herein (and/or a material, e.g., a film formed from such conjugate) may be characterized by improved retention at an ocular site as compared, for example, with an appropriate reference unconjugated polymer moiety (e.g., an unconjugated glycopolymer such as an unconjugated HA) which may, for example, be or comprise a reasonably comparable HA preparation, such as a preparation of the same HA that is present as the HA moiety in the conjugate and/or of the HA that was used to prepare the conjugate, that is not conjugated to, and in some embodiments does not include the retention moiety. [0128] In some embodiments, a conjugate utilized as described herein may include a glycopolymer moiety directly or indirectly (e.g., via a linker) linked to two or more retention moieties; in some such embodiments, a single polymer moiety may be linked with two or more instances of the same retention moiety. Alternatively or additionally, in some embodiments, a single polymer moiety may be linked with two or more different retention moieties. [0129] In some embodiments, association between a polymer moiety and retention moiety as described herein may involve chemical conjugation; in some embodiments chemical conjugation may be or comprise click chemistry. Alternatively or additionally, in some embodiments, association between a retention moiety and an ocular site or moiety (e.g., on a corneal surface) may involve chemical conjugation, for example by click chemistry. Still further, in some embodiments, association of an “other” entity with a polymer moiety and/or with a retention moiety (and particularly with a retention moiety) as described herein may involve chemical conjugation, for example by click chemistry. In embodiments, any or all such associations may be indirect (i.e., via a linker). [0130] In some embodiments, a conjugate as described herein may be present within a system, containing one or more other agents, for example that may be useful for assessment or application of a conjugate or material as described herein. In some such embodiments, one or more conjugates containing different polymer moieties, retention moieties or linkers may be 44 11991680v1 Attorney Docket No.: 2013105-0050 utilized. In some embodiments, a conjugate as described herein may act as an anchor which may be leveraged to bind and/or deliver other agents, drugs, and/or surfactants (e.g., via subsaturation of the retention moiety), for example. Polymer Moiety [0131] The present disclosure provides technologies that utilize conjugate entities (and/or materials, such as films, generated from them, and/or systems that include them) to provide benefit to ocular tissues, including in ophthalmic applications. The present disclosure teaches that, in some embodiments, a conjugate provided and/or utilized in accordance with the present disclosure includes a polymer moiety capable of providing benefit to an ocular site when in contact therewith. Indeed, in some aspects, the present disclosure provides improvements to useful polymers achieved by conjugating them to retention moieties as described herein so that their retention at such ocular site(s) can be extended. In some embodiments, the present disclosure provides conjugates of a polymer moiety that show extended retention relative to a comparable preparation of the same polymer moiety when not so conjugated. Those skilled in the art, reading the present disclosure, will appreciate that conjugates as provided and/or utilized herein are typically produced by linking a retention moiety as described herein with a preparation of a polymer moiety. Those skilled in the art will further appreciate that such polymer moiety preparations are typically not perfectly uniform compositions but rather include some structural diversity of the polymers within them. Those skilled in the art will appreciate that polymer preparations (including, e.g., as may be purchased commercially or prepared) are typically characterized by a molecular weight, or molecular weight range, which is typically representative of an average or median molecular weight of polymer in the preparation. [0132] Still further, those skilled in the art will appreciate that polymer preparations are typically characterized by a polydispersity index, reflecting the weight average divided by the number average molecular weight (M_W/M_n), which provided an assessment of the molecular weight distribution in a polymer preparation. [0133] In some embodiments, conjugates as described and/or utilized herein are prepared from polymer preparations with a PDI within a range of about 1 to about 5, in some 45 11991680v1 Attorney Docket No.: 2013105-0050 embodiments, within a range of about 1.5 to 3.5 to about 1.5 to 2.0. In some embodiments, conjugates as described and/or utilized herein are prepared from polymer preparations with a PDI of about 1.75. [0134] The present disclosure particularly teaches that provided technologies are particularly applicable to (e.g., beneficial when applied to) polymer moieties that are glycopolymer moieties, such as glycosaminoglycan moieties. [0135] In certain embodiments, the present disclosure provides and/or utilizes certain HA conjugates – e.g., those with HA of (e.g., prepared from preparations of HA of) at least 10 kDa, at least 100 kDa, at least 250 kDa, at least 500 kDa or, better yet, at least 1000 kDa or even more, such as at least 1500 kDa, at least 2000 kDa, at least 2500 kDa, etc.; the present disclosure teaches that such HA conjugates are particularly well retained and/or otherwise provide particular advantages when applied to ophthalmic tissue (e.g., to corneas). In some embodiments, the present disclosure teaches that conjugates with HA of (e.g., prepared from preparations of HA of) molecular weight within a range of about 10 to about 2500 kDa, or about 10 to about 2000 kDa, or about 10 kDa to about 1500 kDa, or about 10 kDa to about 1000 kDa, or about 10 kDa to about 500 kDa, or about 10 kDa to about 250 kDa, or about 250 kDa to about 2500 kDa, or about 250 to about 2000 kDa, or about 250 kDa to about 1500 kDa, or about 250 kDa to about 1000 kDa, or about 250 kDa to about 500 kDa, or about 500 kDa to about 2500 kDa, or about 500 kDa to about 2000 kDa, or about 500 kDa to about 1500 kDa, or about 500 kDa to about 1000 kDa, or 1000 kDa to about 2500 kDa, or about 1000 kDa to about 2000 kDa, or about 1000 kDa to about 1500 kDa, or about 1000 kDa, may be particularly well retained and/or otherwise provide particular advantages when applied to ophthalmic tissue (e.g., to corneas). In particular embodiments, especially useful conjugates include such HA conjugated to a CBT moiety as described herein. [0136] In some embodiments, higher molecular weight and/or lower molecular weight HAs may be useful, particularly, for example, if cross-linked, e.g., prior to or substantially contemporaneously with application to the eye as described herein. In some embodiments higher molecular weight HAs may be useful. In some embodiments, lower molecular weight HAs may be useful. In some embodiments, the present disclosure teaches that HA conjugates, including but not limited to, those prepared from higher molecular weight (e.g., 1000 kDa) and/or lower 46 11991680v1 Attorney Docket No.: 2013105-0050 molecular weight HA (e.g., 10 kDa), may be assembled, for example, into a hydrogel (or other such useful material or formulation) via reaction with a cross-linker capable of reacting with, for example, a CBT moiety of the prepared conjugate. In some embodiments, HA conjugates prepared higher molecular weight HA (e.g., 1000 kDa) may be assembled into a hydrogel. In some embodiments, HA conjugates prepared lower molecular weight HA (e.g., 10 kDa) may be assembled into a hydrogel. In some embodiments, a material prepared by reaction of an HA conjugate with a cross-linker as described herein may be characterized by a degree of cross- linking between 0.1 to 100%. In some embodiments, a material comprised of a prepared conjugate as described herein, may be particularly useful, for example, in creating more stable and/or thicker films for application, for example, in eye protection, wound repair, or other such ophthalmic applications. In some embodiments, a material comprised of a prepared conjugate as described herein, may be particular useful in conferring a range of ophthalmic benefits, for example, stabilization or improvement of the function of the tear film, retention of moisture on ocular surface of tissues, maintenance of lubricity of ocular surface of tissues and/or serving as a protective barrier to protect eye tissues from subsequent injury (e.g., trauma, surgery, disease). [0137] In some embodiments, HA, as described herein may be utilized as one of several pharmaceutically relevant hyaluronate salts. In some embodiments, a glycopolymer moiety may be carboxymethylcellulose or a pharmaceutically equivalent analog thereof. In some embodiments, a glycopolymer payload may be one or more of various glycosaminoglycans. Examples of suitable glycosaminoglycans include, but are not limited to, heparan sulphate, heparin, chondroitin sulphate, dermatan sulphate, and keratan sulphate. In some embodiments, a glycosaminoglycan may be in the form of a glycosaminoglycan-based protein glycan, including for example, versican, perlecan, glypican, syndecan, decorin. Retention Moiety [0138] In some embodiments, the present disclosure provides and/or utilizes conjugates (and/or materials, such as films, generated from them, and/or systems that include them) which comprise one or more payload and retention moieties, optionally associated with one another via a linker(s). 47 11991680v1 Attorney Docket No.: 2013105-0050 [0139] In some embodiments, the present disclosure provides an insight that certain retention moieties surprisingly can impart to a conjugate as described herein an ability to exhibit retention at the ocular surface to a desired extent (e.g., hours, days or weeks). [0140] In those embodiments that may comprise a plurality of retention moieties, such retention moieties may, in some embodiments all be the same; in other embodiments, a provided system may comprise a plurality of distinct retention moieties. [0141] For example, in some embodiments, a retention moiety useful in accordance with the present disclosure is characterized by a particular degree of interaction with the ocular surface, for example, when associated (e.g., linked) with a particular polymer moiety. [0142] Those skilled in the art, reading the present disclosure, will appreciate that, in some embodiments, interaction with the ocular surface of a retention moiety comprising a particular polymer moiety may be adjusted, for example through linkage of a plurality of retention moieties (e.g., containing different reaction centers), which may be the same or different and which, individually or together, may be considered or constitute a retention moiety as described herein. [0143] The present disclosure teaches that CBT, or analogs thereof, may be particularly useful as retention moieties for inclusion in conjugates as described herein. [0144] In some embodiments, a retention moiety (e.g., “B” in formulae (II) and (III) herein) may be or comprise optionally substituted benzothiazole. In some embodiments, a retention moiety may be or comprise cyanobenzothiazole (CBT). In some embodiments, a retention moiety may be or comprise 2-cyano-6-hydroxybenzothiazole. In some embodiments, a retention moiety may be or comprise D-luciferin, L-luciferin, D-Aminoluciferin, or L- Aminoluciferin. In some embodiments, a retention moiety may be or comprise a molecule other than benzothiazole. [0145] In some embodiments, a retention moiety may be or comprise a moiety of formula (I): 48 11991680v1 Attorney Docket No.: 2013105-0050 wherein R¹, R², and m are [0146] In some embodiments, a retention moiety may be or comprise a moiety of formula (I-a): (I-a), wherein R¹ and m are defined herein. [0147] In some embodiments, a retention moiety may be or comprise a moiety of formula (I-b): wherein R¹ and m are defined herein. [0148] Without wishing to be bound by any particular theory, the present disclosure proposes that retention moieties as described herein (e.g., CBT and/or analogs thereof, or otherwise appropriately lipophilic entities) may interact with one or more proteins found at or on the ocular surface or tear film, with sufficient strength (e.g., as may be characterized, for example, by measurement of K_a and/or K_d, and/or assessment of stability to expected disruption conditions, such as presence of a solvent such as Triton-X, methanol and/or dichloromethane). It will be appreciated by a person of skill in the art, upon reading the present disclosure that retention moieties may interact with a target area, for example, ocular surface or tear film, through covalent and/or noncovalent interactions, and in some embodiments through covalent 49 11991680v1 Attorney Docket No.: 2013105-0050 interactions (e.g., covalent bonds formed, for example, with cysteine residues, and in particular with terminal cysteines such as may be found in one or more proteins in a target area of interest). [0149] Without wishing to be bound by any particular theory, we note that retention moieties as described herein can, in some embodiments, impart a beneficial penetration ability to a provided conjugate. In some embodiments, penetration may be into and/or possibly through the epithelial layer. In some embodiments, penetration as described in the present disclosure, when occurring at the ocular surface, may for example, achieve a smoothing of the cornea. [0150] Additional chemical structures of benzothiazoles include, but are not limited to, those described in European Journal of Medicinal Chemistry, 5 June 2015, Vol.97, pp.911-927, Curr Top Med Chem.2017;17(2):208-237, PLANT SOIL ENVIRON., 51, 2005 (11): 496–505, Medicinal Chemistry Research, September 2012, Volume 21, Issue 9, pp 2644–2651. Linkers [0151] In some embodiments, a conjugate, as described in the present disclosure, comprises one or more linkers. [0152] For example, in some embodiments, a conjugate includes a linker which conjugates a polymer moiety and a retention moiety. Alternatively or additionally, in some embodiments, a conjugate includes a linker which conjugates a polymer moiety (and/or a retention moiety) with an “other” moiety. [0153] In some embodiments, a linker moiety is referred to as “L”. In some embodiments, a linker may be cleavable or degradable under biological conditions. In some embodiments, a linker may be non-cleavable and/or non-degradable under biological conditions. In some embodiments, a linker may degrade via hydrolysis or enzymatic reaction. In some embodiments, a linker may be cleavable through application of a cleavage promoter (e.g., an electrical, chemical, and/or enzymatic stimulus). In some embodiments, a linker degrades (e.g., over and/or within a specified period of time, such as within hours, days, weeks, or months) after administration of the system. 50 11991680v1 Attorney Docket No.: 2013105-0050 [0154] In particular embodiments, a linker which conjugates a polymer moiety (and/or a retention moiety) with an “other” moiety, and particularly with another moiety that is or comprises a therapeutic agent, is cleavable or degradable. [0155] In some embodiments, conjugation of a two or more moieties with one another can be mediated by a chemical reaction that involves an amine group. In some embodiments, a linker may comprise an amine group. In some embodiments, a linker may comprise an amide group. In some embodiments, a linker may be a bond. [0156] In some embodiments, a conjugate as described herein may include an encapsulating component; in some such embodiments, association of a retention moiety with a glycopolymer moiety as described herein may be via such encapsulating component, e.g., liposomes, nanoparticles, micelles, etc. [0157] In some embodiments, a linker may be associated with a moiety as described herein (e.g., with a polymer moiety, a retention moiety, and/or an “other” moiety) via chemical conjugation; in some embodiments chemical conjugation may be or comprise click chemistry. Thus, in some embodiments, a conjugate as described and/or utilized herein may be formed by and/or may participate in a chemical linkage reaction, e.g., a click chemistry reaction. [0158] In some embodiments, L is selected from the group consisting of –NH–, –O–, –S– , –S(O)–, –S(O)₂–, and –C(O)–. In some embodiments, L is –NH–. In some embodiments, L is – O–. In some embodiments, L is –S–. In some embodiments, L is –S(O)–. In some embodiments, L is –S(O)₂–. In some embodiments, L is –C(O)NH–. In some embodiments, L is –NHC(O)–. In some embodiments, L is –C(O)–. In some embodiments, L is –C(O)O—. In some embodiments, L is --OC(O)--. [0159] In some embodiments, L is polyethylene glycol (PEG). In some embodiments, L may be an ethylene diamine, e.g., a polyethylene glycol diamine, etc. [0160] In some embodiments, L comprises a moiety which results from a “click” reaction. In some embodiments, L comprises a triazole. In some embodiments, L comprises an imine. In some embodiments, L comprises an oxime. In some embodiments, L comprises a hydrazine. In some embodiments, L comprises a moiety which results from a nucleophilic 51 11991680v1 Attorney Docket No.: 2013105-0050 addition. In some embodiments, L comprises a moiety which results from a Michael addition. In some embodiments, L comprises a thiol-ene. [0161] In some embodiments, L is an optionally substituted C_1-6 alkylene chain wherein one, two, or three methylene units of L are optionally and independently replaced by –NH–, –O–, –S–, –S(O)–, –S(O)₂–, or –C(O)–A variety of techniques may be used for conjugating or associating the retention to an active agent. Other Moieties [0162] In some embodiments, a conjugate (and/or materials, such as films, generated from them, and/or systems that include them) as provided and/or utilized herein may furthermore include, or otherwise be associated with, another moiety (i.e., other than the polymer moiety and the retention moiety). [0163] In some embodiments, an “other” moiety is referred to herein as a “payload”. In some embodiments, a “payload” is released from a conjugate or composition (e.g., film, such as a monolayer) after application to an eye. In some embodiments, a payload is retained in association with such conjugate or composition after application to an eye. [0164] For example, in some embodiments, a relevant conjugate may include or be associated with an active agent (e.g., a biologically active agent such as a therapeutic agent) and/or a detectable agent, etc., so that such other moiety is retained (and/or released from the conjugate/ from association of a retained system) on the eye (e.g., to an extent and/or for a time greater than it is under otherwise comparable conditions not included in or otherwise associated with the conjugate, or at least the retention moiety). [0165] In some embodiments, a conjugate provided and/or utilized herein (and/or a material or system comprising or made from such conjugate) may include or otherwise be associated with an “other” moiety which, in some embodiments, may be or comprise a therapeutic agent or a detectable moiety. In some embodiments, a conjugate (and/or a material or system comprising or made from such conjugate) may include or otherwise be associated with a plurality of “other” moieties. In those embodiments that may comprise a plurality of payload moieties, such payload moieties may, in some embodiments, include a plurality of incidences of 52 11991680v1 Attorney Docket No.: 2013105-0050 the same “other” moiety and, in some embodiments may all be the same “other” moiety; alternatively or additionally, in some embodiments embodiments, a provided conjugate, material, or system may comprise a plurality of distinct “other” moieties (and, in some embodiments, may comprise a plurality of instances of one or more, or each distinct “other” moiety). [0166] In some embodiments, an “other” moiety (e.g., a polymer moiety such a therapeutic agent or a detectable moiety) is non-covalently associated (e.g., as a separate physical entity) with a conjugate, material or system as described herein. Alternatively or additionally, in some embodiments, an “other” moiety (e.g., a polymer moiety such a therapeutic agent or a detectable moiety) is covalently associated with a conjugate or material or system formed from or comprising it, for example by a linker. In many such embodiments, such linker is a cleavable linker (e.g., so that the “other” entity may, in some embodiments, be released after application of the conjugate, material or system to the eye. [0167] Thus, in some embodiments, an “other” moiety (e.g., a polymer moiety such a therapeutic agent or a detectable moiety) may be incorporated within a material (e.g., within a film), e.g., via non-covalent or covalent association as described above (e.g., via a covalent linker which in some embodiments may be a cleavable linker). In some such embodiments, such incorporation may be accomplished prior to application of the material to the eye; alternatively or additionally, in some such embodiments, such incorporation may be achieved substantially simultaneously with or shortly after administration of a conjugate, or a system or material formed from or including it, to the eye. In some embodiments, incorporation of an “other” moiety (or entity) within a material may result in “extended release” of such material to the eye. [0168] In some embodiments a polymer moiety (e.g., a therapeutic agent) is or comprises a polypeptide (e.g., an antibody or antigen- binding portion thereof, an enzyme, etc.) or peptidomimetic, a lipid, a nucleic acid, a (poly)saccharide, a small molecule, etc., or a combination thereof. In some embodiments, a polymer moiety (e.g., a therapeutic agent) is or comprises a polymer or includes a polymeric portion. [0169] In some embodiments, an “other” moiety – e.g., which may be or comprise a therapeutic or detectable agent - is a small molecule or low molecular weight compound, e.g., a 53 11991680v1 Attorney Docket No.: 2013105-0050 molecule or compound having a molecular weight of less than or equal to about 1000 Daltons, e.g., less than or equal to about 800 Daltons. Exemplary Therapeutic Agents [0170] In some embodiments, an “other moiety” as described herein may be or comprise a therapeutic agent. [0171] In some embodiments, a therapeutic agent may be directed to one or more of the following drug targets: Kringle domain, Carboxypeptidase, Carboxylic ester hydrolases, Glycosylases, Rhodopsin-like dopamine receptors, Rhodopsin-like adrenoceptors, Rhodopsin- like histamine receptors, Rhodopsin-like serotonin receptors, Rhodopsin-like short peptide receptors, Rhodopsin-like acetylcholine receptors, Rhodopsin-like nucleotide-like receptors, Rhodopsin-like lipid-like ligand receptors, Rhodopsin-like melatonin receptors, Metalloprotease, Transporter ATPase, Carboxylic ester hydrolases, Peroxidase, Lipoxygenase, DOPA decarboxylase, A/G cyclase, Methyltransferases, Sulphonylurea receptors, other transporters (e.g., Dopamine transporter, GABA transporter 1, Norepinephrine transporter, Potassium- transporting ATPase α-chain 1, Sodium-(potassium)-chloride cotransporter 2, Serotonin transporter, Synaptic vesicular amine transporter, and Thiazide-sensitive sodium-chloride cotransporter), Electrochemical nucleoside transporter, Voltage-gated ion channels, GABA receptors (Cys-Loop), Acetylcholine receptors (Cys-Loop), NMDA receptors, 5-HT3 receptors (Cys-Loop), Ligand-gated ion channels Glu: kainite, AMPA Glu receptors, Acid-sensing ion channels aldosterone, Ryanodine receptors, Vitamin K epoxide reductase, MetGluR-like GABAB receptors, Inwardly rectifying K⁺ channel, NPC1L1, MetGluR-like calcium-sensing receptors, Aldehyde dehydrogenases, Tyrosine 3-hydroxylase, Aldose reductase, Xanthine dehydrogenase, Ribonucleoside reductase, Dihydrofolate reductase, IMP dehydrogenase, Thioredoxin reductase, Dioxygenase, Inositol monophosphatase, Phosphodiesterases, Adenosine deaminase, Peptidylprolyl isomerases, Thymidylate synthase, Aminotransferases, Farnesyl diphosphate synthase, Protein kinases, Carbonic anhydrase, Tubulins, Troponin, Inhibitor of IκB kinase-β, Amine oxidases, Cyclooxygenases, Cytochrome P450s, Thyroxine 5-deiodinase, Steroid dehydrogenase, HMG-CoA reductase, Steroid reductases, Dihydroorotate oxidase, 54 11991680v1 Attorney Docket No.: 2013105-0050 Epoxide hydrolase, Transporter ATPase, Translocator, Glycosyltransferases, Nuclear receptors NR3 receptors, Nuclear receptors: NR1 receptors, or Topoisomerase. [0172] In some embodiments, a therapeutic agent targets one of rhodopsin-like GPCRs, nuclear receptors, adrenergic receptors, cholinergic receptors, ligand-gated ion channels, voltage- gated ion channels, penicillin-binding protein, myeloperoxidase-like, sodium: neurotransmitter symporter family, type II DNA topoisomerase, fibronectin type III, or cytochrome P450. [0173] In some embodiments, a therapeutic agent is or comprises an anticancer agent. Suitable anticancer agents include, but are not limited to, Actinomycin D, Alemtuzumab, Allopurinol sodium, Amifostine, Amsacrine, Anastrozole, Ara-CMP, Asparaginase, Azacytadine, Bendamustine, Bevacizumab, Bicalutimide, Bleomycin (e.g., Bleomycin A2 and B2), Bortezomib, Busulfan, Camptothecin sodium salt, Capecitabine, Carboplatin, Carmustine, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Daunorubicin liposomal, Dacarbazine, Decitabine, Docetaxel, Doxorubicin, Doxorubicin liposomal, Epirubicin, Estramustine, Etoposide, Etoposide phosphate, Exemestane, Floxuridine, Fludarabine, Fludarabine phosphate, 5-Fluorouracil, Fotemustine, Fulvestrant, Gemcitabine, Goserelin, Hexamethylmelamine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Irinotecan, Ixabepilone, Lapatinib, Letrozole, Leuprolide acetate, Lomustine, Mechlorethamine, Melphalan, 6-Mercaptopurine, Methotrexate, Mithramycin, Mitomycin C, Mitotane, Mitoxantrone, Nimustine, Ofatumumab, Oxaliplatin, Paclitaxel, Panitumumab, Pegaspargase, Pemetrexed, Pentostatin, Pertuzumab, Picoplatin, Pipobroman, Plerixafor, Procarbazine, Raltitrexed, Rituximab, Streptozocin, Temozolomide, Teniposide, 6-Thioguanine, Thiotepa, Topotecan, Trastuzumab, Treosulfan, Triethylenemelamine, Trimetrexate, Uracil Nitrogen Mustard, Valrubicin, Vinblastine, Vincristine, Vindesine, Vinorelbine, and analogues, precursors, derivatives and pro-drugs thereof. It should be noted that two or more of the above compounds may be used in combination in a prepared conjugate, or a composition comprising a prepared conjugate, as described herein. [0174] In some embodiments, a therapeutic agent may be or comprise an opioid or derivative thereof, and/or an opioid receptor agonist or antagonist, e.g., any of naltrexone, naloxone, nalbuphine, fentanyl, sufentanil, oxycodone, or a pharmaceutically acceptable salt or derivatives thereof. 55 11991680v1 Attorney Docket No.: 2013105-0050 [0175] In some embodiments, suitable therapeutic agents may be selected from anti- neoplastic agents, immunological agents, and neurological agents among others. In some embodiments, suitable therapeutic agents may include, for example, local anesthetics, anti- inflammatory, anti-proliferatives, anti-infectives (such as anti-virals, anti-fungals, or anti- bacterial), etc. Additionally or alternatively, suitable therapeutic agents may include antihistamines, corticosteroids, NSAIDs, beta receptor blockers for glaucoma treatment, carbonic anhydrase inhibitors for treatment of ocular hypertension and glaucoma, prostaglandins for glaucoma treatment, sympathomimetics for eye exams, etc. In some embodiments, suitable therapeutic agents may include steroids, glaucoma medications, and pilocarpine for presbyopia. [0176] In some embodiments, a therapeutic agent is described in U.S. Patent No. 8,791,062, incorporated by reference herein. [0177] In some embodiments, a suitable therapeutic agent is selected from: 16-17α- Epoxyprogesterone (CAS Registry Number:1097-51-4), P-methoxycinnamic acid/4- Methoxycinnamic acid (CAS Registry Number:830-09-1), Octyl Methoxycinnamate (CAS Registry Number:5466-77-3), , Methyl p-methoxy cinnamate (CAS Registry Number:832-01-9), 4-ESTREN-17β-OL-3-ONE (CAS Registry Number:434-22-0), Ethyl-p-anisoyl acetate (CAS Registry Number:2881-83-6), Dihydrouracil (CAS Registry Number:504-07-04), Lopinavir (CAS Registry Number:192725-17-0), RITANSERIN(CAS Registry Number:87051-43-2), Nilotinib (CAS Registry Number:641571-10-0); Rocuronium bromide (CAS Registry Number:119302-91-9), p-Nitrobenzyl-6-(1-hydroxyethyl)-1-azabicyclo(3.2.0)heptane-3,7-dione- 2-carboxylate (CAS Registry Number:74288-40-7), Abamectin (CAS Registry Number:71751- 41-2), Paliperidone (CAS Registry Number:144598-75-4), Gemifioxacin (CAS Registry Number:175463-14-6), Valrubicin (CAS Registry Number:56124-62-0), Mizoribine (CAS Registry Number:50924-49-7), Solifenacin succinate (CAS Registry Number:242478-38-2), Lapatinib (CAS Registry Number:231277-92-2), Dydrogesterone (CAS Registry Number:152- 62-5), 2,2-Dichloro-N-[(1R,2S)-3-fluoro-1-hydroxy-1-(4-methylsulfonylphenyl)propan-2- yl]acetamide (CAS Registry Number:73231-34-2), Tilmicosin (CAS Registry Number:108050- 54-0), Efavirenz (CAS Registry Number:154598-52-4), Pirarubicin (CAS Registry Number:72496-41-4), Nateglinide (CAS Registry Number:105816-04-4), Epirubicin (CAS Registry Number:56420-45-2), Entecavir (CAS Registry Number:142217-69-4), Etoricoxib 56 11991680v1 Attorney Docket No.: 2013105-0050 (CAS Registry Number:202409-33-4), Cilnidipine (CAS Registry Number:132203-70-4), Doxorubicin hydrochloride (CAS Registry Number:25316-40-9), Escitalopram (CAS Registry Number:128196-01-0), Sitagliptin phosphate monohydrate (CAS Registry Number: 654671-77- 9), Acitretin (CAS Registry Number:55079-83-9), Rizatriptan benzoate (CAS Registry Number:145202-66-0), Doripenem (CAS Registry Number:148016-81-3), Atracurium besylate (CAS Registry Number:64228-81-5), Nilutamide (CAS Registry Number:63612-50-0), 3,4- Dihydroxyphenylethanol (CAS Registry Number:10597-60-1), KETANSERIN TARTRATE (CAS Registry Number:83846-83-7), Ozagrel (CAS Registry Number:82571-53-7), Eprosartan mesylate (CAS Registry Number:144143-96-4), Ranitidine hydrochloride (CAS Registry Number:66357-59-3), 6,7-Dihydro-6-mercapto-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (CAS Registry Number:153851-71-9), Sulfapyridine (CAS Registry Number:144-83-2), Teicoplanin (CAS Registry Number:61036-62-2), Tacrolimus (CAS Registry Number:104987- 11-3), LUMIRACOXIB (CAS Registry Number:220991-20-8), Allyl alcohol (CAS Registry Number:107-18-6), Protected meropenem (CAS Registry Number:96036-02-1), Nelarabine (CAS Registry Number:121032-29-9), Pimecrolimus (CAS Registry Number:137071-32-0), 4- [6-Methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2- yloxyphenyl)piperazine-1-carboxamide (CAS Registry Number:387867-13-2), Ritonavir (CAS Registry Number:155213-67-5), Adapalene (CAS Registry Number:106685-40-9), Aprepitant (CAS Registry Number:170729-80-3), Eplerenone (CAS Registry Number:107724-20-9), Rasagiline mesylate (CAS Registry Number:161735-79-1), Miltefosine (CAS Registry Number:58066-85-6), Raltegravir potassium (CAS Registry Number:871038-72-1), Dasatinib monohydrate (CAS Registry Number:863127-77-9), OXOMEMAZINE (CAS Registry Number:3689-50-7), Pramipexole (CAS Registry Number:104632-26-0), PARECOXIB SODIUM (CAS Registry Number:198470-85-8), Tigecycline (CAS Registry Number:220620- 09-7), Toltrazuril (CAS Registry Number:69004-03-1), Vinflunine (CAS Registry Number:162652-95-1), Drospirenone (CAS Registry Number:67392-87-4), Daptomycin (CAS Registry Number:103060-53-3), Montelukast sodium (CAS Registry Number:151767-02-1), Brinzolamide (CAS Registry Number:138890-62-7), Maraviroc (CAS Registry Number:376348- 65-1), Doxercalciferol (CAS Registry Number:54573-75-0), Oxolinic acid (CAS Registry Number:14698-29-4), Daunorubicin hydrochloride (CAS Registry Number:23541-50-6), 57 11991680v1 Attorney Docket No.: 2013105-0050 Nizatidine (CAS Registry Number:76963-41-2), Idarubicin (CAS Registry Number:58957-92-9), FLUOXETINE HYDROCHLORIDE (CAS Registry Number:59333-67-4), Ascomycin (CAS Registry Number:11011-38-4), beta-Methyl vinyl phosphate (MAP) (CAS Registry Number:90776-59-3), , Fexofenadine HCl (CAS Registry Number:83799-24-0), Ketoconazole (CAS Registry Number:65277-42-1), 9,10-difluoro-2,3-dihydro-3-me-7-oxo-7H-pyrido-1 (CAS Registry Number:82419-35-0), , Terbinafine HCl (CAS Registry Number:78628-80-5), Amorolfine (CAS Registry Number:78613-35-1), Methoxsalen (CAS Registry Number:298-81- 7), Olopatadine HCl (CAS Registry Number:113806-05-6), Zinc Pyrithione (CAS Registry Number:13463-41-7), , Cyclosporine (CAS Registry Number: 59865-13-3), and Botulinum toxin and its analogs and vaccine components. Exemplary Polypeptide Payloads [0178] In some embodiments, an “other” moiety may be or comprise a polypeptide (referred to herein as a “polypeptide payload). [0179] In some embodiments, a polypeptide useful as an “other moiety” as described herein may, for example, be selected from the group consisting of cytokines and their receptors (including chimeric proteins that comprise a cytokine and/or a cytokine receptor moiety). Those skilled in the art will be familiar with a variety of cytokines and receptors, and other potentially useful polypeptides including, for example tumor necrosis factor alpha and beta, their receptors and their derivatives; renin; growth hormones, including human growth hormone, bovine growth hormone, methionine-human growth hormone, des-phenylalanine human growth hormone, and porcine growth hormone; growth hormone releasing factor (GRF); parathyroid and pituitary hormones; thyroid stimulating hormone; human pancreas hormone releasing factor; lipoproteins; colchicine; prolactin; corticotrophin; thyrotropic hormone; oxytocin; vasopressin; somatostatin; lypressin; pancreozymin; leuprolide; alpha-1-antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; luteinizing hormone releasing hormone (LHRH); LHRH agonists and antagonists; glucagon; clotting factors such as factor VIIIC, factor IX, tissue factor, and von Willebrands factor; anti-clotting factors such as Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator other than a tissue- type plasminogen activator (t-PA), for example a urokinase; bombesin; thrombin; hemopoietic 58 11991680v1 Attorney Docket No.: 2013105-0050 growth factor; enkephalinase; RANTES (regulated on activation normally T-cell expressed and secreted); human macrophage inflammatory protein (MIP-1-alpha); a serum albumin such as human serum albumin; mullerian-inhibiting substance; relaxin A-chain; relaxin B-chain; prorelaxin; mouse gonadotropin-associated peptide; chorionic gonadotropin; gonadotropin releasing hormone; bovine somatotropin; porcine somatotropin; a microbial protein, such as beta-lactamase; DNase; inhibin; activin; vascular endothelial growth factor (VEGF); receptors for hormones or growth factors; integrin; protein A or D; rheumatoid factors; a neurotrophic factor such as bone-derived neurotrophic factor (BDNF), neurotrophin-3, 4, -5, or -6 (NT-3, NT- 4, NT-5, or NT-6), or a nerve growth factor such as NGF-β; platelet-derived growth factor (PDGF); fibroblast growth factor such as acidic FGF and basic FGF; epidermal growth factor (EGF); transforming growth factor (TGF) such as TGF-alpha and TGF-beta, 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 proteins; CD proteins such as CD-3, CD-4, CD-8, and CD-19; erythropoietin; osteoinductive factors; immunotoxins; a bone morphogenetic protein (BMP); an interferon such as interferon-alpha (e.g., interferonα2A), -beta, -gamma, -lambda and consensus interferon; colony stimulating factors (CSFs), e.g., M-CSF, GM-CSF, and G-CSF; interleukins (ILs), e.g., IL-1 to IL-10; superoxide dismutase; T-cell receptors; surface membrane proteins; decay accelerating factor; viral antigen such as, for example, a portion of the HIV-1 envelope glycoprotein, gp120, gp160 or fragments thereof; transport proteins; homing receptors; addressins; fertility inhibitors such as the prostaglandins; fertility promoters; regulatory proteins; antibodies (including fragments thereof) and chimeric proteins, such as immunoadhesins; precursors, derivatives, prodrugs and analogues of these compounds, and pharmaceutically acceptable salts of these compounds, or their precursors, derivatives, prodrugs and analogues. In some embodiments, proteins or peptides may be native or recombinant and include, e.g., fusion proteins. [0180] In some embodiments, a polypeptide payload is or comprises growth hormone. In some embodiments, growth hormone is human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone, methionine-human growth hormone, des- phenylalanine human growth hormone, and porcine growth hormone; insulin, insulin A-chain, insulin B-chain, and proinsulin; or a growth factor, such as vascular endothelial growth factor 59 11991680v1 Attorney Docket No.: 2013105-0050 (VEGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF), or insulin-like growth factor-I and -II (IGF-I and IGF-II). [0181] In some embodiments, polypeptide payloads that may be particularly useful in certain embodiments of the present disclosure, but are not limited to, Glucagon-like peptide-1 (GLP-1) and precursors, derivatives, prodrugs and analogues thereof. [0182] In some embodiments, a polypeptide payload is or comprises hyaluronidase or another similar entity which may be capable, for example, of modulating or manipulating a component of a prepared conjugate as described herein or the amount of a prepared conjugate on an ocular surface. [0183] In some embodiments, a polypeptide moiety is included in a conjugate as described herein via chemical conjugation with a cysteine residue (e.g., a terminal cysteine). In some particular embodiments, a retention moiety such as a CBT (or an analog thereof) may be conjugated (e.g., via click chemistry) to a polypeptide moiety. Exemplary Nucleic Acid Payloads [0184] In some embodiments, a conjugate useful in accordance with the present disclosure comprises or delivers a nucleic acid agent. [0185] Those skilled in the art will appreciate that a nucleic acid agent is or comprises a nucleic acid; in some embodiments, a conjugate useful in accordance with the present disclosure may be or comprise such nucleic acid, or a precursor thereof. In some embodiments, a nucleic acid agent useful in accordance with the present disclosure may be selected from the group consisting of therapeutic nucleotides, nucleosides and analogues thereof; and therapeutic polynucleotides (e.g., oligonucleotides). [0186] Those of ordinary skill in the art will be aware of a variety of therapeutic nucleic acid agents, many of which may be particularly useful, for example, as anticancer agents, anti- inflammatory agents, antimicrobial agents, and/or antiviral agents. 60 11991680v1 Attorney Docket No.: 2013105-0050 [0187] In some embodiments, suitable nucleic acid agents may include, for example ribozymes, antisense oligodeoxynucleotides (e.g., siRNAs, RNase H-cleavage-mediating ASOs, etc), aptamers, etc. [0188] As noted elsewhere herein, in some embodiments, a nucleic acid may be or include a nucleoside analog such as, for example, cytarabine (araCTP), gemcitabine (dFdCTP), and floxuridine (FdUTP). [0189] In some embodiments, a suitable nucleic acid active agent is an interfering RNA, e.g., shRNA, miRNA or siRNA. In some embodiments, suitable siRNAs include, for example, IL-7 (Interleukin-7) siRNA, IL-10 (Interleukin-10) siRNA, IL-22 (Interleukin-22) siRNA, IL-23 (Interleukin 23) siRNA, CD86 siRNA, KRT6a (keratin 6A) siRNA, K6a N171K (keratin 6a N171K) siRNA, TNFα (tumor necrosis factor α) siRNA, TNFR1(tumor necrosis factor receptor- 1) siRNA, TACE (tumor necrosis factor (TNF)-α converting enzyme) siRNA, RRM2 (ribonucleotide reductase subunit-2) siRNA, and VEGF (vascular endothelial growth factor) siRNA. mRNA sequences of the human gene targets of these siRNAs are known in the art. For IL-7, see, e.g., GenBank Accession: NM—000880.3, GenBank Accession: NM—001199886.1, GenBank Accession: NM—001199887.1, and GenBank Accession: NM—001199888.1; for IL- 10, see, e.g., GenBank Accession: NM—000572.2; for IL-22 see, e.g., GenBank Accession: NM—020525.4; for IL-23, see, e.g., GenBank Accession: NM—016584.2, and GenBank Accession: AF301620.1; for CD86, see, e.g., GenBank Accession: NM—175862.4, GenBank Accession: NM—006889.4, GenBank Accession: NM—176892.1, GenBank Accession: NM— 001206924.1, and GenBank Accession: NM—001206925.1; for KRT6a, see, e.g., GenBank Accession: NM—005554.3; for TNFα, see, e.g., GenBank Accession: NM—000594.2; for TNFR1, see, e.g., GenBank Accession: NM—001065.3; for TACE, see, e.g., GenBank Accession: NM—003183.4; for RRM2, see, e.g., GenBank Accession: NM—001165931.1 and GenBank Accession: NM—001034.3; for VEGF, see, e.g., GenBank Accession: NM— 001025366.2, GenBank Accession: NM—001025367.2, GenBank Accession: NM— 001025368.2, GenBank Accession: NM—001025369.2, GenBank Accession: NM— 001025370.2, NM—001033756.2, GenBank Accession: NM—001171622.1, and GenBank Accession: NM—003376.5. 61 11991680v1 Attorney Docket No.: 2013105-0050 Exemplary Active Payloads [0190] In some embodiments, the present disclosure provides conjugates that include an active agent such as a cosmetic, protective, or detectable agent. [0191] In some embodiments, a detectable agent is or comprises a label. Suitable labels include, e.g, radioactive isotopes, fluorescers, chemiluminescers, chromophores, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chromophores, dyes, metal ions, magnetic particles, nanoparticles and quantum dots. [0192] In some embodiments, a cosmetic or detectable agent is or comprises a pigment or dye. In some embodiments, a cosmetic or detectable agent imparts a cosmetic benefit to the color, shape, or other element of the eye. In some embodiments, a cosmetic or detectable agent as described herein may be a contact lens. In some embodiments, a detectable or cosmetic agent as described herein may be impart the benefits of sunglasses. [0193] In some embodiments, a protective agent is a sunscreen, which may, for example, impart a benefit of increased UV protection to the eye, useful, for example, in the prevention of UV-induced cataracts. In some embodiments, a sunscreen payload may be or comprise any number of inorganic filters, such as titanium dioxide and/or zinc oxide. In some embodiments, a sunscreen payload may be or comprise any number of organic filters, such as benzophenones (e.g., dioxybenzone, oxybenzone, sulisobenzone, etc.), cinnamates (e.g., cinoxate, octinoxate, etc.), para-aminobenzoic acid (PABA) derivates (e.g., padimate O, para-aminobenzoic acid, etc.), salicylates (e.g., homosalate, octisalate, trolamine salicylate, etc.) or other organic filter (e.g., butyl methoxydibenzoyl methane, ecamsule, etc.). [0194] In some embodiments, a diagnostic payload may assess, for example, corneal damage, tissue integrity, hydration, lubricity, tear composition, tissue pO₂ pressures, etc. within the eye or ocular tissue. [0195] Those skilled in the art, reading the present disclosure, will appreciate that it is not limited to any particular loading level of an active agent. For example, in some embodiments, appropriate loading level may be influenced or determined by potency of the relevant agent, its half-life, etc. 62 11991680v1 Attorney Docket No.: 2013105-0050 [0196] In some embodiments, a conjugate as described herein (or a material or system that includes or is generated from such conjugate) include a plurality of “other” moieties, including, in some embodiments, a plurality of cosmetic and/or detectable agents. Nanoparticles [0197] In some embodiments, a conjugate as described herein, or a material or system that includes or is generated from it, includes or is associated with an “other” moiety that is or comprises a nanoparticle. In some embodiments, a conjugate, material or system is encapsulated within a nanoparticle. [0198] In some embodiments, examples of materials used to make nanoparticles include organic polymers such as polylactic co-glycolic acid, polyanhydride, hyaluronic acid, as well as inorganic materials such as gold, silica, and iron oxide, among others. In some embodiments, nanoparticles can also be made of lipids forming liposomes or solid lipid nanoparticles. In some embodiments, [0199] In some embodiments, a retention moiety (e.g., CBT) is conjugated to nanoparticles, for example using a linker. In some embodiments, a linker that conjugates a retention moiety to a nanoparticle may be selected from glycine, other amino acids, polyethylene glycol, succinic acid, adipic acid dihydrazide, among others. Films and Systems [0200] In some embodiments, conjugates as described and/or utilized herein may be cross-linked, for example to form materials such as films. In some embodiments, cross-linking occurs upon application to the eye, e.g., at a site in or on the eye, for example on, at, in, or below the ocular surface, tear film, tear duct, conjunctiva, and/or other ophthalmic structures associated with the eye. [0201] In some embodiments, cross-linking does not involve an exogenous (i.e., not naturally present in, and/or exogenously added to, the site of application) cross-linker. In some embodiments, cross-linking occurs (e.g., is performed) prior to application to an eye, for example 63 11991680v1 Attorney Docket No.: 2013105-0050 using an exogenous cross-linker. In some embodiments, cross-linking occurs substantially contemporaneously with administrations, and for example in some embodiments may include an exogenous cross-linker (e.g., an exogenously added cross-linker, applied simultaneously or sequentially with a polymer such as an HA preparation, which may or may not be chemically identical to an endogenous cross-linker, or moiety thereof). [0202] In some embodiments, a cross-linked film for application to an eye in accordance with the present disclosure includes reactive moiety(ies) sufficient to interact (e.g., non- covalently associate or covalently bond with one or more group(s) in or on the eye. In some particular embodiments, such reactive moiety(ies) participate in click chemistry reaction(s), e.g., with group(s) such as cysteine(s) (e.g., terminal cysteine(s) such as may be found in protein(s)) present in the eye. [0203] In some embodiments, a cross-linked film as described and/or utilized herein (e.g., as may be formed on the eye or generated for application to the eye) is a non-Newtonian fluid. In some embodiments, a cross-linked film as described herein is characterized by a high level of oxygen permeability. Relevant transmissibility levels may be, for example, within the range of 25 to 50 Dk/t. [0204] In some embodiments, a cross-linked film as described and/or utilized herein is characterized by a thin mono layer. In some embodiments, a cross-linked film as described and/or utilized herein (e.g., as may be formed on the eye or generated for application to the eye) has a thickness not greater than about 40 μm, for example a thickness within a range of 0.1 μm to 40.0 μm. [0205] In some embodiments, a cross-linked film as described and/or utilized herein (e.g., as may be formed on the eye or generated for application to the eye) is non-refractive and/or transparent. Cross-linkers [0206] In some embodiments, formation of a material comprising a prepared conjugate as described in the present disclosure utilizes a cross-linker, e.g., an exogenous cross-linker. 64 11991680v1 Attorney Docket No.: 2013105-0050 [0207] In some embodiments, a cross-linker is selected and/or designed to possess a reactive group capable of reacting with one or more complementary reactive groups on a conjugate as described herein (and typically on a retention moiety thereof) so that a reaction product containing a covalent bond between the reactive groups of the cross-linker and conjugate is formed. In certain embodiments, reaction of a conjugate with a cross-linker as described herein results in formation of a material characterized by several distinct polymer moieties covalently linked, for example, via bridges comprised of a reaction product of complementary reactive groups of a cross-linker and a prepared conjugate. In some embodiments, the material product of a reaction between a cross-linker and a conjugate may be characterized, for example, by chemical and viscoelastic properties that may be recognized by those skilled in the art to be consistent with formation of a hydrogel. In some embodiments, a cross-linker is used to cross- link conjugates as described herein, for example to generate a film for application to an eye. [0208] In many embodiments, a cross-linker for use in accordance with the present disclosure is bi-functional (or multi-functional), so that it can react with two or more reactive groups on a conjugate, or with two or more reactive groups on different conjugates, to create covalent linkages there between. In some embodiments, two or more reactive groups of a cross- linker may be of the same chemical form. Alternatively or additionally, in some embodiments, two or more reactive groups of a cross-linker may be of different chemical forms. In some embodiments, two or more reactive groups of a cross-linker may share the same complementary reactive group of a conjugate. Alternatively or additionally, in some embodiments, one or more reactive groups of a cross-linker may have different complementary reactive groups on the prepared conjugate. [0209] In some embodiments, reactive groups of a cross-linker and conjugate may react via a ‘click’ reaction. In some embodiments, the reactive groups of a cross-linker may contain one or more cysteine groups capable of reaction with a complementary CBT group on a conjugate as described in the present disclosure. In some embodiments, reactive groups of a cross-linker and conjugate may be other chemical entities capable of forming a covalent bond there between. [0210] In many embodiments, cross-linkers are characterized by an ability, when contacted with a conjugate as described herein, to react with a reactive group thereon without 65 11991680v1 Attorney Docket No.: 2013105-0050 requiring a catalyst or other non-participating agent. Alternatively or additionally, in some embodiments, reaction between a cross-linker and a conjugate may be initiated by an additional exogenous entity, for example, a catalyst (e.g., metal, small molecule, light or other non- or partially participating agent). [0211] Without wishing to be bound by any particular theory, the present disclosure teaches that, in some embodiments, a cross-linker may be or comprise a conjugate, e.g., that includes one or more reactive groups. For example, in some embodiments, a conjugate that may serve as a cross-linker may be a conjugate of HA with cysteine groups that may react, for example, with CBT-moieties on several other HA conjugates. [0212] Those skilled in the art, reading the present disclosure, will recognize that, in many embodiments, formation of a material or film, for example, via reaction between a cross- linker and a conjugate as described herein, may be advantageously performed prior to administration. In some embodiments, reaction between a cross-linker and a conjugate prior to administration may be desirable, for example, to generate a film or material for administration; in some embodiments, such film or material may possess one or more desirable chemical, optical and/or viscoelastic properties, some or all of which may, for example, not be available to the conjugate when administered without prior cross-linking. Those skilled in the art, reading the present disclosure, will be taught that such a film or material typically desirably includes reactive groups (e.g., un-reacted retention moieties) available for interaction with a site or moiety in or on the eye upon application of such film thereto. In certain embodiments, for example, when reaction between a cross-linker and a conjugate occurs via one or more retention moieties of that conjugate, the stoichiometry of the cross-linker relative to the conjugate may be optimized as to ensure availability of retention moieties for interaction with the ocular surface. [0213] In some embodiments, an exogenous cross-linker is applied substantially contemporaneously (e.g., substantially simultaneously or sequentially) with a conjugate or film as described herein) – e.g., as a system therewith. In some embodiments, a cross-linker that is so applied is characterized as being biocompatible. In some embodiments, one or more reactive groups of a cross-linker may be selected as to encourage reaction between a cross-linker and a conjugate as opposed to between a conjugate and a biological structure. Alternatively or additionally, one or more reactive groups of a cross-linker may be selected as to encourage 66 11991680v1 Attorney Docket No.: 2013105-0050 reaction between the cross-linker and a biological structure. Without wishing to be bound by any particular theory, the present disclosure proposes that, in some embodiments, substantially contemporaneous application of a conjugate and cross-linker may be desirable as to impart certain desirable chemical, optical and/or viscoelastic properties. Alternatively or additionally, in some embodiments, substantially contemporaneous application of conjugates and cross-linkers may be desirable, for example, to desirably and/or precisely tune a chemical, optical or viscoelastic property of the system. Formulations [0214] In some embodiments, a conjugate, material, or system provided by or for use in accordance with the present disclosure, may be provided and/or utilized (e.g., applied to the eye) in a formulation such as a liquid, a gel, a film, etc. In some embodiments, a provided conjugate or material (e.g., a material prepared therefrom) may be provided and/or utilized, for example, in the form of a liquid contact lens and/or an ocular bandage. [0215] In some embodiments, a conjugate, material or system may be present in a particular formulation (e.g., for application to the eye) at a weight (e.g., w/w) percentage within a range between a lower boundary and an upper boundary (inclusive), the upper boundary being larger than the lower boundary, wherein the upper boundary may be about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%, and the lower boundary may be about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5% or about 1%. [0216] In some embodiments, a formulation comprises about 0.001% w/w to about 5.00% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 0.01% w/w to about 5.00% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 0.1% w/w to about 5.00% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 1% w/w to about 5.00% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 1 % w/w to about 3% w/w of a conjugate, material, or system. In some embodiments, a formulation 67 11991680v1 Attorney Docket No.: 2013105-0050 comprises about 2% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises PBS and about 2% w/w of a conjugate, material, or system. [0217] In some embodiments, a formulation comprises a conjugate as described herein, or a material that includes or is made from it, or a system that includes it (e.g., and a cross-linker) and a carrier. In some embodiments, a formulation comprises about 1% w/w to about 50% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 10% w/w to about 50% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 20% w/w to about 50% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 30% w/w to about 50% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 40 % w/w to about 50% w/w of a conjugate, material, or system. In some embodiments, a formulation comprises about 45 % w/w to about 50% w/w of a conjugate, material, or system. [0218] Various forms of formulations can be used to administer a conjugate, material or system as described herein. [0219] Those skilled in the art will be familiar with various pharmaceutically acceptable excipients that can be utilized in accordance with the present disclosure. Those skilled in the art will further be aware that particular choice of excipient may, in some embodiments, be determined at least in part by the particular components (e.g., polymer moiety, retention moiety, and/or other moiety) included in a conjugate, material or system, and/or by the particular method used to administer the formulation (e.g., as a conjugate without any prior crosslinking and/or without a concomitantly administered cross-linker vs as a conjugate together with a cross-linker vs as a partially or fully cross-linked material [e.g., a film, in some embodiments with available reactive retention moiety(ies)] and/or as a liquid contact lens and/or an ocular bandage. [0220] In some embodiments, a formulation provided and/or utilized in accordance with the present disclosure includes a buffer, for example, at a physiological pH. [0221] In some embodiments, a formulation may be provided as a liquid, a gel, a powder, an aerosol, etc. 68 11991680v1 Attorney Docket No.: 2013105-0050 [0222] In some embodiments, a formulation may be provided in a vessel such as a vial, a tube, a plate, or a syringe. In some embodiments a formulation may be provided in a vessel such as an eye dropper or mister. [0223] In various embodiments, a formulation is sterile. [0224] In many embodiments, a formulation comprises saline, is or comprises a contact lens solution, and/or comprises one or more pharmaceutically acceptable ophthalmic excipients. Administration [0225] A skilled person, reading the present disclosure, will appreciate that provided conjugates, particularly when cross-linked (either in situ or separately), may form a hydrated composite, for example by association with ions and water molecules. [0226] A conjugate as described herein, or a cross-linked material generated therefrom, may bind a mucosal membrane, for example, mucosa of the eye (or, if desired, lip, mouth, vagina, upper respiratory tract [such as nose and nasal passages, paranasal sinuses, pharynx, and portion of the larynx above the vocal folds (cords)], lungs, GI tract, urethral opening, and anus). It will be appreciated by a person of skill in the art that such an embodiment would form a barrier to pathogen entry and may, in some embodiments, retain active agent(s) of interest and/or serve to recruit proteins such as, for example, cytokines and/or growth factors. [0227] In made embodiments, conjugates, materials, and/or systems as described herein are administered by topical application to the eye. In some embodiments, for example, compositions may be administered via drops, sprays, eye washes, misting and/or other methods of instillation (e.g., contact lenses and/or ocular bandages). In some embodiments, administration via an eye dropper includes delivering a tunable dose of a conjugate. [0228] In some embodiments, provided technologies utilize conjugates comprising a polymer moiety which may, in some embodiments, be or comprise a hyaluronic acid (HA) moiety conjugated to a retention moiety, which, in some embodiments, be or comprise a CBT moiety or an analog thereof. Certain HA-CBT conjugates have been described in the art and demonstrated to effectively achieve transdermal delivery (see, for example, WO2016/201382, 69 11991680v1 Attorney Docket No.: 2013105-0050 WO2020/093022, and WO2020/214889). The present disclosure surprisingly demonstrates that certain HA-CBT conjugates (e.g., made with or otherwise including high molecular weight HA and/or sufficiently structurally complex – e.g., complexed into a matrix material) can be useful in surface applications including specifically ophthalmic applications (e.g., in which such conjugates, or materials, such as films, formed therefrom are retained on the eye, such as on corneal surfaces). [0229] In some embodiments, conjugates and/or materials (e.g., films) generated therefrom and/or systems comprising either of the foregoing, are administered to the eye relatively infrequently (e.g., no more often than 2x per day, no more often than 3x per day, or no more often than 4x per day). Exemplification [0230] The present Examples describe, among other things, certain strategies that may be used to characterize and/or assess conjugates (and/or materials or systems that include or are prepared from them) as described herein. Such strategies (or their equivalents as will be appreciated by those skilled in the art reading the present disclosure) may be used to assess conjugates, components (e.g., moieties), compositions, or combinations thereof or generated therefrom for suitability for use in accordance with the present disclosure. In some embodiments, therefore, the present disclosure provides technologies for characterizing and/or selecting useful moieties, linkers, conjugates, materials, and systems as described herein. Example 1: Preparation of Exemplary Conjugates [0231] The present Example describes preparation of certain exemplary conjugates for assessment and/or use in accordance with the present disclosure. [0232] The present disclosure appreciates that certain forms of hyaluronic acid have been proposed to be useful in the treatment of dry eye disease (reviewed, for example, in Hynnekleic et al. Acta Ophthalmol.100:844, 2022), typically as an additive to eye drops. Although benefits attributed to use of HA have been reported, the present disclosure appreciates that various 70 11991680v1 Attorney Docket No.: 2013105-0050 challenges exist. Among other things, the present disclosure provides an insight that the source of one problem with various existing approaches to using HA in ophthalmic indications is insufficient retention time. Furthermore, the present disclosure notes that significant uncertainty exists, for example, with respect to useful molecular weight(s) and/or formats of HA to achieve ophthalmic benefits. [0233] The present disclosure provides a specific insight that certain HA formats have been described in which an HA is conjugated to a reactive entity capable of forming chemical cross-links with an appropriate partner reactive group (see, for example, WO2016/201382, WO2020/093022, WO 2020/214889, and/or references cited therein). In particular, conjugates in which an HA is linked with a CBT moiety (or an analog thereof) have been described. Among the attributes of such described CBT (or CBT analog) conjugates is transdermal penetration. The present disclosure surprisingly demonstrates that utilization of certain HAs (e.g., larger molecular weight HAs) can avoid or limit such transdermal penetration, allowing a conjugate as described herein to remain on the surface of an eye. Alternatively or additionally, the present disclosure provides an insight that cross-linked versions of conjugates, including those generated from lower molecular weight HAs, may also be retained on the eye surface. [0234] Without wishing to be bound by any particular theory, the present disclosure proposes that particularly useful materials for ophthalmic applications as described herein include those in which retention moiety(ies) or other conjugate components can interact with (e.g., form bonds or interweave with), for example, reactive group(s) on ocular structures, and that such interaction may contribute to improved retention. [0235] The present disclosure demonstrates that certain HA-containing materials, and in particular certain materials that are or include (e.g., are generated from) conjugates of an HA moiety with a retention moiety, are particularly useful for ophthalmic applications. [0236] The present Example, in particular, describes conjugates of HA moieties of various molecular weights with a CBT moiety (specifically by conjugation with gly-CBT) at various mole percentages. The following specific conjugates are described in this Example: 71 11991680v1 Attorney Docket No.: 2013105-0050 Table 1: Exemplary Conjugates g [0237] y, HA (molecular weight 10 - 2500 kD) was dissolved in deionized (DI) water till it dissolved. After dissolution, an equal volume of dimethyl sulfoxide (DMSO) was added to get final polymer concentration of 4- 10 mg/mL. The pH of the polymer solution was adjusted with 1 M HCl to 5 – 5.5. Thereafter, 72 11991680v1 Attorney Docket No.: 2013105-0050 under vigorous stirring, N-Hydroxysulfosuccinimide (20 mg/mL in DI water), followed by 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide•hydrochloride, (20 mg/mL in DMSO) and CBT-gly (20 mg/mL in DMSO) were added to the polymer solution. The reaction solution was stirred overnight at room temperature (RT). [0238] Conjugates were purified in a 4-step process of precipitation in ethanol-phosphate buffered saline (PBS) and re-dissolution in DI water. In the first step, 35 mL of ethanol was added to 5 mL of reaction solution followed by vortexing for 10 sec. Afterwards, 1 mL of PBS was added to the solution and was vortexed for 10 sec. The precipitated HA was centrifuged at 2,500 g for 5 min and the supernatant was discarded. Thereafter, the polymer was redissolved in DI water to obtain ~10 mg/mL solution, to which 35 mL ethanol was added and vortexed for 10 sec. Then, 0.75 mL of PBS was added and the solution was vortexed for 10 sec, which comprised the second step of the 4-step process. Centrifugation, re-dissolution, and vortex were repeated in the third and final steps as well using 35 mL ethanol along with PBS 0.5 and 0.25 mL, respectively. After the final precipitation step, the ethanol and water from the product was evaporated off completely. Further purification was performed by dissolving the polymer in DI water at ~10 mg/mL and dialyzing the polymer overnight (using 2 kDa filters). After dialysis, the polymer solution was frozen at -80 °C and lyophilized to obtain the final solid product. Formulations of conjugates, for use in ex vivo or in vivo studies, were prepared by dispersing appropriate amounts of lyophilized conjugate in 0.9% saline solution to concentrations of 0.1 – 0.3%. [0239] Prepared conjugates can be assessed, for example, using techniques such as gel permeation chromatography (GPC) and/or nuclear magnetic resonance (¹H NMR). Those skilled in the art will appreciate that GPC assessments are particularly useful, for example, to assess integrity (e.g., degree of breakdown) of HA, and ¹H NMR analysis is particularly useful, for example, to determine molecular loading of CBT onto HA in a conjugate preparation. [0240] Figures 1 and 2 present representative GPC and ¹H NMR of a conjugate preparation of 500 kDa HA with 10 mole% gly-CBT loading. For the depicted GPC analysis, Agilent 1260 high performance liquid chromatography (HPLC) connected to a diode-array- detection detector (326 nm) was used. An Agilent PL aquagel-OH MIXED-M column (8 μm 300 x 7.5 mm) and an Agilent PL aquagel-OH 20 (8 μm 300 x 7.5 mm) column in series were used. 73 11991680v1 Attorney Docket No.: 2013105-0050 The mobile phase comprised 0.2 M NaNO3 in 9:1 DI water: methanol at a flow rate of 1 mL/min. The polymer was dissolved at 2 mg/mL in DI water for analyses. For the presented NMR analysis, the polymer was dissolved at ~3 mg/mL in D2O and ¹H NMR was performed using 500 mHz NMR instrument with 128 scans and relaxation time 1 sec. [0241] Conjugate preparations, for example, prepared as exemplified or otherwise described herein can desirably be sterilized. Those skilled in the art will be aware of various appropriate sterilization technologies. Preparations utilized in in vivo studies described herein were sterilized using 0.22 or 0.45 μm pore size syringe filters. Conjugate integrity was analyzed by GPC before and after such filtration; no change in conjugate concentration was observed before or after sterilization for 0.1% conjugate preparations. However, a significant decrease in concentration after sterilization was noted for 0.3% conjugate preparations. Alternative sterilization strategies, such as electron beam irradiation, are contemplated. Example 2: Tolerability of Exemplary Conjugates Applied to Eye [0242] The present Example demonstrates tolerability of various conjugate preparations when applied in vivo to rabbit eyes. [0243] Tolerability of conjugates can be assessed, for example, via ocular examination with an ophthalmoscope using Draize’s scale during a multi-day study. Those skilled in the art will appreciate that such ocular examinations are useful to detect, for example, irritation, or the lack thereof, to the ocular surface. In certain embodiments, this may include, for example, the presence of conjunctival palpebral/bulbar redness, discharge and/or watering. Additionally, those skilled in the art will recognize that compatibility of conjugates can likewise be assessed, for example, by tracking changes, or the lack thereof, in behavior and body weight. [0244] In the study described in the present example, 21 albino rabbits (New Zealand strain) were divided into 7 groups corresponding to 7 treatments as described in Table below. 74 11991680v1 Attorney Docket No.: 2013105-0050 Table 2: Study groups 11991680v1 Attorney Docket No.: 2013105-0050 [0245] All conjugate formulations were prepared in saline (0.1% concentration or 1 mg/mL) and sterilized using 0.22 or 0.45 μm pore size syringe filters. Installations were performed in the right eye of each animal; the left eye was left untreated for comparison. The schedule for installation and ocular examinations is summarized in Table 3. Table 3: Schedule table Study date Design Ocular examination n d Attorney Docket No.: 2013105-0050 [0246] As indicated, on Day 1, general clinical observations and body weight measurements were performed, followed by 5 sample installations over 20 min (5 min ± 1 min span in between installations). After the first installation, ocular examination using Draize’s scale was performed. Additional ocular examinations were performed 0.5 h ± 3 min, 1 h ± 6 min and 4 h ± 24 min after the last installation. Following the first day of instillation, samples were refrigerated at 5 ± 3°C. On Day 2, general clinical observations and an ocular examination using Draize’s scale were performed, followed by 2 sample installations with 8h ± 48 min span in between each. After the last installation, an additional ocular examination was performed. On Day 3, general clinical observations and an ocular examination using Draize’s scale were performed, followed by 4 sample installations with 2.5h ± 15 min span in between each. After the last installation, an additional ocular examination was performed. On Day 4, general clinical observations and an ocular examination using Draize’s scale were performed, followed by 6 installations with 1 h ± 6 min span in between. After the last installation, an additional ocular examination was performed. On Day 5, general clinical observations, body weight measurements and an ocular examination using Draize’s scale were performed, followed by 8 installations with 1 h ± 6 min span in between. After the last installation, an additional ocular examination was performed and rabbits from groups 1, 3, 5 and 7 were euthanized. On Days 6-8, general clinical observations and body weight measurements were performed on rabbits from groups 2, 4 and 6; no sample was installed. On Day 8, the rabbits from groups 2, 4, and 6 were euthanized and whole eyeballs from both eyes (including optic nerve, conjunctivae and extraocular muscles) were immediately fixed in 0.8% Davidson’s solution (homemade) between 24 h and 48 h. [0247] General clinical observations and body weight measurements indicated body weight remained normal and no behavior changes were observed throughout the study. Results of ocular evaluations on right treated eyes performed on Days 1-5 are summarized in Table 4. 77 11991680v1 Attorney Docket No.: 2013105-0050 Table 4: Summarized data – Ocular examinations with an ophthalmoscope (Draize’s scale) on right treated eyes Ocular fi Vehicle (Saline) 2 eyes on Day 1 (the same eye at 0.5h and 1h after last administration) njunctivae - - ( - Cornea ( - I_ris ⁽ - - = Nothing r t, 78 11991680v1 Attorney Docket No.: 2013105-0050 e’s ry levels of HA, even after 3 days without additional treatment. [0250] Formulations containing conjugates as described herein can be assessed, for example, via histological and/or histopathological evaluation after colloidal iron or Alcian Blue and Hematoxylin eosin safran staining of whole eyeballs fixed with 0.8% Davidson’s solution (homemade). Those skilled in the art will appreciate that staining with colloidal iron or Alcian Blue is particularly useful, for example, to assess the degree of HA present within, for example, corneal stroma, corneo-limbic junction, or other relevant tissue section(s) within the eye. Those skilled in the art will also appreciate that Hematoxylin eosin safran staining is particularly useful, for example, to observe pathological findings, or the lack thereof, within, for example, limbus stroma, conjunctiva, oedematous ciliary processes or other relevant tissue sections within the eye. [0251] In the particular study described in the present Example, whole eyeballs of rabbits from groups 2, 4, and 6 of Example 2, were euthanized on Day 8 of the tolerability study, immediately fixed with 0.8% Davidson’s solution (homemade) between 24 h and 48 h and stained with colloidal iron and Hematoxylin eosin safran. As measured in this current Example by colloidal iron staining, eyes treated with 10 kDa HA with 10 mole% gly-CBT (right eye) showed the same quantity of hyaluronic acid on cornea as untreated eyes (left eye) of this group. Eyes treated with 250 kDa with 5 mole% gly-CBT showed more hyaluronic acid in corneal stroma than the untreated eyes of this group. Eyes treated with 1000 kDa HA with 5 mole% gly- CBT showed more hyaluronic acid in corneal stroma and epithelium of corneo-limbic junction than the untreated eyes of this group. Representative histological images of cornea after colloidal iron staining are presented in Figures 3-6. Colloidal iron stain levels in corneal stroma and 79 11991680v1 Attorney Docket No.: 2013105-0050 corneo-limbic junction of different rabbits that were untreated or treated with formulations prepared from high molecular weight conjugates are shown in Figures 7 and 8. [0252] In this present study, no pathological findings were found in any of the eyes observed on Day 8 (after 3 days without treatment). Slight signs of irritation (dilated vessels, extravasated lymphocytes in limbus stroma and/or conjunctiva, oedematous ciliary processes), observed in right treated as well as in left untreated eyes are incidental and unrelated to treatment. [0253] The study described in the present Example therefore demonstrates that hyaluronic acid treatments (e.g., formulation groups 2, 4 and 6) are microscopically well tolerated according to the Draize’s scale evaluation as well as the untreated eyes. Example 4: Ex Vivo Studies in Cornea [0254] The present Example describes assessments that may be useful, for example, in evaluating the persistence of hyaluronic acid conjugates (and/or materials, such as films, generated from them, and/or systems that include them) as described herein on ex vivo mice or porcine corneal tissue sections using histological analysis. Those skilled in the art will appreciate that histological analysis of corneal tissue sections stained by Alcian Blue can be particularly useful, for example, in analyzing levels and distribution of HA within tissue sections. [0255] For example, corneas from porcine eyeballs can be cut out and washed with saline. Thereafter, such corneas can be mounted on Franz diffusion cells, and 100 μL of 0.1% HA 10, 250, 500, 1000, 1500 or 2500 kDa with 2, 5 or 10 mole% gly-CBT loading can be added to the donor chamber of the Franz diffusion cell. In such a study, no solution is present in the acceptor chamber of the Franz diffusion cell and the set-up is left undisturbed for 1 h at 37 °C. After 1 h, corneas are removed from the diffusion cell and placed in 10% formalin solution. Samples can then be stained with Alcian Blue for hyaluronic acid level and/or distribution analysis. Without wishing to be bound by any particular theory, it may be observed in some embodiments that conjugates of higher MW HA (e.g., of 500 kDa or, better yet, 1000 kDa) are particularly well retained (e.g., for a longer period of time) and/or distributed (e.g., more evenly) at/on the site of administration. 80 11991680v1 Attorney Docket No.: 2013105-0050 [0256] Alternatively or additionally, corneas from mice eyeballs can be cut out, frozen, and cryosectioned to obtain thin slices. The slices can then be incubated with dye-tagged HA- CBT derivatives or unmodified HA for 2 h, washed at least 3 times with phosphate buffered saline to remove loosely bound HA-CBT derivatives/HA. Slices can be stained and imaged to visualize the corneal surface-bound conjugate. Without wishing to be bound by any particular theory, methods described herein demonstrate that HA-CBT derivatives have highly differentiated ability to be retained on the corneal surface (see Figure 9). Example 5: In Vivo Efficacy Studies in Rodents with Dry-Eye Disease [0257] The present Example describes assessments that may be useful, for example, in determining efficacy of exemplary conjugates (and/or materials, such as films, generated from them, and/or systems that include them) in the treatment of dry-eye disease. [0258] In some embodiments, for example, staining experiments involving fluorescein and/or phenol red can be utilized to assess efficacy of conjugates as described herein and/or of films or other materials generated from them (before or after application to an eye). Those skilled in the art will recognize that corneal fluorescein staining is particularly useful, for example, in evaluating superficial punctate keratitis, and phenol red thread tear tests, are particularly useful, for example, in performance of tear secretion analysis. [0259] Rodent models of dry eye disease, including but not limited to, extra-orbital lacrimal gland excision model or scopolamine induced dry-eye disease model can be utilized in assessments contemplated by the present Example. Exemplary conjugates of interest can be evaluated by corneal fluorescein staining to determine superficial punctate keratitis and tear secretion analysis using phenol red thread tear test. Alternatively or additionally, tests such as evaluation of levels of pro-inflammatory cytokines, matrix metalloproteases, quantitation of corneal permeability, determination of corneal smoothness, goblet cell density, CD4 + T cell infiltration and histological analyses can be performed. [0260] Without wishing to be bound by any particular theory, following treatment with exemplified conjugates as described herein, corneal fluorescein staining (e.g., as described in the present example) may result in significant decrease and/or return to baseline levels (e.g., those 81 11991680v1 Attorney Docket No.: 2013105-0050 observed prior to DED induction) in superficial punctate keratitis. Without wishing to be bound by any particular theory, following treatment with exemplified conjugates as described herein, phenol red tear test (e.g., as described in the present example) may demonstrate an increase in wet length from <10mm under severe DED to borderline DED with wet length of 10-19 mm or to normal wet length of 20 mm or more. Without wishing to be bound by any particular theory, following treatment with exemplified conjugates as describe herein, levels of pro-inflammatory cytokine may demonstrate significant decrease. Additionally or alternatively, following treatment with exemplified conjugates as described herein, corneal surface may become smoother. Additionally or alternatively, goblet cell density may increase. Additionally or alternatively, levels of matrix metalloproteases, for example, MMP-9, may decrease. Example 6: In Vitro Studies to Determine Binding of HA Conjugates on Cornea Cell Surface [0261] The present Example describes assessments that may be useful, for example, in evaluating binding properties of conjugates and/or film(s) or other material(s) generated from them (before or after application to cells), as described herein with corneal epithelial cells. [0262] For example, corneal epithelial cells or EpiCorneal tissues can be grown in appropriate culture medium. Fluorescently labeled conjugates (or film(s) or other material(s) generated from them) and relevant control(s) (e.g., presence of a cross-linker) can be added to such cells, and incubated at 35-37 °C for specific time periods to allow interaction between the cells and the test material(s). If cross-linker is used, quantity and/or sequence of addition of such cross-linker can also be tested (e.g, cross-linker added together with HA conjugate, or before/after such HA conjugate is added). After an incubation period, culture medium can be aspirated, and cells can be washed, for example with physiological buffer. Confocal microscopy images of washed cells can assess retention (e.g., binding) of HA conjugate (and/or of film(s) or other material(s) generated from them before or after application to the cells) on cell surfaces. Alternatively or additionally, retention (e.g., binding) of HA conjugates on lipid membranes and/or proteins that are known to have N-terminal cysteines and are expressed on eye surface/conjunctiva can be assessed, for example using surface plasmon resonance. 82 11991680v1 Attorney Docket No.: 2013105-0050 Example 7: Ex Vivo Studies to Determine Binding of HA Conjugates on Corneal Surface [0263] The present Example describes assessments that may be useful, for example, in evaluating binding/retention properties and/or may be used to tune the thickness of conjugates and/or film(s) or other material(s) generated from them (before or after application to cells), as described herein with mouse corneal tissues. [0264] For example, fresh frozen mouse eyeballs were thawed and placed in a 96 well plate containing saline. Different formulations (outlined in the Table 5 below) were prepared in saline (pH 7) and incubated at 37 °C for solubilization. The next morning, the eyeballs were treated with the formulations and incubated at 37 °C in the incubator. Post incubation, the eyeballs were dipped in PBS to wash off unbound HA, gly-CBT, HA-gly-CBT, and/or crosslinker (cysteine ethylene diamine cysteine) and were fixed in 10% Formalin. For staining and imaging, tissues were washed with PBS for 15 mins followed by 1% PBST for 15 mins. Tissues were then blocked with blocking solution (5% donkey serum in 1% PBST) for 1 hour at RT. Tissues were then incubated with primary antibodies (Rabbit-anti-CDH1, 1:500 concentration) for 3 nights at 4 °C. At the end of 3 days, tissues were washed with 1% PBST 3-4 times for 1 hour each. Tissues were then incubated with secondary antibody (donkey-anti-rabbit- 555) and dyes (Hoechst, WGA-488; 1:500 concentration) for 2 nights at 4 °C. At the end of incubation period, tissues were washed with 1% PBST 3-4 times for 1 hour each. Tissues were then dehydrated first with 50% methanol in PBS for 15 mins followed by 100% methanol for 1 hour. Tissues were then placed in 3% H202 in methanol overnight at 4 °C. The next morning, tissues were washed with 100% methanol and placed in BABB (1:2, benzyl alcohol: benzyl benzoate) solution. Samples were imaged using a confocal microscope at 10x magnification. For image analysis the images were processed using ImageJ by converting to 16-bit and setting threshold to 100. Using local thickness tool, the average thickness was measured across the different z slices. 83 11991680v1 Attorney Docket No.: 2013105-0050 Table 5: Experimental setup Treatment No of Formulation at interval of 30 mins Total incubation mouse time eyeballs ^{T0 T30 T60 T90 T120} _(hrs) A 3 HA-gly-CBT 2 B 3 HA- cysteine HA-gly-CBT 2 gly- ethylene CBT diamine cysteine C 3 HA- cysteine HA- cysteine HA- 2 gly- ethylene gly- ethylene gly- CBT diamine CBT diamine CBT cysteine cysteine D 2 Unmodified HA 2 E 1 Saline 2 [0265] Fi ures 10-12 resent re resentative ima es taken of mouse corneal tissues using re m % e els [0266] Conjugate preparations, for example, prepared as exemplified or otherwise described herein can desirably be modulated by addition of a crosslinker in between application of HA-CBT derivatives to tune the thickness of the HA layer. Those skilled in the art will be 84 11991680v1 Attorney Docket No.: 2013105-0050 aware of various appropriate application techniques. Thickness of the HA film was visualized with a confocal microscope after addition of the conjugate; a significant increase in thickness after addition of a crosslinker in between application of HA-CBT derivatives was observed as compared to those samples that did not include this additional crosslinker application step. Alternatively and/or additionally, thickness of the HA layer can be modulated by the sequence of application of the different conjugate moieties (i.e., glycopolymer, retention, and linker groups) and the frequency of their application. Without wishing to be bound by any particular theory, thickness of the HA layer will likely influence oxygen and nutrient transport to corneal cells as well as the stability and persistence of the film itself. The present example supports the ability of CBT (and analogs thereof) to form cross-links, for example with cysteines in or on the eye (such as on the cornea surface) in order to contribute to improved retention of HA (e.g., of HA in the conjugate). 85 11991680v1

Claims

Attorney Docket No.: 2013105-0050 Claims We claim: 1. A population of conjugates comprising a glycopolymer moiety conjugated to a retention moiety, wherein: the molecular weight of the glycopolymer moieties in the population is about 10 kDa or more; and the retention moiety includes a reactive group that associates with an ocular moiety such that the conjugate is retained in or on the eye for an extended period of time relative to that for which unconjugated glycopolymer moiety is retained. 2. The population of claim 1 wherein the molecular weight of the glycopolymer moiety is between 10kDa and 2500 kDa. 3. The population of claim 1 wherein the molecular weight of the glycopolymer moiety is between 10 kDa and 1000 kDa. 4. The population of claim 1 wherein the molecular weight of the glycopolymer moiety is between 1000 kDa and 2500 kDa. 5. The population of claim 1 wherein the molecular weight of the glycopolymer moiety is 1000 kDa. 6. The population of claims 1-5 wherein the glycopolymer moiety is hyaluronic acid (HA) or a therapeutically equivalent variant thereof. 7. The population of claim 1, wherein the retention moiety has a structure that is or comprises formula (I): wherein R¹ is independently –H, halogen, –CN, optionally substituted C_1-6 aliphatic, optionally substituted 5-10-membered heterocyclyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5-10-membered heteroaryl; 86 11991680v1 Attorney Docket No.: 2013105-0050 R² is –H, halogen, –CN, optionally substituted C_1-6 aliphatic, optionally substituted 5- 10-membered heterocyclyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5-10-membered heteroaryl; and m is 1-4. ^ 8. The population of claim 1 wherein conjugates of the population have a structure that is or comprises formula (II-c): (II-c), or pharmaceutically acceptable salt thereof, wherein A is a polymer moiety. 9. The population of claim 1 wherein conjugates of the population have a structure that is or comprises formula (II-e): (II-e), or pharmaceutically acceptable salt thereof, wherein A is a polymer moiety. 10. The system of claims 1-9 wherein the mol% of binding moiety relative to glycopolymer is between 0.01 – 100%. 11. The system of claims 1-9 wherein the mol% of binding moiety relative to glycopolymer is between 1 – 50%. 12. The systems of claim 1-9 wherein the mol% of binding moiety relative to glycopolymer is between 2-10%. 13. The systems of claim 1-12 wherein the glycopolymer moiety and retention moiety are covalently bound through a linker. 87 11991680v1 Attorney Docket No.: 2013105-0050 14. A population of glycopolymer conjugates prepared by a process comprising steps of: conjugating a glycopolymer preparation characterized by a molecular weight of 10 kDa or more with a reaction partner, under conditions and for a time sufficient in amount that a glycopolymer conjugate as recited in claims 1-12 is generated. 15. A method of preparing glycopolymers of molecular weight 5000 kDa or more, the method comprising: (i) functionalizing a glycopolymer with molecular about 500 kDa or more with a reactive moiety (ii) adding a cross-linker to a solution of said functionalized glycopolymer (iii) purifying the product via chromatographic methods. 16. The method of claim 15 wherein the glycopolymer is HA. 17. A system comprising: A population of glycopolymers as described in claim 1; and a cross-linking agent. 18. The system of claim 17 wherein the cross-linking agent is bifunctional. 19. The system of claim 17 wherein the system is prepared prior to application. 20. The system of claim 17 wherein the system is prepared substantially contemporaneously with application. 21. A formulation for use in administration to a patient to treat an ocular disease comprising a glycopolymer conjugate as recited in claims 1-12. 22. The formulation of claim 21 wherein the glycopolymer moiety has a molecular weight of about 10 kDa or more. 23. The formulation of claims 21-22 wherein the formulation is characterized as a gel, powder, aerosol, or liquid. 24. The formulation of claims 21-23 wherein the formulation is characterized as a liquid. 25. The formulation of claims 21-23 wherein the formulation is characterized as a gel. 26. The formulation of claims 21-23 wherein the formulation is characterized as a hydrogel. 27. The formulation of claims 21-23 wherein the formulation is characterized as a powder. 28. The formulation of claims 21-23 wherein the formulation is characterized as an aerosol. 29. The formulation of claim 21-22 comprising saline. 30. The formulation of claim 21-22 comprising contact lens solution. 88 11991680v1 Attorney Docket No.: 2013105-0050 31. The formulation of claim 21-22 comprising one or more pharmaceutically acceptable ophthalmic excipients. 32. The formulation of claims 21-31 wherein the concentration of conjugate therein is 0.1-0.5% w/v. 33. The formulation of claim 21-32 comprising a variant of HA. 34. The formulation of claims 21-33 wherein the formulation is characterized as sterile. 35. A film comprising the population of claim 1 or claim 17 prepared for application to an ocular surface. 36. The film of claim 35 wherein a retention moiety of the film interacts covalently or non- covalently with an element of an ocular surface. 37. The film of claims 35-36 wherein a retention moiety of the film interacts covalently with an element of an ocular surface. 38. The film of claims 35-36 wherein a retention moiety of the film interacts non-covalently with an element of an ocular surface. 39. The film of claim 35 wherein the film is characterized by improved retention to the ocular surface relative to a suitable reference film not comprising the population of claim 1 or claim 17. 40. The film of claim 35 wherein the film is characterized by a thickness of 40 μm or less. 41. The film of claim 35 wherein the film is characterized by a thickness of 2 μm or less when assessed by confocal laser scanning microscopy (CLSM). 42. The film of claim 35 wherein the film is characterized by a thickness between 0.1 Pm to 40.01 μm. 43. The film of claim 35 wherein the film is characterized as a non-Newtonian fluid. 44. The film of claim 35 wherein the film is characterized as transparent. 45. The film of claim 35 wherein the film is characterized as non-refractive. 46. The film of claim 35 wherein the film is characterized by an oxygen permeability between 25 Dk/t to 50 Dk/t. 47. In a system comprising a hyaluronic acid component formulated for topical application to an eye, the improvement that comprises: utilizing as the hyaluronic acid component a population of claim 1 or claim 14. 89 11991680v1 Attorney Docket No.: 2013105-0050 48. The system of claim 47 wherein retention of the hyaluronic acid component is improved relative to a reference application not comprising the population of claim 1 or claim 14. 49. The system of claim 47 wherein the topical application is administered 10 or fewer times per day. 50. A method of reducing the signs and symptoms of dry eye disease (DED) and related ophthalmic conditions, the method comprising steps of: (i) functionalizing a glycopolymer with a reactive moiety; (ii) administering one or more doses of a formulation of the reactive moiety-conjugated glycopolymer to an ocular surface so as to establish a conjugated glycopolymer-containing film on or near the ocular surface. 51. The method of claim 50 wherein the formulation is administered 10 or fewer times per day. 52. The method of claim 50 wherein administration is performed at intervals such that a subsequent dose is administered before prior dose is cleared. 53. The method of claim 52 wherein the frequency of dose administration decreases over time. 54. A method of modulating the effects of a hyaluronic acid treatment comprising: (i) functionalizing an enzyme with a reactive moiety (ii) administering one or more doses of a formulation of reactive moiety-conjugated enzyme to an ocular surface. 55. The method of claim 54 wherein the enzyme is hyaluronidase. 56. A method of imparting a benefit to the eye, the method comprising administration of an entity comprising the population of claim 1. 57. A method of imparting a benefit to the eye, the method comprising administration of an entity comprising the population of claim 14. 58. A method of imparting a benefit to the eye, the method comprising administration of an entity comprising the system of claim 17. 59. A method of imparting a benefit to the eye, the method comprising administration of an entity comprising the formulation of claim 21. 60. A method of imparting a benefit to the eye, the method comprising administration of an entity comprising the film of claim 35. 61. The methods of claims 56-57 wherein the entity comprises a variant of hyaluronic acid. 90 11991680v1