Radical cross-linked zwitterionic gels and uses thereof

Abstract

The present invention provides radically crosslinked zwitterionic gels, methods for preparing the radically crosslinked zwitterionic gels, and methods for using the radically crosslinked zwitterionic gels to treat wounds.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 173,017, filed April 9, 2021, and incorporated herein in its entirety.

[0002] The present disclosure generally relates to radically crosslinked zwitterionic gels, methods for preparing radically crosslinked zwitterionic gels, compositions including radically crosslinked zwitterionic gels, and methods of treating wounds using the radically crosslinked zwitterionic gels. [Background technology]

[0003] The skin is the largest organ of the human body and protects the body from microbial invasion and other external damage. However, this organ can be subject to damage (i.e., wounds) produced by mechanical or thermal damage. Depending on the size and depth of the wound, the wound can be life-threatening. If the wound is difficult to heal, it can become chronic due to dysregulation of inflammation.

[0004] Chronic wounds can be caused by diabetes, burns, immunological conditions, and vascular insufficiency, among others. In diabetic patients, for example, impaired healing is caused by neuropathy, ischemia, and / or trauma. These factors can lead to opportunities for infection to be introduced into the area, which can result in life-threatening infections. Chronic skin wounds are a significant problem that has reached epidemic proportions and are estimated to affect 20-60 million people worldwide by 2026. Unlike acute wounds that heal after a certain period of time, chronic skin wounds heal slowly (over 8 weeks) or do not heal at all. Chronic wounds can lead to prolonged hospitalization with a significant burden on the health care system due to medical costs associated with wound care products, surgery, and physician and nurse resources. Medical assistance does not prevent significant complications such as foot amputation, morbidity, and death, as efficient treatments have not been developed. In fact, the 5-year mortality rate of chronic skin wounds is comparable to or worse than that of several common types of cancer, including prostate, breast, and colon cancer.

[0005] Hydrogels have long been considered promising materials for wound dressing materials due to their good oxygen transmission and high water content, which can help maintain a moist environment around the wound. More importantly, therapeutic molecules such as growth factors or antibiotics can be easily loaded into hydrogels to promote wound healing, protect the wound from bacterial infection, and accelerate the healing process. Unfortunately, these hydrogels generally have a large release rate due to the highly porous structure of the gel, resulting in a rapid release (typically several hours) of therapeutic molecules. The rapid release of therapeutic agents not only reduces the efficiency of the therapy, but can also cause side effects due to the rapid increase in blood levels of these molecules.

[0006] What is needed are hydrogels that are conveniently prepared and have enhanced properties such as high water content, good oxygen permeability, low degradation rate, bioinertness, and cytocompatibility, allowing for the controlled release of therapeutic agents over extended periods of time. Summary of the Invention [Means for solving the problem]

[0007] The present invention relates generally to wound dressings useful for administering active ingredients to wounds. More specifically, it relates to crosslinked zwitterionic gel wound dressings having a water-soluble wound-facing layer comprising zwitterionic and non-zwitterionic monomers, methods of using such wound dressings for controlled or sustained delivery of active ingredients to wounds, and methods of making the same. The wound dressings of the present invention can provide controlled and sustained release of the active ingredient for at least about 12 hours.

[0008] In one aspect, a radically crosslinked zwitterionic gel is disclosed herein, the radically crosslinked zwitterionic gel comprising a zwitterionic monomer selected from the group consisting of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA), [(methacryloyloxy)ethyl]dimethylammonio]propionic acid (CBMA), 2-methacryloyloxyethyl phosphorylcholine (MPC), and combinations thereof, and a non-zwitterionic monomer. In some embodiments, the zwitterionic monomer and the non-zwitterionic monomer are at least partially crosslinked. In some embodiments, the radically crosslinked zwitterionic gel has an average pore size greater than about 50 mm and less than about 100 mm.

[0009] In various embodiments, the radically crosslinked zwitterionic gel can be formed as a hydrated gel, a lyophilized powder that can be hydrated as needed, or a lyophilized foam.

[0010] In some embodiments, the crosslinked zwitterionic gels of the invention are characterized by highly tunable mechanical properties. That is, the invention provides techniques that enable the generation and use of crosslinked zwitterionic gels that are characterized by mechanical properties (e.g., pore size, strength [e.g., as assessed by storage modulus], flexibility, stiffness, etc.) that are particularly suitable for use in supporting cell growth, function, viability, and / or differentiation. For example, in some embodiments, the crosslinked zwitterionic gels are characterized by mechanical properties that support living cells, as evidenced, for example, by the results of elongation of human mesenchymal stem cells.

[0011] In some embodiments, the crosslinked zwitterionic gels of the invention are characterized by a desired high storage modulus value. In some embodiments, a high storage modulus value corresponds to a strong and / or robust hydrogel. In some embodiments, the crosslinked zwitterionic gel comprises a high storage modulus value. In some specific embodiments exemplified herein, the covalently crosslinked hydrogels provided are characterized by a storage modulus value of about 50 Pa to about 5,000 Pa without showing signs of plastic deformation. In some specific embodiments exemplified herein, the crosslinked zwitterionic gels are characterized by a storage modulus value of greater than about 1 kPa without showing signs of plastic deformation. In some embodiments, the crosslinked zwitterionic gels of the invention are characterized by resisting degradation and recovering from at least 100% shear strain without showing signs of plastic deformation.

[0012] In some embodiments, the crosslinked zwitterionic gels are characterized by high elasticity. Elasticity or elastic deformation generally measures the tendency of a material to return to its original size and / or shape after a force is applied to the material and the force that deformed the material is subsequently removed. In contrast, plastic deformation occurs after applying sufficient pressure to the material to cause a change in the size and / or shape of the material in a non-reversible manner such that the material does not return to its original size and / or shape. Plastic deformation specifically involves a change to the structure of the material, such as a shift or rearrangement of molecules and / or atoms, from which the material cannot recover. In some embodiments, the crosslinked zwitterionic gels of the invention are characterized by having a tangent modulus value of about 50 Pa to about 50,000 Pa without showing signs of plastic deformation. In some embodiments, the covalently crosslinked hydrogels of the invention are characterized by resisting degradation and recovering from a compressive strain of at least 75% without showing any evidence of plastic deformation.

[0013] In some embodiments, the crosslinked zwitterionic gels are characterized by high resilience. Resilience provides an indication of the material's ability to absorb energy when a force is applied and the material is deformed, and then release the energy when the force is removed and the material is allowed to return to its natural state. In some embodiments, the crosslinked zwitterionic gels of the invention are characterized as being highly resilient to highly cycled and repeatedly applied forces. In some embodiments, the crosslinked zwitterionic gels of the invention are characterized as recovering from exposure to at least 10% compressive strain without showing evidence of deformation. In some embodiments, the crosslinked zwitterionic gels of the invention are characterized as recovering from exposure to at least 10% shear strain without showing evidence of plastic deformation.

[0014] In some embodiments, the crosslinked zwitterionic gel is configured to support encapsulation of at least one therapeutically active agent. In some embodiments, the crosslinked zwitterionic gel may encapsulate or otherwise contain at least one therapeutically active agent. In some embodiments, the crosslinked zwitterionic gel containing at least one therapeutically active agent may release the agent in a slow or sustained release manner for a period of at least or about 6 hours, at least or about 12 hours, at least or about 18 hours, at least or about 24 hours, at least or about 48 hours, 72 hours, or at least or about 96 hours.

[0015] In some embodiments, crosslinked zwitterionic gels are configured to support the incorporation and / or modification with one or more functional moieties. In some embodiments, crosslinked zwitterionic gels of the invention provide tunable mechanical properties to support, e.g., cell engineering and / or tissue regeneration applications, including, e.g., in the treatment or prevention of a disease, disorder, or condition, and / or for inducing tissue repair.

[0016] In another aspect, provided herein is a method for preparing a radically crosslinked zwitterionic gel.

[0017] In yet another aspect, provided herein is a method of treating a wound, the method comprising administering or applying a radically crosslinked zwitterionic gel to a wound in a subject in need thereof.

[0018] Other features and iterations of the invention are described in more detail below. [Brief description of the drawings]

[0019] [Figure 1a] Figures 1a and 1b show photographs of the radical cross-linked zwitterionic gels prepared under white light and 405 nm light. [Figure 1b] Same as above.

[0020] [Diagram 2]FIG. 2 is a graph of the percentage of cell viability for various radically crosslinked zwitterionic gels.

[0021] [Diagram 3] FIG. 3 is a series of photographs comparing the fouling prevention of radically crosslinked zwitterionic gels compared to glass slides.

[0022] [Figure 4a] FIG. 4a is a graph showing the storage modulus of various radically crosslinked zwitterionic gels against ambient and UV light.

[0023] [Figure 4b] FIG. 4b is a graph showing the shear storage modulus of various radically crosslinked zwitterionic gels.

[0024] [Figure 4c] FIG. 4c is a graph showing the shear storage modulus of various 25% and 50% radically crosslinked zwitterionic gels.

[0025] [Figure 4d] FIG. 4d is a graph showing the shear storage modulus of various 25% and 50% radically crosslinked zwitterionic gels.

[0026] [Diagram 5] FIG. 5 is a graph showing the swelling ratio of radically crosslinked zwitterionic gels over a 14 day period.

[0027] [Figure 6] FIG. 6 is a graph showing the degradation rate of radically crosslinked zwitterionic gels over a 14 day period.

[0028] [Figure 7] FIG. 7 shows a series of photographs regarding the injectability, stretchability, compression and release, and self-healing characteristics of the white light prepared radically crosslinked zwitterionic gels.

[0029] [Figure 8] Figure 8 shows a series of photographs regarding the injectability, stretchability, compression and release, and self-healing characteristics of the radically crosslinked zwitterionic gels prepared with 405 nm light.

[0030] [Figure 9] FIG. 9 is a series of photographs comparing the injectability of radically crosslinked zwitterionic gels and frozen (cryo) zwitterionic gels.

[0031] [Figure 10a] FIG. 10a is a graph showing the myoglobin release of various radically crosslinked zwitterionic gels over time.

[0032] [Figure 10b] FIG. 10b is a graph showing the release of cerium oxide nanoparticles (CNPs) from various radically crosslinked zwitterionic gels over time.

[0033] [Figure 11] FIG. 11 is a series of photographs showing wound closure of various radically crosslinked zwitterionic gels over a 16 day period.

[0034] [Figure 12a] 12a and 12b are graphs showing percentage and complete wound closure in mice. [Figure 12b] Same as above.

[0035] [Figure 13] FIG. 13 shows a photograph of a zwitterionic gel containing methacrylated hyaluronic acid.

[0036] [Figure 14] FIG. 14 shows photographs of zwitterionic gels made with SBMA, HEMA, LAP, and / or PEGDMA.

[0037] [Figure 15]FIG. 15 shows photographs of zwitterionic hydrogels made without and with resveratrol (antioxidant).

[0038] [Figure 16] FIG. 16 shows photographs of zwitterionic hydrogels made using ammonium persulfate and TEMED as radical initiators.

[0039] [Figure 17] FIG. 17 shows photographs of photocrosslinked hydrogels with various amounts of ascorbic acid added during polymerization.

[0040] [Figure 18] FIG. 18 shows quantitative tissue adhesion data for various zwitterionic hydrogels.

[0041] [Figure 19] FIG. 19 shows photographs of freeze-dried and rehydrated zwitterionic hydrogel samples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] In one aspect, the present disclosure provides radically crosslinked zwitterionic gels. These gels are easily prepared and have many desirable properties, such as high stretchability, injectability, low degradation over time, bioinertness, and highly sustained release of therapeutic agents. In certain embodiments, the gels of the present disclosure may prevent protein absorption during use.

[0043] definition In order that this disclosure may be more readily understood, certain terms are first defined below. Additional definitions for the following terms, as well as other terms, are set forth throughout the specification.

[0044] In this application, unless otherwise clear from the context, the term "a" may be understood to mean "at least one." As used in this application, the term "or" may be understood to mean "and / or." As used in this application, the terms "comprising" and "including" may be understood to encompass the specified component or step, whether presented by itself or together with one or more additional components or steps. Unless otherwise stated, the terms "about" and "approximately" may be understood to allow for standard variations as understood by those of ordinary skill in the art. When ranges are provided herein, endpoints are included. As used in this application, the term "comprise," and variations of that term, such as "comprising" and "comprises," are not intended to exclude other additional items, components, integers, or steps.

[0045] As used in this application, the terms "about" and "approximately" are used as equivalents. Any numbers used in this application, with or without about / approximately, are meant to cover any normal variations understood by those skilled in the relevant art. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less) of the stated reference value, unless otherwise stated or clear from the context (except where such number exceeds 100% of the possible values).

[0046] As used herein, the term "associated" typically refers to two or more entities that are in physical proximity to each other, either directly or indirectly (e.g., via one or more additional entities that function as linking agents), forming a structure that is sufficiently stable so that the entities remain in physical proximity under relevant conditions, e.g., physiological conditions. In some embodiments, the associated entities are covalently bound to each other. In some embodiments, the associated entities are non-covalently bound. In some embodiments, the associated entities are linked to each other by specific non-covalent interactions (i.e., by interactions between interacting ligands that distinguish their interacting partners from other entities present in the context of use, e.g., streptavidin / avidin interactions, antibody / antigen interactions, etc.). Alternatively, or in addition, a sufficient number of weaker non-covalent interactions can provide sufficient stability for the moieties to remain associated. Exemplary non-covalent interactions include, but are not limited to, affinity interactions, metal coordination, physical adsorption, host-guest interactions, hydrophobic interactions, pi-stacking interactions, hydrogen bonding interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, dipole-dipole interactions, and the like.

[0047] As used herein, the term "biocompatible" refers to a material that, when placed in contact with living tissue, e.g., in vivo, does not cause significant harm to the living tissue. In certain embodiments, a material is "biocompatible" if it is not toxic to cells. In certain embodiments, a material is "biocompatible" if addition of the material to cells in vitro results in 20% or less cell death and / or if administration of the material in vivo does not induce significant inflammation or other such adverse effects.

[0048] As used herein, the term "biodegradable" refers to a material that, when introduced into a cell, is broken down (e.g., by cellular mechanisms such as enzymatic degradation, hydrolysis, and / or a combination thereof) into components that the cell can reuse or discard without significant toxic effects to the cell. In certain embodiments, the components produced by the degradation of a biodegradable material are biocompatible and therefore do not induce significant inflammation and / or other adverse effects in vivo. In some embodiments, a biodegradable polymeric material is broken down into its component monomers. In some embodiments, the degradation of a biodegradable material (e.g., including a biodegradable polymeric material) involves hydrolysis of ester bonds. Alternatively, or additionally, in some embodiments, the degradation of a biodegradable material (e.g., including a biodegradable polymeric material) involves cleavage of urethane bonds.

[0049] As used herein, the term "comparable" refers to two or more agents, entities, circumstances, sets of conditions, etc. that may not be identical to one another, but are sufficiently similar to permit a comparison between them and conclusions may reasonably be drawn based on the differences or similarities observed. Those of skill in the art will understand what degree of identity is required in any given situation in context for two or more such agents, entities, circumstances, sets of conditions, etc. to be deemed comparable.

[0050] As used herein, the terms "conjugated," "linked," "attached," and "associated," when used in reference to two or more moieties, mean that the moieties are physically associated or linked to one another, either directly or through one or more additional moieties that function as binding agents, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. Typically, the moieties are attached by either one or more covalent bonds, or by mechanisms involving specific binding. Alternatively, a sufficient number of weaker interactions may provide sufficient stability for the moieties to remain physically associated.

[0051] As used herein, the term "controlled release" refers to a drug-containing formulation in which the manner and profile of drug release from the formulation is controlled. This includes immediate release formulations and non-immediate release formulations, which include, but are not limited to, sustained release formulations and delayed release formulations. The term "sustained release" (also called "sustained release") is used herein in its conventional sense to refer to a drug formulation that provides a gradual release of drug over an extended period of time, which can result in a substantially constant level of drug over an extended period of time. The term "delayed release" is used herein in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of drug therefrom. "Delayed release" may or may not involve a gradual release of drug over an extended period of time, and therefore may or may not be a "sustained release".The term "extended" release, as used herein, refers to a drug formulation that is capable of releasing a drug for at least 2 hours, 3 hours, 4 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours, 100 hours, 0 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours Between, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, By this means, the composition is constructed and arranged to deliver therapeutic levels of the active ingredient for 99 hours, 100 hours, 101 hours, 102 hours, 103 hours, 104 hours, 105 hours, 106 hours, 107 hours, 108 hours, 109 hours, 110 hours, 111 hours, 112 hours, 113 hours, 114 hours, 115 hours, 116 hours, 117 hours, 118 hours, 119 hours, or 120 hours.

[0052] The term "encapsulated" is used herein to refer to a substance that is completely surrounded by another material.

[0053] As used herein, a "functional" biological molecule is a biological molecule in a form in which it exhibits a property and / or activity by which it is characterized. A biological molecule can have two functions (i.e., bifunctional) or many functions (i.e., multifunctional).

[0054] As used herein, the term "hydrolytically degradable" is used to refer to a material that degrades by hydrolytic cleavage. In some embodiments, the hydrolytically degradable material degrades in water. In some embodiments, the hydrolytically degradable material degrades in water in the absence of any other agents or materials. In some embodiments, the hydrolytically degradable material degrades completely by hydrolytic cleavage, for example, in water. In contrast, the term "non-hydrolytically degradable" typically refers to a material that does not degrade completely by hydrolytic cleavage and / or in the presence of water (e.g., in the presence of water alone).

[0055] As used herein, the terms "hydrophilic" and / or "polar" refer to the tendency to mix with water or to dissolve readily in water.

[0056] As used herein, the terms "hydrophobic" and / or "non-polar" refer to the tendency to repel water, not mix with water, or not readily dissolve in water.

[0057] As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharma- ceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to an appropriate population. In some embodiments, the pharmaceutical composition may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as buccal, sublingual, and targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as subcutaneous, intramuscular, intravenous, or epidural injection, such as a sterile solution or suspension, or a sustained release formulation; topical application, such as a cream, ointment, or controlled release patch or spray applied to the skin, lungs, or oral cavity; vaginal or rectal use, such as a pessary, cream, or foam; sublingual; ophthalmic; transdermal; or nasal; pulmonary; and other mucosal surfaces.

[0058] As used herein, the phrase "physiological conditions" refers to the range of chemical (e.g., pH, ionic strength) and biochemical (e.g., enzyme concentrations) conditions likely to be encountered in the intracellular and extracellular fluids of a tissue. For most tissues, physiological pH ranges from about 6.8 to about 8.0, temperature ranges from about 20-40°C, about 25-40°C, about 30-40°C, about 35-40°C, about 37°C, and atmospheric pressure of about 1. In some embodiments, physiological conditions utilize or include an aqueous environment (e.g., water, saline, Ringer's solution, or other buffer), and in some such embodiments, the aqueous environment is or includes a phosphate buffer (e.g., phosphate buffered saline).

[0059] As used herein, the term "porosity" refers to a measure of voids in a material, expressed as a percentage between 0 and 100%, as a fraction of the volume of voids relative to the total volume. Determination of porosity uses standardized techniques, such as mercury porosimetry and gas adsorption (e.g., nitrogen adsorption), and are known to those skilled in the art.

[0060] As used herein, the term "solution" broadly refers to a homogenous mixture composed of one phase. Typically, a solution includes a solute dissolved in a solvent. The properties of the mixture (concentration, temperature, density, etc.) are characterized in that they can be uniformly distributed throughout the volume. Thus, in the context of this application, a "silk fibroin solution" refers to a soluble form of silk fibroin protein dissolved in a solvent, such as water. In some embodiments, a silk fibroin solution can be prepared from a solid silk fibroin material (i.e., silk matrix), such as silk films and other scaffolds. Typically, the solid silk fibroin material is reconstituted with an aqueous solution, such as water and buffers, to become a silk fibroin solution. It should be noted that liquid mixtures that are not homogenous, such as colloids, suspensions, and emulsions, are not considered solutions.

[0061] As applied to compositions herein, the term "stable" means that the composition maintains one or more aspects of its physical structure and / or activity over a period of time under a specified set of conditions. In some embodiments, the period is at least about one hour, and in some embodiments, the period is about 5 hours, about 10 hours, about 1 day, about 1 week, about 2 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 24 months, about 36 months, or more. In some embodiments, the period is within the range of about 1 day to about 24 months, about 2 weeks to about 12 months, about 2 months to about 5 months, etc. In some embodiments, the specified conditions are ambient conditions (e.g., room temperature and ambient pressure). In some embodiments, the specified conditions are physiological conditions (e.g., in vivo or at about 37° C., e.g., in serum or phosphate buffered saline). In some embodiments, the specified conditions are under cold storage (e.g., at or below about 4° C., at or below −20° C., or at or below −70° C.). In some embodiments, the specified conditions are in the dark.

[0062] As used herein, the term "substantially" and grammatical equivalents refer to a qualitative condition indicating the extent or degree of the total or near total of a feature or characteristic of interest. Those skilled in the art will understand that biological and chemical phenomena rarely, if ever, go to completion and / or reach a point of completion, or achieve or avoid absolute results.

[0063] The term "sustained release" is used herein in accordance with the art-understood meaning of release occurring over an extended period of time. An extended period of time can be at least about 3 days, about 5 days, about 7 days, about 10 days, about 15 days, about 30 days, about 1 month, about 2 months, about 3 months, about 6 months, or even about 1 year. In some embodiments, the sustained release is substantially burst-free. In some embodiments, the sustained release involves a steady release over an extended period of time such that the release rate does not change by more than about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or about 50% over an extended period of time. In some embodiments, the sustained release involves release with first order kinetics. In some embodiments, the sustained release involves an initial burst followed by a period of steady release. In some embodiments, the sustained release does not include an initial burst. In some embodiments, the sustained release is substantially burst-free release.

[0064] As used herein, the term "therapeutic agent" refers to any agent that induces a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it shows a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, the appropriate population may be defined by various criteria, such as a particular age group, sex, genetic background, pre-existing clinical conditions, etc. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, mitigate, inhibit, prevent, delay the onset of, reduce the severity, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition.

[0065] As used herein, the term "treat" refers to the partial or complete alleviation, amelioration, mitigation, inhibition, prevention (for at least a period of time), delay in onset, reduction in severity, reduction in frequency, and / or reduction in incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who does not exhibit symptoms, signs, or characteristics of a disease and / or who exhibits only early symptoms, signs, and / or characteristics of a disease, for example, to reduce the risk of developing pathology associated with the disease. In some embodiments, treatment may be administered after the onset of one or more symptoms, signs, and / or characteristics of a disease.

[0066] The term "zwitterion" is a neutral molecule that bears a positive and a negative charge.

[0067] (I) Radical cross-linked zwitterionic gel The present disclosure encompasses radically crosslinked zwitterionic gels comprising zwitterionic monomers and non-zwitterionic monomers. In some embodiments, the zwitterionic monomers are at least partially crosslinked with the non-zwitterionic monomers. In various embodiments, the crosslinked zwitterionic gels are easy to apply, extrudable, stretchable, and easily conform to wounds.

[0068] In some embodiments, the crosslinked zwitterionic gels of the invention are made from commonly available reagents. In some embodiments, the crosslinked zwitterionic gels of the invention can be produced without the need for volatile chemicals to induce gelation. In some embodiments, the crosslinked zwitterionic gels of the invention can be produced using all aqueous processing. In some embodiments, the crosslinked zwitterionic gels of the invention can be produced without the need to rely on expensive or complex equipment (power supplies, sonicators, vortexers, etc.). In some embodiments, the crosslinked zwitterionic gels of the invention are inexpensive to prepare, easy to prepare, and amenable to bulk manufacturing.

[0069] In some embodiments, the crosslinked zwitterionic gels of the invention are prepared under mild, physiologically safe reaction conditions. In some embodiments, the mild aqueous-based processing is suitable for incorporation of therapeutically active agents during formation. In some embodiments, the hydrogels provide ease of penetration of, for example, therapeutically active agents. In some embodiments, the crosslinked zwitterionic gels of the invention are biocompatible and biodegradable. In some embodiments, the crosslinked zwitterionic gels are not cytotoxic. In some embodiments, the crosslinked zwitterionic gels are non-immunogenic.

[0070] In some embodiments, the crosslinked zwitterionic gels are characterized by excellent resilience and elasticity. In some embodiments, the crosslinked zwitterionic gels of the invention are characterized by full recovery from large strains or prolonged cyclic compression. In some embodiments, the crosslinked zwitterionic gels of the invention are characterized in that they withstand prolonged pressure with little change in elastic modulus and without signs of significant changes in mechanical properties such as plastic deformation. In some embodiments, the crosslinked zwitterionic gels of the invention are characterized in that they can withstand repeated strain. In some embodiments, the crosslinked zwitterionic gels of the invention, which have been shown to exhibit the above-identified characteristics and / or properties, are formed from solutions of zwitterionic and non-zwitterionic monomers.

[0071] In some embodiments, the crosslinked zwitterionic gels of the invention swell up to 50%, up to 100%, up to 150%, up to 200%, up to 300%, or up to 400% when exposed to a solvent. In some embodiments, the crosslinked zwitterionic gels of the invention are configured to support encapsulation of a therapeutic agent. In some embodiments, the crosslinked zwitterionic gels of the invention provide for direct encapsulation of one or more therapeutic agents. In some embodiments, the crosslinked zwitterionic gels exhibit long-term storage capabilities with or without a therapeutic agent.

[0072] The zwitterionic monomer may be [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA), [(methacryloyloxy)ethyl]dimethylammonio]-propionic acid (CBMA), 2-methacryloyloxyethyl phosphorylcholine (MPC), and combinations thereof. In one embodiment, the zwitterionic monomer is 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA).

[0073] The non-zwitterionic monomer may be hydroxyethyl methacrylate (HEMA).

[0074] In general, the weight ratio of zwitterionic monomers to non-zwitterionic monomers can range from about 1:19 to about 19:1. In various embodiments, the weight ratio of zwitterionic monomers to non-zwitterionic monomers can range from about 1:19 to about 19:1, from about 1:18 to about 18:1, from 1:17 to about 17:1, from about 1:16 to about 16:1, from 1:15 to about 15:1, from about 1:14 to about 14:1, from 1:13 to about 13:1, from about 1:12 to about 12:1, from 1:11 to about 11:1, from about 1:10 to about 10:1, from 1:9 to about 9:1, from about 1:8 to about 8:1, from 1:7 to about 7:1, from about 1:6 to about 6:1, from 1:5 to about 5:1, from about 1:4 to about 4:1, from 1:3 to about 3:1, or from about 1:2 to about 2:1.

[0075] The radically crosslinked zwitterionic gel may further include an optional crosslinker that provides additional crosslinking to the zwitterionic and non-zwitterionic monomers after polymerization. The crosslinker is selected from the group consisting of glycerol dimethacrylate (GDMA), methylene bisacrylamide (MBA), polyethylene glycol dimethacrylate (PEGDMA), and combinations of two or more crosslinkers. In one preferred embodiment, the crosslinker is polyethylene glycol dimethacrylate (PEGDMA).

[0076] In general, the concentration percentage ratio of the crosslinker to the radical crosslinked zwitterionic gel can range from about 0.0:1.0 to about 0.25:1.0. In various embodiments, the concentration percentage ratio of the crosslinker to the radical crosslinked zwitterionic gel can range from about 0.0:1.0 to about 0.25:1.0, from about 0.001:1.0 to about 0.2:1.0, from about 0.005:1.0 to about 0.15:1.0, from about 0.01:1.0 to about 0.1:1.0.

[0077] The radical crosslinked zwitterionic gel may further include a rheology modifier. The rheology modifier further enhances the rheological properties of the radical crosslinked zwitterionic gel. Non-limiting examples of suitable rheology modifiers may be various clays. In one embodiment, the rheology modifier is a synthetic smectic clay. In some embodiments, the crosslinked zwitterionic gel includes an additive, such as a therapeutic agent, a prophylactic agent, and / or a diagnostic agent.

[0078] The radical cross-linked zwitterionic gel may further include an antioxidant. The antioxidant further enhances the storage capacity and properties of the radical cross-linked zwitterionic gel. Non-limiting examples of suitable antioxidants include resveratrol, various vitamins, uric acid, and glutathione. In one embodiment, the antioxidant is resveratrol. In other embodiments, the antioxidant may be A5G81 peptide, ascorbic acid (vitamin C), astaxanthin, capric acid, cerium oxide nanoparticles, curcumin, cyaniding, epigallocatechin gallate, forskolin, gingerol, ginkgo, glutamine, glutathione, glycyrrhizin, phosphatidylserine, piperine, quercetin, resveratrol, sulforaphane, superoxide dismutase, taurine, ubiquinol, uric acid, ursolic acid, vitamin E, and the like. In other embodiments, the antioxidant may be a NADPH-oxidase inhibitor (e.g., 2-acetylphenothiazine (ML171), apocynin, APX-115, G6PDi-1, GKT136901, GLX351322, GSK2795039, Setanaxib (GKT137831), VAS2870, etc.).

[0079] In some embodiments, the crosslinked zwitterionic gel comprises an additive, e.g., a therapeutic, prophylactic, and / or diagnostic agent.

[0080] The radically crosslinked zwitterionic gel can further include a therapeutic agent. The therapeutic agent can be covalently bonded through a hydroxyl group, ionically bonded to one or more ions in the radically crosslinked zwitterionic gel, hydrogen bonded, bonded via van der Waals interactions with the radically crosslinked zwitterionic gel, or a combination of two or more thereof. The therapeutic agent can be released from the radically crosslinked zwitterionic gel over an extended period of time after administration or application, for example, to enhance wound healing.

[0081] Any suitable therapeutic agent useful in treating wounds may be used in conjunction with the radical crosslinked zwitterionic gels of the present disclosure. Non-limiting therapeutic agents include myoglobin, cerium oxide nanoparticles (CNP), miRNA, siRNA, mRNA, growth factors, and combinations thereof. By way of example, the therapeutic agent may include silver, colloidal silver, DNAse 1 (e.g., dornase alpha), miRNA, siRNA, mRNA, (e.g., miRNA-146a), citrullination inhibitors (e.g., Cl-amidine), growth factors (e.g., VEGF, PDGF (e.g., Regranex), EGF, FGF, TGF-b, GM-CSF, and isoforms thereof), hyaluronic acid, tacrolimus, and AMD3100, insulin, collagenase-debridement, broad-spectrum antibiotics (e.g., erythromycin ... Examples include gentamicin, vancomycin, trimethoprim / sulfamethoxazole (e.g., Bactrim), amoxicillin / clavulanic acid (Augmentin), ampicillin, doxycycline, minocycline, aminoglycosides, azithromycin, carbapenems, piperacillin-tazobactam combination, quinolones (e.g., ciprofloxacin), tetracyclines, chloramphenicol, ticarcillin, and others.

[0082] Other suitable therapeutic agents that may be used in conjunction with the radical crosslinked zwitterionic gels of the present disclosure include acid / alkali labile drugs, pH-dependent drugs, or drugs that are weak acids or weak bases. Examples of acid labile drugs include statins (e.g., pravastatin, fluvastatin, and atorvastatin), antibiotics (e.g., penicillin G, ampicillin, streptomycin, erythromycin, clarithromycin, and azithromycin), nucleoside analogs (e.g., dideoxyinosine (ddI or didanosine), dideoxyadenosine (ddA), dideoxycytosine (ddC)), salicylates (e.g., aspirin), digoxin, bupropion, pancreatin, midazolam, and methadone. Drugs that are soluble only at acid pH include nifedipine, emonapride, nicardipine, amosulalol, noscapine, propafenone, quinine, dipyridamole, josamycin, dilevalol, labetalol, enisoprost, and metronidazole. Drugs that are weak acids include phenobarbital, phenytoin, zidovudine (AZT), salicylates (e.g., aspirin), propionic acid compounds (e.g., ibuprofen), indole derivatives (e.g., indomethacin), fenamic acid compounds (e.g., meclofenamic acid), pyrrolealkanoic acid compounds (e.g., tolmetin), cephalosporins (e.g., cephalothin, cephalaxin, cefazolin, cephradine, cephapirin, cefamandole, and cefoxitin), 6-fluoroquinolones, and prostaglandins.Drugs that are weak bases include adrenergic drugs (e.g., ephedrine, desoxyephedrine, phenylephrine, epinephrine, salbutamol, and terbutaline), cholinergic drugs (e.g., physostigmine and neostigmine), antispasmodics (e.g., atropine, methantheline, and papaverine), curare-like agents (e.g., chlorisondamine), tranquilizers and muscle relaxants (e.g., fluphenazine, thioridazine, trifluoperazine, chlorpromazine, and triflupromazine), antidepressants (e.g., amitriptyline and nortriptyline), antihistamines (e.g., diphenhydramine, chlorpheniramine, niramin, dimenhydrinate, tripelennamine, perphenazine, chlorprophenazine, and chlorprofenpyridamine), cardioactive drugs (e.g., verapamil, diltiazem, gallapomil, cinnarizine, propranolol, metoprolol, and nadolol), antimalarials (e.g., chloroquine), analgesics (e.g., propoxyphene and meperidine), antifungals (e.g., ketoconazole and itraconazole), antibacterial agents (e.g., cefpodoxime, proxetil, and enoxacin), caffeine, theophylline, and morphine.

[0083] In another embodiment, a therapeutic agent that may be used in conjunction with the radically crosslinked zwitterionic gels of the present disclosure may be an antibacterial agent. Suitable antibacterial agents include aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, and tobramycin), carbecephems (e.g., loracarbef), carbapenems (e.g., certapenem, imipenem, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalexin, cefaclor, cefamandole, cephalexin, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone), macrolides (e.g., azithromycin, clarithromycin, dirithromycin, erythromycin, and troleandomycin), monobactams, penicillins (e.g., amoxicillin, ampicillin, carbenicillin, cloxacillin, dicloxacillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, and ticarcillin), polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and trovafloxacin), sulfonamides (e.g., mafenide, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole, and trimethoprim-sulfamethoxazole), and tetracyclines (e.g., demeclocycline, doxycycline, minocycline, and oxytetracycline).

[0084] In an alternative embodiment, a therapeutic agent that may be used in conjunction with the radically crosslinked zwitterionic gels of the present disclosure may be an antiviral protease inhibitor (e.g., amprenavir, fosamprenavir, indinavir, lopinavir / ritonavir, ritonavir, saquinavir, and nelfinavir).

[0085] In some embodiments, the additive is or includes one or more therapeutic agents. In general, a therapeutic agent is or includes a small molecule and / or organic compound that has pharmaceutical activity (e.g., activity that has been demonstrated with statistical significance in one or more relevant preclinical models or clinical settings). In some embodiments, a therapeutic agent is a clinically used drug. In some embodiments, the therapeutic agent is or comprises a cell, a protein, a peptide, a nucleic acid analog, a nucleotide, an oligonucleotide, a nucleic acid (DNA, RNA, siRNA), a peptide nucleic acid, an aptamer, an antibody or a fragment or portion thereof, an anesthetic, an anticoagulant, an anticancer drug, an inhibitor of an enzyme, a steroid, an anti-inflammatory agent, an anti-neoplastic agent, an antigen, a vaccine, an antibody, a nasal decongestant, an antihypertensive agent, a sedative, a contraceptive, a progestational agent, an anticholinergic agent, an analgesic agent, an antidepressant, an antipsychotic agent, a beta-adrenergic blocker, a diuretic, a cardiovascular active agent, a vasoactive agent, an antiglaucoma agent, a neuroprotective agent, an angiogenesis inhibitor, a hormone, a hormone antagonist, a growth factor or recombinant growth factor and fragments and variants thereof, a cytokine, an enzyme, an antibiotic or antimicrobial compound, an antifungal agent, an antiviral agent, a toxin, a prodrug, a chemotherapeutic agent, a small molecule, a drug (e.g., a drug, a dye, an amino acid, a vitamin, an antioxidant), a pharmacological agent, and combinations thereof.

[0086] In some embodiments, the crosslinked zwitterionic gel comprises one or more cells. Cells suitable for use herein include, but are not limited to, progenitor or stem cells, smooth muscle cells, skeletal muscle cells, cardiac muscle cells, epithelial cells, endothelial cells, urothelial cells, fibroblasts, myoblasts, chondrocytes, chondroblasts, osteoblasts, osteoclasts, keratinocytes, hepatocytes, bile duct cells, pancreatic islet cells, thyroid, parathyroid, adrenal, hypothalamus, pituitary, ovary, testis, salivary gland cells, adipocytes, and progenitor cells.

[0087] In some embodiments, the crosslinked zwitterionic gel comprises one or more antibiotics. Antibiotics suitable for incorporation into the hydrogel include, but are not limited to, aminoglycosides (e.g., neomycin), ansamycins, carbacephems, carbapenems, cephalosporins (e.g., cefazolin, cefaclor, cefditoren, ceftobiprole), glycopeptides (e.g., vancomycin), macrolides (e.g., erythromycin, azithromycin), monobactams, penicillins (e.g., amoxicillin, ampicillin, cloxacillin, dicloxacillin, flucloxacillin), polypeptides (e.g., bacitracin, polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, ofloxacin, etc.), sulfonamides (e.g., sulfasalazine, trimethoprim, etc.), and the like. rim, trimethoprim-sulfamethoxazole combination (cotrimoxazole), tetracyclines (e.g., doxycycline, minocycline, tetracycline, etc.), chloramphenicol, lincomycin, clindamycin, ethambutol, mupirocin, metronidazole, pyrazinamide, thiamphenicol, rifampicin, thiamphenicl, dapsone, clofazimine, quinupristin, metronidazole, linezolid, isoniazid, fosfomycin, fusidic acid, beta-lactam antibiotics, rifamycin, novobiocin, sodium fusidate, capreomycin, colistimethate, gramicidin, doxycycline, erythromycin, nalidixic acid, and vancomycin. For example, the beta-lactam antibiotic can be aziocillin, aztreonam, carbenicillin, cefoperazone, ceftriaxone, cephaloridine, cephalothin, moxalactam, piperacillin, ticarcillin, and combinations thereof.

[0088] In some embodiments, the crosslinked zwitterionic gel comprises one or more anti-inflammatory agents, which may include corticosteroids (e.g., glucocorticoids), cycloplegics, nonsteroidal anti-inflammatory drugs (NSAIDs), immunoselective anti-inflammatory derivatives (ImSAIDs), and any combination thereof. Exemplary NSAIDs include, but are not limited to, celecoxib (Celebrex®), rofecoxib (Vioxx®), etoricoxib (Arcoxia®), meloxicam (Mobic®), valdecoxib, diclofenac (Voltaren®, Cataflam®), etodolac (Lodine®), sulindac (Clinori®), aspirin, alclofenac, fenclofenac, diflunisal (Dolobid®), benorylate, fosfosal, acetylsalicylic acid, sodium acetylsalicylate, calcium acetylsalicylate, and salicylic acid, including sodium salicylate, ibuprofen (Motrin), ketoprofen, carprofen, fenbufen, flurbiprofen, oxaprozin, suprofen, triaprofenic acid, acid), fenoprofen, indoprofen, pyroprofen, flufenam, mefenam, meclofenam, niflum, salsalate, rolmerin, fentiazac, tilomisole, oxyphenbutazone, phenylbutazone, apazone, feprazone, sudoxicam, isoxicam, tenoxicam, piroxicam (Feldene®), indomethacin (Indocin®), nabumetone (Relafen®), naproxen (Naprosyn®), tolmetin, lumiracoxib, parecoxib, licofelone (ML3000), including pharmaceutically acceptable salts, isomers, enantiomers, derivatives, prodrugs, crystalline polymorphs, amorphous modifications, co-crystals, and combinations thereof.

[0089] In some embodiments, the crosslinked zwitterionic gel comprises one or more antibodies. Antibodies suitable for incorporation into the hydrogel include, but are not limited to, abciximab, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, ibritumomab tiuxetan, infliximab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab, altumomab pentetate, arcitumomab, atlizumab, bectumomab, belimumab, besilezomab, biciromab, canakinumab, cytomegalovirus ... These include numab, capromab pendetide, catumaxomab, denosumab, edrecolomab, efungumab, ertumaxomab, etaracizumab, fanolesomab, fontolizumab, gemtuzumab ozogamicin, golimumab, igovomab, imciromab, labetuzumab, mepolizumab, motavizumab, nimotuzumab, nofetumomab merpentan, oregovomab, pemtumomab, pertuzumab, lovelizumab, ruplizumab, suresomab, tacatuzumab tetraxetan, tefibazumab, tocilizumab, ustekinumab, visilizumab, votumumab, zalutumumab, and zanolimumab.

[0090] In some embodiments, the crosslinked zwitterionic gel comprises one or more polypeptides (e.g., proteins), including but not limited to one or more antigens, cytokines, hormones, chemokines, enzymes, and any combination thereof as drugs and / or functional groups. Exemplary enzymes suitable for use herein include, but are not limited to, peroxidases, lipases, amylases, organophosphate dehydrogenases, ligases, restriction endonucleases, ribonucleases, DNA polymerases, glucose oxidase, laccases, and the like.

[0091] In some embodiments, the crosslinked zwitterionic gels include one or more therapeutic agents useful for wound healing. In some embodiments, agents useful for wound healing include stimulators, enhancers, or positive mediators of the wound healing cascade that 1) promote or accelerate the natural wound healing process, or 2) reduce the effects associated with improper or delayed wound healing, including, for example, deleterious inflammation, epithelialization, angiogenesis, and matrix deposition, as well as scarring and fibrosis.

[0092] The amount of therapeutic agent used for radical crosslinking can vary depending on the particular therapeutic agent, the amount of therapeutic agent that needs to be administered per day, and the particular radical crosslinked zwitterionic gel used. In general, the concentration percentage ratio of the therapeutic agent to the radical crosslinked zwitterionic gel can range from about 0.001:1.0 to about 1.0:1.0. In various embodiments, the concentration percentage ratio of the therapeutic agent to the radical crosslinked zwitterionic gel can range from about 0.001:1.0 to about 1.0:1.0, from about 0.01:1.0 to about 0.5:1.0, or from about 0.05:1.0 to about 0.1:1.0.

[0093] The radical crosslinked zwitterionic gels have several novel and unique properties. The radical crosslinked zwitterionics have an average pore size of greater than about 50 mm and less than about 100 mm. In various embodiments, the average pore size D 90is about 51mm, about 52mm, about 53mm, about 54mm, about 55mm, about 56mm, about 57mm, about 58mm, about 59mm, about 60mm, about 61mm, about 62mm, about 63mm, about 64mm, about 65mm, about 66mm, about 67mm, about 68mm, about 69mm, about 70mm, about 71mm, about 72mm, about 73mm, about 74mm, about 75mm , about 76 mm, about 77 mm, about 78 mm, about 79 mm, about 80 mm, about 81 mm, about 82 mm, about 83 mm, about 84 mm, about 85 mm, about 86 mm, about 87 mm, about 88 mm, about 89 mm, about 90 mm, about 91 mm, about 92 mm, about 93 mm, about 94 mm, about 95 mm, about 96 mm, about 97 mm, about 98 mm, or about 99 mm. This pore size is important to allow for timed release of the optional therapeutic agent.

[0094] The radically cross-linked zwitterionic gel is elastic, injectable, and compressible. After compression is complete, the radically cross-linked zwitterionic gel is released and returns to its original form. Additionally, the radically cross-linked zwitterionic gel is self-healing. The term self-healing refers to removing a piece of the radically cross-linked zwitterionic gel from the main body of the radically cross-linked zwitterionic gel and placing the removed piece on the remaining main body of the radically cross-linked zwitterionic gel, where the removed piece fits together within the main body and re-establishes cross-links.

[0095] Typically, the radical crosslinked zwitterionic gel has a storage modulus of about 50 Pa to about 2,000 Pa. In various embodiments, the radical crosslinked zwitterionic gel has a storage modulus of about 50 Pa to about 2,000 Pa, about 100 Pa to about 1,800 Pa, about 200 to about 1,700 Pa, about 300 to about 1,600 Pa, about 400 to about 1,500 Pa, about 500 to about 1,400 Pa, about 600 to about 1,300 Pa, about 700 to about 1,200 Pa, about 800 to about 1,100 Pa, about 900 to about 1,000 Pa, or about 500 Pa to about 750 Pa.

[0096] Typically, the radical crosslinked zwitterionic gel has an elastic modulus of about 1,000 Pa to about 20,000 Pa. In various embodiments, the radical crosslinked zwitterionic gel has an elastic modulus of about 1,000 Pa to about 20,000 Pa, about 2,000 Pa to about 17,250 Pa, about 2,500 to about 15,000 Pa, about 3,000 to about 12,500 Pa, about 3,500 to about 10,000 Pa, about 4,000 to about 7,500 Pa, or about 5,000 to about 10,000 Pa.

[0097] The physical properties of the radically crosslinked zwitterionic gels of the present disclosure are antifouling, adhesive, self-healing, and cytocompatible, providing hydrogel materials that offer improved wound healing. In certain aspects, the self-healing properties of the radically crosslinked zwitterionic gels of the present disclosure facilitate the ability of the gel to conform to the size and shape of the wound.

[0098] Table 1 provides the effect of crosslinking time on different embodiments of the present invention. [Table 1]

[0099] (II) Method for preparing radical cross-linked zwitterionic gels In another aspect, the present disclosure provides a method of preparing a radically crosslinked zwitterionic gel, the method comprising: (a) mixing a zwitterionic monomer, a non-zwitterionic ionic monomer, an optional crosslinker, an optional rheology modifier, an optional antioxidant, and a solvent (e.g., water) to form a reaction mixture, (b) optionally filtering the reaction mixture through a particulate filter, e.g., a 0.22 μm pore filter, thereby forming a filtered reaction mixture, and (c) exposing the reaction mixture and / or the filtered reaction mixture to light and / or other suitable radical initiator, thereby polymerizing the zwitterionic monomer and the non-zwitterionic monomer to form the radically crosslinked zwitterionic gel, the radically crosslinked zwitterionic gel having an average pore size greater than about 50 mm and less than about 100 mm. In some embodiments, the preparation methods of the present disclosure may further include washing the radically crosslinked zwitterionic gel to remove unreacted monomer, crosslinker, and optional initiator by-products (if present), thereby forming a washed radically crosslinked zwitterionic gel.

[0100] The zwitterionic monomer, non-zwitterionic monomer, and optional crosslinker are detailed above. In general, the reaction mixture and / or the filtered reaction mixture may be mixed for a duration sufficient to provide a homogenous solution. Various mixing methods are known in the art. In certain embodiments, the reaction mixture and / or the filtered reaction mixture may be mixed prior to exposure to light or other suitable radical generators, or the reaction mixture and / or the filtered reaction mixture may be mixed simultaneously with exposure to light or other suitable radical generators.

[0101] In one embodiment, the zwitterionic monomer is 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA), the non-zwitterionic monomer is hydroxyethyl methacrylate (HEMA), and the crosslinker is optionally polyethylene glycol dimethacrylate (PEGDMA).

[0102] Generally, the weight ratio of zwitterionic monomers to non-zwitterionic monomers in the initial reaction mixture can range from about 1:19 to about 19: 1. In various embodiments, the weight ratio of zwitterionic monomers to non-zwitterionic monomers in the initial reaction mixture can range from about 1:19 to about 19:1, from about 1:9 to about 9:1, from about 1:4 to about 4:1, or from about 2:1 to about 1:2.

[0103] In general, the concentration percentage ratio of the crosslinker initially present in the reaction mixture to the radically crosslinked zwitterionic gel formed can range from about 0.0:1.0 to about 0.25:1.0. In various embodiments, the concentration percentage ratio of the crosslinker initially present in the reaction mixture to the radically crosslinked zwitterionic gel form can range from about 0.0:1.0 to about 0.25:1.0, about 0.001:1.0 to about 0.2:1.0, about 0.005:1.0 to about 0.15:1.0, about 0.01:1.0 to about 0.1:1.0.

[0104] Generally, the volume of solvent (e.g., water) can range from about 0.1:1.0 to about 500.0:1.0, based on the weight of zwitterionic monomer, non-zwitterionic monomer, and optional crosslinker present in the initial reaction mixture. In various embodiments, the volume of solvent can range from about 0.1:1.0 to about 500.0:1.0, from about 1.0:1.0 to about 250.0:1.0, or from about 5.0:1.0 to about 100.0:1.0, based on the weight of zwitterionic monomer, non-zwitterionic monomer, and optional crosslinker in the initial reaction mixture.

[0105] The reaction mixture may optionally include an initiator. Without being limited by theory, the initiator may promote polymerization between the zwitterionic monomer, the non-zwitterionic monomer, and the optional crosslinker. By way of non-limiting example, initiators useful in connection with the preparation method of the present disclosure include sodium persulfate, ruthenium(II)-tris(2,2'-bipyridyl)dichloride, and combinations thereof.

[0106] In general, the weight ratio of the initiator to the weight ratio of the zwitterionic monomer, non-zwitterionic monomer, and optional crosslinker in the initial reaction mixture can range from 0.001:1.0 to 0.1:1.0. In various embodiments, the weight ratio of the initiator to the weight ratio of the zwitterionic monomer, non-zwitterionic monomer, and optional crosslinker in the initial reaction mixture can range from 0.001:1.0 to 0.1:1.0, from about 0.005:1.0 to about 0.05:1.0, or from about 0.01:1.0 to about 0.02:1.0.

[0107] Once formed, the reaction mixture may optionally be filtered, for example through a 0.22 μm pore filter, to reduce particle size, thereby forming a filtered reaction mixture. Without intending to be limited by theory, filtration removes undissolved materials from the reaction mixture, facilitating the formation of a homogenous reaction mixture, allowing polymerization to occur more efficiently.

[0108] The reaction mixture and / or filtered reaction mixture may then be exposed to light and / or other suitable radical generators to initiate polymerization. Without intending to be limited by theory, light and / or radical generator initiation allows the zwitterionic monomer, non-zwitterionic monomer, optional crosslinker, and optional rheology modifier to form a radical crosslinked zwitterionic gel. The optional initiator may further enhance the crosslinking polymerization.

[0109] Various forms of light and / or radical generators can be used to polymerize the reaction mixture. Wavelengths of light useful for generating radicals generally range from 400 nm to 700 nm. Non-limiting examples of useful forms of light can be UV light, visible light, or white light, e.g., 405 nm. The light can be sunlight, filtered sunlight, or from an artificial source (e.g., incandescent light, LED light, UV light, etc.).

[0110] Other suitable radical generators may be used alone or in combination with light exposure. Non-limiting examples of suitable radical generators may be ammonium persulfate (APS), N,N,N'N'-tetramethylethylene-1,2-diamine (TEMED), ascorbic acid, organic peroxides, and combinations thereof. In some embodiments, suitable radical generators may include APS / TEMED or APS / ascorbic acid (e.g., 10 mM ascorbic acid, 10 mM APS). Other thermal and non-thermal initiators known in the art may also be used. In certain embodiments, non-thermal radical generators may release heat during the reaction and may require cooling. As examples, K2S2O8 (decomposition temperature of 50-60°C) or 4,4'-azobis(4-cyanovaleric acid) (decomposition of 70°C) may be used. Table 2 shows the effect of radical scavenger concentration on gel stiffness. Table 2 shows the effect of various concentrations of ammonium persulfate (APS) on gel toughness and adhesion. [Table 2]

[0111] Without intending to be limited by theory, the use of ascorbic acid as a free radical activator in in situ polymerization opens up the possibility of removing harmful substances, for example from ceramic slurries. Ascorbic acid (one of its forms is commonly known as vitamin C) is a naturally occurring compound that can be found in single-cell organisms, plants and animals and is produced from glucose. It is well soluble in water and is not harmful to humans and the environment. Furthermore, while the addition of the alkaline amine N,N,N',N'-tetramethylethylenediamine leads to the solidification of some ceramic slurries, the mild acidic properties of ascorbic acid may have a positive impact on the stability of ceramic suspensions. Table 3 shows the effect of radical scavenger concentration on gel stiffness. [Table 3]

[0112] The reaction mixture may be placed in a suitable container and exposed to a light source and / or other suitable radical generator. In certain embodiments, the reaction container may be configured to allow light of a particular wavelength to contact the reaction mixture to provide polymerization. The duration of exposure of the reaction mixture to light and / or other suitable radical generator may vary depending on the amount of monomer, optional crosslinker, optional initiator, optional rheology modifier, type of monomer used, and optional antioxidant used. Generally, the duration of exposure of the reaction mixture to light and / or other suitable radical generator may range from about 1 minute to 24 hours. In various embodiments, the exposure period may range from about 30 minutes to 24 hours, about 45 minutes to 6 hours, or about 1 hour to 2 hours. In one embodiment, the exposure period is about 1 hour.

[0113] In certain embodiments, the radically crosslinked zwitterionic gel may be washed, for example, with a buffered saline solution, thereby removing unreacted monomer, unreacted crosslinker, and optional initiator by-products, thereby forming a washed radically crosslinked zwitterionic gel.

[0114] Generally, the radically cross-linked zwitterionic gel may be washed at least once with a buffered saline solution. In various embodiments, the radically cross-linked zwitterionic gel may be washed once, twice, or more than twice with a buffered saline solution. Each wash of the radically cross-linked zwitterionic gel not only removes unreacted material but also increases the purity. Each wash of the buffered saline solution may be incubated with the radically cross-linked zwitterionic gel for a period of time to allow unreacted monomer, unreacted cross-linker, and initiator by-products to dissipate from the gel.

[0115] In general, a wide variety of buffered saline solutions may be used to wash the radically crosslinked zwitterionic gel. Representative examples of suitable buffered saline solutions include, but are not limited to, phosphate, carbonate, citrate, Tris buffer, and buffered saline salts. In one embodiment, the buffered saline useful in the present method is phosphate buffered saline.

[0116] The amount of buffered saline solution may vary depending on the preparation size of the radical crosslinked zwitterionic gel, the type of monomer and optional crosslinker, the amount of optional initiator, and the buffered saline used. In general, the volume of the buffered saline solution may range from about 1.0:1.0 to about 100:1.0, based on the weight of the amount of zwitterionic monomer, non-zwitterionic monomer, optional crosslinker, and initiator in the initial reaction mixture. In various embodiments, the volume of the buffered saline solution may range from about 1.0:1.0 to about 100:1.0, from about 5.0:1.0 to about 90.0:1.0, from about 10.0:1.0 to about 50.0:1.0, or from about 15:1.0 to about 30.0:1.0, based on the weight of the amount of zwitterionic monomer, non-zwitterionic monomer, and optional crosslinker in the initial reaction mixture.

[0117] Generally, the preparation methods of the present disclosure may be carried out at a temperature ranging from 0°C to about 40°C. In various embodiments, the preparation methods may be carried out at a temperature ranging from 0°C to about 40°C, from about 10°C to about 30°C, or from about 15°C to about 25°C. In one embodiment, the preparation methods may be carried out at room temperature (e.g., about 23°C). The preparation methods of the present disclosure are typically carried out under ambient pressure and may be carried out under an inert atmosphere, e.g., nitrogen, argon, or helium. The radical crosslinked zwitterionic gels prepared according to the methods disclosed herein may be stored at 4°C prior to use.

[0118] The radical cross-linked zwitterionic gel may be further lyophilized to prepare a dry power of the radical cross-linked zwitterionic gel. This lyophilization method allows for a convenient powder that can be rehydrolyzed before use. In this form, the radical cross-linked zwitterionic gel has an extended shelf life.

[0119] In some embodiments, the radical crosslinked zwitterionic gel may be dissolved in a solvent prior to final use, followed by precipitation using a co-solvent. Without intending to be limited by theory, residual initiators and stabilizers generally remain in solution, and the polymer is isolated as a solid (powder, gum or fiber). This process may be repeated until the desired polymer characteristics are obtained. This fractional precipitation is also effective in removing lower molecular weight polymers, resulting in a narrower molecular weight distribution. Solvent / co-solvent pairs that may be used include toluene / hexane, toluene / methanol, THF / water, etc.

[0120] Additional aspects of the preparation methods of the present disclosure are provided in the Appendix.

[0121] (III) Methods for Treating Wounds In another aspect, the present disclosure encompasses a method of treating a wound or providing wound healing. The method includes administering or applying the radically crosslinked zwitterionic gel (or washed radically crosslinked zwitterionic gel) described herein to a wound of a subject in need thereof and leaving the gel in place for a sufficient time to provide wound healing. In certain embodiments, the wound healing provided according to the methods of the present disclosure can be partial wound healing (e.g., wound closure) or complete wound healing (e.g., wound closure). In certain embodiments, the wound can be at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or completely healed (e.g., closed) compared to the wound before treatment.

[0122] In certain embodiments, the radically crosslinked zwitterionic gel (or the washed radically crosslinked zwitterionic gel) may be applied topically to the surface of the wound or injected into the wound. The radically crosslinked zwitterionic gel may be applied to wounds of various sizes and shapes. In certain embodiments, the wound may be a diabetic ulcer. In other embodiments, the wound may be a surgical wound or a trauma wound. One or more applications of the radically crosslinked zwitterionic gel may be applied over an extended period of time.

[0123] The radically crosslinked zwitterionic gel can be applied to the wound by a variety of means. Non-limiting methods are by syringe, using a tongue depressor to apply the radically crosslinked zwitterionic gel, or by applying the radically crosslinked zwitterionic gel to a dressing or band-aid and then applying the dressing to the wound. Freeze-dried radically crosslinked zwitterionic gels can be easily rehydrated and applied directly to the wound.

[0124] Subjects that may be treated according to the methods of the present disclosure include humans, livestock animals, companion animals, laboratory animals, or zoological animals. In one embodiment, the subject may be a rodent, such as a mouse, rat, guinea pig, etc. In another embodiment, the subject may be a livestock animal. Non-limiting examples of suitable livestock animals can include pigs, cows, horses, goats, sheep, llamas, and alpacas. In yet another embodiment, the subject may be a companion animal. Non-limiting examples of companion animals can include pets, such as dogs, cats, rabbits, and birds. In yet another embodiment, the subject may be a zoo animal. As used herein, "zoo animal" refers to an animal that may be found in a zoo. Such animals can include non-human primates, big cats, wolves, and bears. In certain embodiments, the animal is a laboratory animal. Non-limiting examples of laboratory animals can include rodents, canines, felines, and non-human primates. In certain embodiments, the animal is a rodent. Non-limiting examples of rodents include mice, rats, guinea pigs, etc. In a preferred embodiment, the subject is a human.

[0125] Additional aspects of the therapeutic methods of the present disclosure are provided in the Appendix.

[0126] Since various changes can be made in the above-described methods without departing from the scope of the present invention, it is intended that all matter contained in the above description and in the examples given below be interpreted as illustrative and not in a limiting sense. EXAMPLES

[0127] material: [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA) was purchased from AFG Scientific (Northbrook, IL), 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionic acid (CBMA) was purchased from TCI Chemicals (Portland, OR). Hydroxyethyl methacrylate (HEMA), sodium persulfate (SPS), polyethylene glycol dimethacrylate (PEGDMA), and ruthenium(II) tris-bipyridyl (Ru(bpy)) dichloride were purchased from Sigma Aldrich (St. Louis, MO).

[0128] Example 1: Preparation of radically cross-linked zwitterionic gels using white light (more detailed procedure needed) CBMA, SBMA, and HEMA were used as received without further processing. PEGDMA was diluted to 10% v / v in water, and SPS and Ru(bpy) were dissolved at 10 mg / mL. The desired dry weight of zwitterionic monomer was added to a 1.5 mL microcentrifuge tube. Various volumes of HEMA, SPS, Ru(bpy), and PEGDMA were then added to the tube. The total volume of the solution was then increased to 1 mL with water, and the solution was vortexed for 15 seconds to completely dissolve the zwitterionic monomer. The solution was then sterile filtered through a 0.22 μm pore filter. The tube was then placed under ambient white light for 1 hour to induce polymerization. After polymerization, the gels were rinsed three times with sterile PBS and stored at 4°C. Table 4 shows the amounts of monomer and optional crosslinker, as well as the results of these experiments. [Table 4]

[0129] Example 2: Preparation of radically cross-linked zwitterionic gels using 405 nm light CBMA, SBMA, and HEMA were used as received without further processing. The desired dry weight of zwitterionic monomer was added to a 1.5 mL microcentrifuge tube along with the desired volume of HEMA. The total solution volume was then brought up to 1 mL with water. The solution was vortexed for 15 seconds to dissolve all components and sterile filtered through a 0.22 μm pore filter. The solution was then placed in a custom light box with near-UV, 405 nm light for 1 hour. After polymerization, the gels were rinsed with sterile PBS and stored at 4 °C. Table 5 shows the amounts of monomer and optional crosslinker, as well as the results of these experiments. Figures 1a and 1b show photographs of radically crosslinked zwitterionic gels. [Table 5]

[0130] Example 3: Cytocompatibility of radically crosslinked zwitterionic gels The gel was made according to the protocol described above. The gel was then aliquoted onto a transwell membrane with a pore size of 0.4 μm in a 24-well plate. To rinse excess unreacted monomers and reagents, the gel was immersed in sterile 1X PBS (pH 7.4) for three days. Every day, the PBS was aspirated and replaced with fresh solution. After the rinsing step, 50,000 human dermal fibroblasts (hDF) were seeded into a tissue culture (TC)-treated 24-well plate, and the transwell membrane containing the gel was placed on top of the culture. The culture was incubated with humidity for 37 h at 4°C for 1 h. 0 The cells were incubated at 37 °C and 5% CO2 for 24 h. To test cell viability after 24 h, 50 μL of CCK8 (Dojindo) was added to 500 μL of cell culture medium and incubated for one hour according to the manufacturer's protocol. 100 μL of medium was then transferred to a 96-well plate (n=3) and the absorbance was read at 450 nm using a microplate reader. Figure 2 shows the results of these experiments.

[0131] Example 4: Antifouling of radically cross-linked zwitterionic gels The antifouling ability of the zwitterionic gel was measured using fluorescence microscopy. Circular borosilicate glass cover slips were rinsed with absolute ethanol and then dried thoroughly for 10 min. The glass slides were then transferred to a 24-well plate and covered with 200 μL of zwitterionic gel solution. The gel was allowed to polymerize for one hour, after which the slides were transferred to unused wells. 200 μL of FITC-BSA solution (0.2 mg / mL) was then added to each glass slide and the slides were briefly shaken to ensure complete coverage of the protein solution. The plates were then covered with foil to protect them from light and incubated for 37 h. 0 The slides were incubated at λ C overnight. The following day, ex = 495 nm and λ em Imaged using a Lecia fluorescence microscope at =520 nm. Figure 3 shows a photograph of this anti-fouling behavior in comparison to a glass slide.

[0132] Example 5: Rheological measurements of radically crosslinked zwitterionic gels Gel samples with a diameter of approximately 22 mm and height of approximately 4 mm were prepared in 12-well plates. To determine the rheological properties of the gels, frequency sweep and strain sweep tests were performed using an AR-G2 rheometer (TA Instruments) with 20 mm diameter cross-hatched parallel plates at 37 °C. Frequency sweep measurements were performed at 1% strain. Strain sweep measurements were performed at 10 rad / s frequency. For FTIR measurements, gel samples were freeze-dried and the dried powder was analyzed using a Nexus 470 ESP FT-IR spectrometer equipped with an ATR accessory (Specac, Golden Gate). Figures 4a-4d show the results of these measurements.

[0133] Example 6: Swelling test of radically cross-linked zwitterionic gels To determine the swelling behavior of the radical zwitterionic hydrogels, the as-prepared gels were weighed to determine the mass of the initial sample (m 初期) was determined, immersed in PBS (pH: 7.4) and allowed to swell in an incubator at 37 °C. The hydrogels were sampled at selected time intervals and transferred from one Petri dish to another several times to remove excess water from the hydrogel surface, then weighed and the mass (m 湿潤ゲル ), the swelling of the gel was determined. Figure 5 shows the swelling ratio of the radical cross-linked zwitterionic gel.

[0134] Example 7: Decomposition test of radical cross-linked zwitterionic gel To determine the degradation behavior of the hydrogels, the gels were immersed in PBS (pH 7.4) and seated in an incubator at 37 °C. The hydrogels were harvested at selected time intervals, lyophilized, and weighed to determine the degradation percentage at different time intervals. Figure 6 shows the degradation ratio of the radical cross-linked zwitterionic gels.

[0135] Example 8: Injectability, stretchability, compression and release, and self-healing of radically crosslinked zwitterionic gels FIG. 7 shows a series of photographs regarding the injectability, stretchability, compression and release, and self-healing characteristics of the white light prepared radically crosslinked zwitterionic gels.

[0136] Figure 8 shows a series of photographs regarding the injectability, stretchability, compression and release, and self-healing characteristics of the radically crosslinked zwitterionic gels prepared with 405 nm light.

[0137] Example 9: Injectability of radically crosslinked zwitterionic gels. FIG. 9 shows photographs of the injectability characteristics of radically crosslinked zwitterionic gels compared to zwitterionic gels prepared using a cryogenic process.

[0138] Example 10: Sustained release of therapeutic agents 10a and 10b are graphs showing the release of myoglobin and CNP for various radically crosslinked zwitterionic gels over time.

[0139] Example 11: Wound closure experiments Radical crosslinked zwitterionic gels were evaluated for closure of human wounds.(more details needed). Figure 11 is a series of photographs showing radical crosslinked zwitterionic gels applied to wounds enhancing healing over a 16 day period.

[0140] Example 12: Wound closure experiments in mouse studies The radical crosslinked zwitterionic gel was applied to a series of mice to determine the percentage of wound closure over several days. As the data shows, the wound was completely closed by two weeks. Figures 12a and 12b show graphs of the % wound closure measured against time.

[0141] Other Embodiments and Equivalents While the present disclosure has been described in conjunction with various embodiments and examples, it is not intended that they be limited to such embodiments or examples. On the contrary, the present disclosure encompasses various alternatives, modifications, and equivalents, as will be understood by those skilled in the art. Thus, the descriptions, methods, and figures should not be read as limited to the described order of elements, unless stated to that effect.

[0142] Although the present disclosure has described and illustrated specific embodiments, it is to be understood that the present disclosure is not limited to those specific embodiments, but rather, the present disclosure includes all embodiments that are functional and / or equivalent to the specific embodiments and features that have been described and illustrated.

Claims

1. A radically crosslinked zwitterionic gel, comprising: a zwitterionic monomer selected from the group consisting of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA), [(methacryloyloxy)ethyl]dimethylammonio]-propionic acid (CBMA), 2-methacryloyloxyethyl phosphorylcholine (MPC), and combinations thereof; and a non-zwitterionic monomer.

2. 2. The radical crosslinked zwitterionic gel of claim 1, wherein the non-zwitterionic monomer is hydroxyethyl methacrylate (HEMA).

3. 10. The radically crosslinked zwitterionic gel of claim 1, further comprising a crosslinker.

4. 4. The radical crosslinked zwitterionic gel of claim 3, wherein the crosslinker is selected from the group consisting of glycerol dimethacrylate (GDMA), methylene bisacrylamide (MBA), polyethylene glycol dimethacrylate (PEGDMA), and a combination of two or more crosslinkers.

5. 5. The radical crosslinked zwitterionic gel of claim 4, wherein the crosslinker is polyethylene glycol dimethacrylate (PEGDMA).

6. 10. The radically crosslinked zwitterionic gel of claim 1, further comprising an antioxidant.

7. 7. The radical crosslinked zwitterionic gel of claim 6, wherein the antioxidant is resveratrol.

8. 10. The radical crosslinked zwitterionic gel of claim 1, further comprising a rheology modifier.

9. The radical crosslinked zwitterionic gel of claim 8, wherein the rheology modifier is a clay.

10. 10. The radically crosslinked zwitterionic gel of claim 1, further comprising a therapeutic agent.

11. 2. The radically cross-linked zwitterionic gel of claim 1, wherein the radically cross-linked zwitterionic gel is elastic.

12. 2. The radically cross-linked zwitterionic gel of claim 1, wherein the radically cross-linked zwitterionic gel is injectable.

13. 2. The radically cross-linked zwitterionic gel of claim 1, wherein the radically cross-linked zwitterionic gel is compressible and releasable.

14. 2. The radically cross-linked zwitterionic gel of claim 1, wherein the radically cross-linked zwitterionic gel is self-healing by re-establishing cross-links.

15. 2. The radical cross-linked zwitterionic gel of claim 1, wherein the radical cross-linked zwitterionic gel is cytocompatible.

16. 2. The radically cross-linked zwitterionic gel of claim 1, wherein the radically cross-linked zwitterionic gel has a storage modulus of about 500 Pa to about 2,000 Pa.

17. 2. The radically cross-linked zwitterionic gel of claim 1, wherein the radically cross-linked zwitterionic gel has an elastic modulus of about 1,000 Pa to about 20,000 Pa.

18. 2. The radically cross-linked zwitterionic gel of claim 1, wherein the radically cross-linked zwitterionic gel swells in the presence of an aqueous solution.

19. 10. The radically crosslinked zwitterionic gel of claim 1, wherein the radically crosslinked zwitterionic gel releases a therapeutic agent over an extended period of time.

20. 1. A method for preparing a radically crosslinked zwitterionic gel, comprising: (a) contacting a zwitterionic monomer, a non-zwitterionic ionic monomer, an optional crosslinker, an optional initiator, an optional rheology modifier, an optional antioxidant, and water to form a reaction mixture; (b) optionally filtering the reaction mixture through a 0.22 μm pore filter to form a filtered reaction mixture; (c) exposing the reaction mixture and / or the filtered reaction mixture to light or other suitable radical generator, thereby polymerizing the zwitterionic monomers and the non-zwitterionic monomers to form a radically crosslinked zwitterionic gel; (d) optionally washing the radically crosslinked zwitterionic gel to form a washed crosslinked zwitterionic gel; The method of claim 1, wherein the radically crosslinked zwitterionic gel and / or the washed crosslinked zwitterionic gel has an average pore size greater than about 50 mm and less than about 100 mm.

21. 21. The method of claim 20, wherein the zwitterionic monomer is selected from the group consisting of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA), [(methacryloyloxy)ethyl]dimethylammonio]-propionic acid (CBMA), 2-methacryloyloxyethyl phosphorylcholine (MPC), and combinations thereof.

22. 21. The method of claim 20, wherein the non-zwitterionic monomer is hydroxyethyl methacrylate (HEMA).

23. 21. The method of claim 20 further comprising the step of adding a cross-linking agent.

24. 24. The method of claim 23, wherein the cross-linking agent is selected from the group consisting of glycerol dimethacrylate (GDMA), methylene bisacrylamide (MBA), polyethylene glycol dimethacrylate (PEGDMA), and combinations of two or more cross-linking agents.

25. 21. The method of claim 20, wherein the cross-linking agent is polyethylene glycol dimethacrylate (PEGDMA).

26. 21. The method of claim 20 further comprising the step of adding a radical initiator.

27. 27. The method of claim 26, wherein the initiator is selected from the group consisting of sodium persulfate, ruthenium(II)-tris(2,2'-bipyridyl)dichloride, and combinations thereof.

28. 21. The method of claim 20, wherein the light is near UV light, visible light, or white light.

29. 21. The method of claim 20, wherein the chemical free radical generator is ammonium persulfate (APS), N,N,N',N'-tetramethylethylene-1,2-diamine, organic peroxide (TEMED), ascorbic acid, and combinations thereof.

30. 21. The method of claim 20, wherein the antioxidant is resveratrol.

31. 21. The method of claim 20, wherein the rheology modifier is a clay.

32. 21. The method of claim 20, wherein the radically crosslinked zwitterionic gel is washed with a buffered saline solution.

33. 33. The method of claim 32, wherein the buffered saline aqueous solution comprises phosphate buffered saline.

34. 21. The method of claim 20, wherein the method is carried out at room temperature.

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