US 20160287745A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/02877.45 A1 Grinstaff et al. (43) Pub. Date: Oct. 6, 2016

(54) DISSOLVABLE HYDROGEL COMPOSITIONS Publication Classification FOR WOUND MANAGEMENT AND METHODS OF USE (51) Int. Cl. (71) Applicant: TRUSTEES OF BOSTON A6IL 26/00 (2006.01) UNIVERSITY, Boston, MA (US) (52) U.S. Cl. CPC ...... A61L 26/008 (2013.01); A61L 26/0028 (72) Inventors: Mark W. Grinstaff, Brookline, MA (US); Cynthia Ghobril, Reyersviller (2013.01); A61L 26/0066 (2013.01) (FR); Michel Christophe Wathier, Allston, MA (US); Marlena Dagmara Konieczynska, Lawrenceville, NJ (US) (57) ABSTRACT (73) Assignee: TRUSTEES OF BOSTON UNIVERSITY, Boston, MA (US) The inventions provided herein relate to dissolvable hydro (21) Appl. No.: 14/901,858 gel compositions and methods of uses, e.g., but not limited to, in wound management. Accordingly, methods for wound (22) PCT Fed: Jun. 30, 2014 management involving the dissolvable hydrogel composi (86) PCT No.: PCT/US1.4/44908 tions are also provided herein. In some embodiments, the dissolvable hydrogel composition comprises an adhesive S 371 (c)(1), thioester hydrogel, which can facilitate adherence of the (2) Date: Dec. 29, 2015 dissolvable hydrogen composition to a Surface (e.g., a Related U.S. Application Data wound) and can be controllably dissolved later upon addi (60) Provisional application No. 61/841,746, filed on Jul. tion of a thiolate compound to release the dissolvable 1, 2013. hydrogel composition from the Surface (e.g., the wound). Patent Application Publication Oct. 6, 2016 Sheet 1 of 11 US 2016/02877.45 A1

FIGS 1A-1B A Chemistry of Native Chemica? ligation (NCL) S. O O C O ji rsr 4. hN N-Rgif pH 8 g-ana B. want R N N R S RS N-, ------B Dissolution of PEG-lysSH hydroge based on NCL w a W f : w\ aw 'w': & : iy DendraftW Ni w * N &: ** l kiss t y-8' . i : . \5. } SWA-Pesya is . \ ^* ' ' , A-, 5---Yeeyee. e N- s h O f : S S. *S. A. Y t A.-- \ Sa s RyW “VVy r - ck wawa E.r r Art?\/\'sSere S w i. hides aii of ydrogWofoe stroy y g y exchange fy fy's S *- V EG-Lys.She hydroge s

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Time (min) Patent Application Publication Oct. 6, 2016 Sheet 3 of 11 US 2016/02877.45 A1

: Patent Application Publication Oct. 6, 2016 Sheet 4 of 11 US 2016/02877.45 A1

Patent Application Publication Oct. 6, 2016 Sheet 5 of 11 US 2016/02877.45 A1

FIG. 7

Stability of PEG-LyssH 30 wt.%

O :4 equiv. CME in PBS 8.5 SeHC 1N, phi () S. Naoh N, pH 14 0.01 Time (min)

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Key: a) EDC, phosphate buffer ph 6, 80% NHHC (A) Patent Application Publication Oct. 6, 2016 Sheet 6 of 11 US 2016/02877.45 A1

CH.HN l FIG. 8B S O O O O O HO \1 NHHC No-o-o: C r O O t NHHC Step 1 (A) wrpEG wo O

S 4. HO '-'-o-ra- ydrogei O t HN 1 OAPEGMA O

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S000 S & G s 4000 s Š G e 3000 S. 200 Š 1000 o lumŠ. Solution 1 Solution 2 Hydroge hydroges reversibility 611 Patent Application Publication Oct. 6, 2016 Sheet 7 of 11 US 2016/02877.45 A1 Patent Application Publication Oct. 6, 2016 Sheet 8 of 11 US 2016/02877.45 A1

FG, 9B

f S O O N. --- ~N- HO O 1-a- an- ch (i.O o N,N- to DIPEA, DC, rt, 16 hrs "1'so on-syo 3. 8. 1. Etna, Et O NE A. 2O O TFA, DC PyBop, DIPEA, DMF, rt, 16 hrs i 1N- ce --- N 90% O HN 2. AcO, reflux N-V 1 hr., r \-N-TFAA O 2hrs 58% O NBoc quart, O 8 O O MN -----, ~-a- N-a k o rs or-s"-s O

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oi ...S. Hydrogel Patent Application Publication Oct. 6, 2016 Sheet 9 of 11 US 2016/02877.45 A1

Patent Application Publication Oct. 6, 2016 Sheet 10 of 11 US 2016/02877.45 A1 Patent Application Publication Oct. 6, 2016 Sheet 11 of 11 US 2016/02877.45 A1

O HO US 2016/02877.45 A1 Oct. 6, 2016

DISSOLVABLE HYDROGEL COMPOSITIONS thrombin and factor XIII, as well as fibrinogen/photosensi FOR WOUND MANAGEMENT AND tizers systems. However, autologous products (which are METHODS OF USE time-consuming in emergency) or treatments of allogenic products before clinical use are needed to avoid any con CROSS-REFERENCE TO RELATED tamination to a patient. APPLICATIONS 0006 Synthetic materials, e.g., polymers and hydrogels, 0001. This Application claims benefit under 35 U.S.C. have been developed for wound closure. For example, S119(e) of the U.S. Provisional Application No. 61/841,746 alkyl-cyanoacrylates ("Super glues') have been previously filed Jul. 1, 2013, the content of which is incorporated herein discussed for the repair of cornea perforations. However, by reference in its entirety. monomers of these 'super glues,” in particular those with short alkyl chains, can be toxic and polymerize too quickly, GOVERNMENT SUPPORT leading to difficulty in treating a wound. Once polymerized, the Surface of the glue is rough and hard. This can cause 0002 This invention was made with Government Sup discomfort to the patient and, for example, in case of cornea port under Contract No. EB013721 awarded by the National perforation treatment, a contact lens needs to be worn. Other Institutes of Health. The Government has certain rights in materials have been commercialized such as "Biobrane II the invention. (composite of polydimethylsiloxane on nylon fabric) and “Opsite' (polyurethane layer with vinyl ether coating on one TECHNICAL FIELD side). A new polymeric hemostat (poly-N-acetyl glu 0003. The inventions described herein generally relate to cosamine) has been assessed for biomedical applications dissolvable hydrogel compositions, kits comprising the Such as treatment of gastric varies in order to replace same and methods of uses. In some embodiments, the cyanoacrylate (Kulling et al., Endoscopy, 30(3): S41-42 dissolvable hydrogel compositions and kits described herein (1998)). Adhesives based on modified gelatin are also found are formulated for wound management. to treat skin wounds. Photopolymerizable poly(ethylene glycol) Substituted with lactate and acrylate groups are BACKGROUND previously discussed for sealing air leaks in lung Surgery. 0004 Skin is an organ that can be damaged by disease or 0007 Sealants and adhesives can help patients recover injury. Skin plays a vital role of protecting the body from from Surgery or trauma. There are medical sealant/adhesive fluid loss and disease. Skin grafts have been prepared products, CoSeal?TM, DuraSealTM, and Adherus(R, currently previously from animal skin or the patient’s skin, more existing in the market that are based on hydrogel formula recently “artificial skin' formed by culturing epidermal tions. These products comprise multiple components housed cells. In U.S. Pat. No. 4,485,097 Bell discusses a skin in separate containers. CoSealTM Surgical Sealant equivalent material composed of a hydrated collagen lattice (CoSealTM) is composed of two synthetic polyethylene gly with platelets and fibroblasts and cells such as keratinocytes. cols (PEGs), a dilute hydrogen chloride solution and a U.S. Pat. No. 4,060,081, to Yannas et al. discuss a multilayer Sodium phosphate/sodium carbonate solution. The membrane useful as synthetic skin formed from an insoluble DuraSealTM Dural Sealant System consists of components non-immunogenic and a non-toxic material Such as a syn for preparation of a synthetic, absorbable sealant and an thetic polymer for controlling the moisture flux of the applicator for delivery of the sealant to the target site the overall membrane. In U.S. Pat. No. 4,458,678, Yannas et al. sealant is composed of two solutions, a polyethylene glycol discuss a process for making a skin-equivalent material (PEG) ester solution and a trilysine amine solution. wherein a fibrous lattice formed from collagen cross-linked Adherus(R) is composed of two solutions of polyethylene with glycosaminoglycan is seeded with epidermal cells. glycol (PEG) ester NHS derivative and polyalkyleneimine. However, one of the disadvantages to these artificial skins is 0008 Fibrin glues are also sold in packaging and appli that the matrix is formed from a “permanent' synthetic cator systems that are similar to those used for CoSealTM and polymer. Thus, these artificial skins are not dissolvable. DuraSealTM. One example is Baxter's Tisseel. Tisseel VH Additional limitations of these materials are also discussed (Fibrin Sealant) consists of a two-component fibrin bioma in Yannas and Burke, J. Biomed. Mater. Res., 14, 65-81 trix that offers highly concentrated human fibrinogen to seal (1980). tissue and stop diffuse bleeding. However, all of the existing 0005 Classical suture technique is another method for wound dressing, Sealants or glues cannot be dissolved after treatment of a wound closure. However, depending on the application to the tissue site. That is, they have to be type and/or origin of a wound as well as the location of a removed by mechanical debridement and/or Surgical inci patient, use of tissue adhesives (e.g., glues, Sealants, patches, Sion, if needed. films and the like) can be a more attractive alternative to use 0009 Hydrogels are one class of biomaterials currently of Sutures. In addition to an easy and fast application on a used in medical and clinical applications, including sealing wound, other criteria for an adhesive include, but are not of wounds. See, e.g., Ruan, L. et al., PNAS 2009, 106, limited to an ability to bind to a tissue (necrosed or not, 5105-5110; Aboushwareb, T. et al. J. Biomed. Mater. Res. Sometimes wet) with an adequate adhesion force, non-toxic Part B: Appl. Biomater. 2009, 90B, 45-54; Hattori, H. et al., material, biodegradable or resorbable material, sterilizable Annals of Biomedical Engineering, 2010, 38, 3724-3732: material, material selectively permeable to gases but imper and Luo, Z. et al. Biomaterials, 2011, 32, 2013-2020. meable to bacteria and able to control evaporative water Hydrogels can be used as coatings (e.g. biosensors, cath loss, material mechanically strong enough to protect the eters, and Sutures), as "homogeneous' materials (e.g. contact wound and to enhance the healing process or at least not lenses, burn dressings, and dentures), and as devices (e.g. prevent it. Adhesive hemostats, based on fibrin, have been artificial organs and drug delivery systems) (Peppas, N. A. previously used and are usually constituted of fibrinogen, Hydrogel in Medicine and Pharmacy, Vol I and II 1987. US 2016/02877.45 A1 Oct. 6, 2016

Wichterle, O. Lim, D. Nature 1960, 185, 117-118. Otten a skin tissue or as a sealant to seal a blood vessel puncture brite, R. M.; Huang, S.J.; Park, K. Hydrogels and Biode or as a bandage to treat a burn wound. gradable polymers for Bioapplications 1994; Vol. 627, pp 268). 0014. In some embodiments, a thioester hydrogel can be 0010) Synthetic hydrogel based hemostats/sealants can derived from multi-thioester-containing linear, branched, offer a number of advantages because the chemical compo and/or dendritic macromolecules (e.g., but not limited to sition of the hydrogels can be tuned for various properties, multi-thioester-containing peptide dendrimers, and/or den e.g., but not limited to, water content, sensitivity to envi drons), and activated ester-containing linear, branched, and/ ronmental conditions (e.g., but not limited to, pH, tempera or dendritic macromolecules (e.g., but not limited to acti ture, solvent, stress), softness, tissue adhesion, rubbery vated ester-containing poly(ethylene glycol)). In some consistency, mechanical. degradation, and Swelling proper embodiments, a thioester hydrogel can be derived from ties. However, we are not aware of a hydrogel reported, e.g., multi-amine-containing linear, branched and/or dendritic for emergency care, where a hydrogel is applied to a wound macromolecules (e.g., but not limited to multi-amine-con and can be subsequently removed to allow for definitive taining peptide dendrimers, and/or dendrons) and activated Surgical care at the hospital. ester-thioester-containing linear, branched and/or dendritic 0011. A desirable or useful hydrogel or sealant system, macromolecules (e.g., but not limited to, activated ester e.g., for trauma scenarios Sustained in military injuries or in thioester-containing polyethylene glycol)). In some embodi rural or wilderness settings, should: (1) provide consistent ments, a thioester hydrogel can be derived from multi hemostasis for several hours; (2) adhere to the tissue; (3) be amine- and thioester-containing linear, branched and/or easily applied; (4) enable controlled dissolution of the dendritic macromolecules (e.g., but not limited to multi sealant in the Surgical theatre setting to allow for gradual amine- and thioester-containing peptide dendrimers, and/or wound re-exposure during definitive Surgical care. Alam, H. dendrons) and activated ester containing linear, branched B. et al. Military Medicine 2005, 170, 63-69. However, we and/or dendritic macromolecules (e.g., but not limited to, are not aware of a dissolution capability present in any activated ester-containing poly(ethylene glycol)). In some available wound hemostatic system as discussed above. embodiments, a thioester hydrogel can be derived from Indeed, removal of a clotting agent or dressing from a multi-amine- and thioester-containing linear, branched and/ or dendritic macromolecules (e.g., but not limited to multi wound is currently performed via mechanical debridement amine- and thioester-containing peptide dendrimers, and/or and/or Surgical excision, which could potentially cause dendrons) and activated ester-thioester-containing linear, additional damage to tissue at and/or surrounding the branched and/or dendritic macromolecules (e.g., but not wound. Accordingly, there is a need for an improved wound limited to, activated ester-thioester-containing poly(ethylene dressing or sealant composition, e.g., for use in wound glycol)). In some embodiments, a thioester hydrogel can be management. derived from multi-thiol-containing linear, branched and/or dendritic macromolecules (e.g., but not limited to multi SUMMARY thiol-containing peptide dendrimers, and/or dendrons) and 0012 Existing materials for use in wound dressings, maleimide-thioester-containing linear, branched and/or den sealants or clotting agents are generally not reversible or dritic macromolecules (e.g., but not limited to, maleimide dissolvable. Thus, once a dressing material is adhered on a thioester-containing poly(ethylene glycol)). wound and/or tissue surrounding the wound, mechanical debridement or Surgical incision is usually required if the 0015. Accordingly, embodiments of various aspects dressing material is desired to be removed or replaced later. described herein relate to dissolvable hydrogel composi Yet the physical removal process can cause additional tissue tions, kits, and methods of uses. The dissolvable hydrogel damage or trauma or pain. Accordingly, there is a need for compositions each comprises a thioester hydrogel (e.g., as a an improved material for wound management such that it layer), which can be dissolved and/or washed away by can be easily or controllably removed from a wound in a addition of a composition comprising at least one nucleop minimally invasive manner if needed. Embodiments of hile. In one embodiment, at least one nucleophile comprises various aspects described herein stem in part from develop a thiol moiety. The dissolvable hydrogel compositions can ment of thioester hydrogels that are not only mechanically be optionally loaded with one or more biologically and/or strong, e.g., for use as a sealant, dessing, bandage, glue, or pharmacologically active agent and/or chemically modified scaffold, but can also adhere to a surface and be controllably to contain or couple to active agent(s). removed or dissolved on-demand later by contacting the 0016. The dissolvable hydrogel compositions, kits and/or hydrogels with a thiolate compound/composition. Such dis methods described herein can be used in any application Solution capability of thioester hydrogels allows for gradual where a Surface or void (e.g., a physical or environmental re-exposure of a Surface, e.g., a wound Surface for further surface/void or a biological surface/void) needs to be cov examination and/or treatment. ered, filled, and/or sealed. In some embodiments, the dis 0013. In a particular embodiment, a thioester hydrogel Solvable hydrogel compositions, kits, and/or methods derived from multi-thiol-containing linear, branched, and/or described herein can be used in any application where a dendritic macromolecules (e.g., but not limited to multi Surface or Void requires temporary and/or immediate treat thiol-containing peptide dendrimers, and/or dendrons) and ment, covering and/or structural Support, which can be activated ester-containing linear, branched, and/or dendritic removed later to expose the surface or void for additional macromolecules (e.g., but not limited to, activated ester care and/or management (e.g., but not limited to, examina containing poly(ethylene glycol)) was developed and tion, drug treatment, and/or Surgical treatment). In these assessed for its mechanical properties, adhesive strength, embodiments, a new composition, but not necessarily a new and controlled dissolution in the presence of a thiolate dissolvable hydrogel composition described herein, can be composition (e.g., a thiolate solution) when it was applied on applied on the exposed Surface, if necessary. US 2016/02877.45 A1 Oct. 6, 2016

0017. Accordingly, in some embodiments of various together via any art-recognized chemical reactions, includ aspects described herein, the dissolvable hydrogel compo ing, e.g., but not limited to an amine-ester reaction. sitions, kits and methods of uses described herein can be 0020. In some embodiments of various aspects described used for wound management, e.g., but not limited to, seal herein where vacuum assisted closure is applied, the method ing, treating, and/or repairing wounds, treatment of burns or can further comprise removing the dissolved hydrogel from other traumatized or degenerative tissue, or repair or the wound with vacuum. replacement of tissues or organs. In some embodiments of 0021. Without wishing to be bound by theory, a thiol various aspects described herein, the hydrogel compositions, thioester exchange reaction between thioester linkages pres kits and methods of uses described herein can be used for ent in the dissolvable hydrogel layer and thiols of a thiolate wound management with vacuum assisted closure. compound or molecule leads to dissolution of the dissolv 0018. In some aspects, methods for wound management able hydrogel layer. In some embodiments, the thioester are provided herein. In one aspect, the method comprises (a) thiol exchange can also result in formation of an amide contacting a wound in a Subject with a hydrogel composition linkage, thereby preventing re-formation of the dissolvable comprising a dissolvable hydrogel layer, wherein the dis hydrogel. Solvable hydrogel layer comprises linear, branched, and/or 0022. In some embodiments of this aspect and other dendritic crosslinkable polymers held together by thioester aspects described herein, the hydrogel composition can be linkages formed between the first crosslinkable polymer and present as a thin sheet or layer. In some embodiments of this the second crosslinkable polymer; and (b) allowing the aspect and other aspects described herein, the hydrogel dissolvable hydrogel layer to adhere to tissue Surrounding composition can be present as a thin sheet or layer Supported the wound. In some embodiments, the method further com by a sheet Support member to provide mechanical strength. prises dissolving the dissolvable hydrogel layer by adding a In alternative embodiments of this aspect and other aspects nucleophile, thereby releasing the hydrogel layer from the described herein, the hydrogel composition can be a multi wound. In one embodiment, the nucleophile can comprise a layer composite comprising at least one layer of the dissolv thiolate compound or molecule. In some embodiments, the able hydrogel layer described herein and at least one addi first crosslinkable polymers and the second crosslinkable tional layer. The additional layer can be a drug-releasing polymers do not necessarily possess thioester linkage or layer, another material layer (e.g., another polymer layer), functional group in their molecular structures. In these and/or a sheet Support member. embodiments, thioester linkages present within a dissolvable 0023. In some embodiments of this aspect and other hydrogel can result or be formed from covalent interaction aspects described herein, the hydrogel composition can between the first crosslinkable polymers and the second further comprise at least one active agent. The active agent crosslinkable polymers. For example, the thioester linkages can be incorporated into the dissolvable hydrogel layer present within a dissolvable hydrogel can result from react and/or additional layer(s), if any. In some embodiments, the ing a first crosslinkable polymer comprising at least two active agent can be a bioactive agent. Non-limiting thiols with a second crosslinkable polymer comprising examples of bioactive agents include pharmaceutical agents, crosslinking moieties (e.g., but not limited to N-Succinim drugs, cells, gases and gaseous precursors, Synthetic organic idyl moiety and/or activated ester groups), wherein neither molecules, proteins, enzymes, growth factors, vitamins, of the crosslinkable polymers has any thioester bonds in steroids, polyanions, nucleosides, nucleotides, polynucle their molecular structure. otides, polymer nanoparticles, metal nanoparticles, diagnos 0019. In another aspect, the method comprises (a) con tic agents, genetic materials, and any combinations thereof. tacting a wound in a Subject with a hydrogel composition 0024. The hydrogel compositions of various aspects comprising a dissolvable hydrogel layer, wherein the dis described herein can be adapted to form any wound man Solvable hydrogel layer comprises first linear, branched, agement devices or articles, e.g., but not limited to, a and/or dendritic crosslinkable polymers and second linear, dressing, bandage, glue, Sealant, coating, and/or covering. In branched, and/or dendritic crosslinkable polymers cova Some embodiments, the hydrogel compositions of various lently held together, wherein the first crosslinkable polymers aspects described herein can be adapted for use with vacuum and/or the second crosslinkable polymers comprise at least assisted closure. Accordingly, one aspect described herein one thioester linkage or functional group in their molecular relates to a dissolvable hydrogel composition or a wound structures; and (b) allowing the dissolvable hydrogel layer to management device comprising an adhesive hydrogel layer, adhere to tissue surrounding the wound. In some embodi wherein the adhesive hydrogel layer comprises a first water ments, the method further comprises dissolving the dissolv soluble linear, branched, and/or dendritic crosslinkable poly able hydrogel layer by adding a nucleophile, thereby releas mer and a second water Soluble linear, branched, and/or ing the hydrogel layer from the wound. In one embodiment, dendritic crosslinkable polymer held together by thioester the nucleophile can comprise a thiolate compound or mol linkages between the first crosslinkable polymer and the ecule. In these embodiments, at least some of the thioester second crosslinkable polymer. linkages present within a dissolvable hydrogel network can 0025. The adhesiveness and reversibility of the dissolv be contributed from one or both of the first crosslinkable able hydrogel described herein provide a novel means of polymers and the second crosslinkable polymers that com wound management. The dissolvable hydrogel layer or the prise a thioester linkage or functional group in their molecu dissolvable hydrogel composition or the wound manage lar structure. For example, the thioesters can be present ment device can be dissolved partially or completely, when within the crosslinkable macromolecules or polymers such ever appropriate, after the dissolvable hydrogel layer is that a new covalent bond is formed (e.g., amide) which adhered to tissue Surrounding a wound. In accordance with results in a hydrogel containing thioester linkages. In some embodiments of various aspects described herein, the dis embodiments, the first crosslinkable polymers and/or the Solvable hydrogel layer can be dissolved, partially or com second crosslinkable polymers can be covalently linked pletely, by addition of a thiolate compound or molecule. US 2016/02877.45 A1 Oct. 6, 2016

Examples of thiolate compounds/molecules include, without exposure to different concentrations of (L)-cysteine methyl limitations, linear, branched and/or dendritic multi-thiol ester (CME) in a buffered solution, e.g., PBS, at different macromolecules, poly(ethylene glycol) thiol, thiol-contain pHs, e.g., pH -7.4 and pH -8.5, or to -0.3 M (L)-lysine ing glycerol, thiol-containing glycerol polymers, thiol-con methyl ester (LME) in PBS at pH -8.5, or to -0.3 M taining peptides, cysteine, cystine, alkyl ester of cysteine, 2-mercaptoethancsulfonate (MES) in PBS at pH -8.5. Stor alkyl ester of cystine, MeSCHSH, (R)/(S)-3-methyl-3-sul age moduli G' values were normalized to the highest G' fanylhexan-1-ol, Ethanethiol, 1-Propanethiol, 2-Propa value for each experiment. nethiol, Butanethiol, tert-Butyl mercaptan, Pentanethiols, 0032 FIGS. 5A-5C are photographs showing adhesion Thiophenol, Dimercaptosuccinic acid. Thioacetic acid, strength and dissolution of hydrogels PEG-LysSH and PEG 5-mercapto-4H-1,2,4-triazol-3-ol, 2-mercaptoacetamide, LysNH. FIGS. 5A-5B are photographs of hydrogels PEG 2-Mercaptoethanol. 1.2-Ethanedithiol, Ammonium thiogly LyssH (green; upper panel) and PEG-LysNH (pink; lower colate, Cysteamine, Methyl thioglycolate. Thiolactic acid, panel) adhered to human tissue skin, under torsional stress. 1-Mercapto-2-propanol, 2-methoxyethanethiol. 3-Mer FIG. 5C is a set of photographs showing dissolution of capto-1-propanol. 2,3-Dimercapto-1-propanol, 1-Thioglyc PEG-LysSH hydrogel in -0.3 MCME solution in PBS at pH erol, Mercaptosuccinic acid, 4-ethyl-5-mercapto-4H-1,2,4- -8.5, at different time intervals (0, ~10, -20 and ~30 min). triazol-3-ol, N-Carbamoyl-L-cysteine, 2-Methyl-3- PEG-LysNH used as control, swelled and did not dissolve. Sulfanylpropanoic acid, 4-mercaptobutyric acid, The PEG-LysSH and PEG-LysNH hydrogel sealants were N-Acetylcysteamine, 3-Methyl-1-butanethiol, 1.5-Pentan dyed with green food coloring or nile red dye, respectively. edithiol, 4-Chlorothiophenol, 4-Aminothiophenol, Benzyl 0033 FIGS. 6A-6F are photographs showing an example mercaptan, 2-furanmethanethiol, 3-mercaptohexanol, furfu use of one embodiment of a dissolvable hydrogel as a tissue ryl thiol, derivatives thereof, a disulfide complex of one or sealant. FIG. 6A is a photograph of a beef jugular vein. FIG. more of the aforementioned compounds, and any combina 6B shows the vein linked to a syringe pump and filled with tions thereof. a buffered solution, e.g., PBS at pH -7.4: FIG. 6C shows 0026. The thiolate compound/molecules can be formu generation of a ~2.5 mm puncture on the vein Surface. FIG. lated in any form to Suit the application format, e.g., but not 6D shows PEG-LysSH hydrogel (e.g., -30 wt %) applied on limited to spraying and/or injection. In some embodiments, the puncture. The hydrogel was dyed in green. FIG. 6E the thiolate compound/molecules can be formulated in a shows PEG-LysSH hydrogel (e.g., -30 wt %) applied on a form of a solution, a spray, a powder, or any combinations deep second-degree burn wound model. FIG. 6F is a set of thereof. photographs showing the dissolution of PEG-LysSH hydro 0027. Additional objects, advantages, and features will gel upon exposure to cysteine methyl ester Solution. The left become apparent from the following description and the panel shows applying a cysteine methyl ester Solution on the claims that follow, considered in conjunction with the hydrogel Surface. The right panel shows complete dissolu accompanying drawings. tion of the hydrogel after application of the cysteine methyl ester Solution. BRIEF DESCRIPTION OF THE DRAWINGS 0034 FIG. 7 is a data graph showing the stability of 0028 FIGS. 1A-1B are schematic representations, PEG-LysSH hydrogel (e.g., -30 wt %) subjected to different respectively, showing chemistry of native chemical ligation conditions, as indicated by normalized storage moduli G' (NCL) (FIG. 1A). and a cross-linked PEG-LysSH hydrogel values. For example, reducing the equivalent number of (in accordance with one embodiment described herein) thiols present in a thiolate solution (e.g., with a pH -8.5) to formed between Dendron 1 and N-hydroxysuccinimide four based on the number of thioester linkages resulted in containing PEG molecule 3 (e.g., SVA-PEG-SVA) and its almost no change in mechanical properties after at least reversibility based on NCL (FIG. 1B). about 60 minutes with the thiol-thioester exchange reaction 0029 FIG. 2 shows an exemplary scheme of a synthetic occurring slowly. In addition, the PEG-LysSH hydrogel route to form PEG-peptide dendrons 1 and 2. The alphabets Substantially maintained its mechanical property after expo in the figure indicate process condition as described follows: sure to pH 0 for at least about 60 minutes. However, the (a) MPEG2000-NH, DIPEA, HOBT, EDCI, DMF, room mechanical property of the PEG-LysSH hydrogel decreased temperature, 16 hrs, 90%; (b) Pd/C, H, (1 atm), MeOH, over time as it was exposed to pH~14, indicating a gradual room temperature, 16 hrs, 90%; (c) PFP-3 (tritylthio)propi dissolution of the hydrogel. onic acid, HOBT, DMF, room temperature, 24 hrs, 76%; (d) 0035 FIGS. 8A-8C show another embodiment of a thio EtSiH, TFA, DCM, room temperature, 3 hrs, 95%. ester hydrogel (using citric acid and NHS-PEG-NHS) and its Cbz-benzyloxycarbonyl, DIPEA-diisopropylethylamine, rheological properties. FIG. 8A is a schematic representation DMF=N,N-dimethylformamide, EDCI=1-(3-dimethylam showing a chemical reaction of citric acid and cysteamine to inopropyl 3-ethyl-carbodiimide, HOBT=1-hydroxybenzo form S.S.S-tris(2-aminoethyl) 2-hydroxypropane-1,2,3-tris triazole, PFP pentafluorophenol, Tr–trityl, (carboxylothioate) hydrochloride salt (product A), which is TFA=trifluoroacetic acid. then reacted with NHS-PEG-NHS (MW ~2400 Da) to form 0030 FIG. 3 is a bar graph showing the storage modulus a thioester hydrogel in accordance with one embodiment G' of dissolvable hydrogel compositions according to one or described herein, as shown in step 1 of FIG. 8B. By addition more embodiments described herein before and after of a cysteine solution to the thioester hydrogel, the thioester 48-hour swelling. The storage modulus G' was performed hydrogel dissolved (step 2 of FIG. 8B). FIG. 8C is a bar for -10 wt % and -30 wt % PEG-LysSH and -30 wt % graph showing storage modulus G' and loss modulus G" of PEG-LysNH hydrogels at ~50 Pa oscillatory stress, ~1 Hz the thioester gel and its precursors. frequency, and -20° C. 0036 FIGS. 9A-9E show another embodiment of a thio 0031 FIG. 4 is a line graph showing the reversibility of ester hydrogel (using dendron 1 described in FIG. 2 and PEG-LysSH and PEG-LysNH hydrogels at -30 wt % upon MAL-thio-PEG-thio-MAL 9 containing thioester linkages US 2016/02877.45 A1 Oct. 6, 2016

within its structure) and its rheological properties. FIG. 9A a skin tissue or as a sealant to seal a blood vessel puncture is a schematic representation showing the reaction of the or as a bandage to treat a burn wound. In another embodi precursors to form the hydrogel. FIG. 9B details the syn ment, a thioester hydrogel derived from multi-thiol-contain thetic route of the second-water soluble crosslinkable mac ing linear, branched and/or dendritic macromolecules (e.g., romolecule, MAL-thio-PEG-thio-MAL 9. FIG. 9C is a bar but not limited to multi-thiol-containing peptide dendrimers, graph showing storage modulus G' and loss modulus G" of and/or dendrons) and maleimide-thioester-containing linear, the thioester hydrogel. FIG. 9D shows the efficacy of the branched and/or dendritic macromolecules (e.g., but not hemostatic thioester hydrogel in an in vivo model of venous limited to maleimide-containing poly(ethylene glycol)) was hemorrhage (where the hydrogel was applied on a hepatic also developed and assessed for its mechanical properties, incision of an in vivo rat model) (left panel), followed by its dissolution using methyl ester cysteine solution (right adhesive strength and controlled dissolution in the presence panel). FIG. 9E shows the efficacy of the hemostatic thio of a thiolate composition (e.g., a thiolate solution) when it ester hydrogel in an in vivo model of arterial hemorrhage was applied as a hemostatic dressing in an aortic and/or (where the hydrogel was applied on an aortic incision of an hepatic injury model. In other embodiments, thioester in vivo rat model) (left panel), followed by its dissolution hydrogels derived from linear, branched and/or dendritic using methyl ester cysteine solution (right panel). crosslinkable polymers comprising the thioester linkages 0037 FIGS. 10A-10B show another embodiment of a within their structures were developed and assessed for their thioester hydrogel (using dendron 2 described in FIG. 2 and mechanical properties, adhesive strength and controlled NHS-thio-PEG-thio-NHS 10 containing thioester linkages dissolution in the presence of a thiolate composition (e.g. a within its structure). FIG. 10A is a schematic representation thiolate solution). For example, a thioester hydrogel can be showing the reaction of the precursors to form the hydrogel. derived from multi-amine-containing linear, branched and/ FIG. 10B details the synthetic route of the second-water or dendritic macromolecules (e.g., but not limited to multi soluble crosslinkable macromolecule, NHS-thio-PEG-thio amine-containing peptide dendrimers, and/or dendrons) and NHS 10. activated ester-thioester-containing linear, branched and/or dendritic macromolecules (e.g., but not limited to, activated DETAILED DESCRIPTION OF THE ester-thioester-containing poly(ethylene glycol)). In some embodiments, a thioester hydrogel can be derived from INVENTION multi-amine- and thioester-containing linear, branched and/ 0038. In military fields or rural areas, injuries or wounds or dendritic macromolecules (e.g., but not limited to multi may sometimes not be able to receive immediate medical amine- and thioester containing peptide dendrimers, and/or treatment. Thus, temporary covering and/or treatment of a dendrons) and activated ester-containing linear, branched wound or an injury can help minimize its exposure to and/or dendritic macromolecules (e.g., but not limited to, pathogen infection (e.g., bacterial infection) and/or addi activated ester-containing poly(ethylene glycol)). In some tional tissue damage before it is attended for an appropriate embodiments, a thioester hydrogel can be derived from medical treatment. However, existing materials for use in multi-amine- and thioester-containing linear, branched and/ wound dressings, Sealants or clotting agents are generally or dendritic macromolecules (e.g., but not limited to multi not reversible or dissolvable or easily detached from tissue amine-containing peptide dendrimers, and/or dendrons) and after adhering thereto, thus currently requiring mechanical activated ester-thioester-containing linear, branched and/or debridement or surgical incision for removal of the dress dendritic macromolecules (e.g., but not limited to, activated ings, Sealants, or clotting agents to re-expose a tissue Sur ester-thioester-containing poly(ethylene glycol)). face, e.g., a wound, for example, in order to permit further examination and/or treatment as needed. Further, the 0040. Accordingly, embodiments of various aspects removal process can cause additional tissue damage or described herein relate to dissolvable hydrogel composi trauma. Accordingly, there is a need for an improved mate tions, kits, and methods of uses. The dissolvable hydrogel rial for wound management such that, after the material compositions each comprise a thioester hydrogel (e.g., as a adheres to a wound or tissue, it can be easily or controllably layer), which can be dissolved and/or washed away by removed therefrom in a minimally-invasive manner, when addition of a composition comprising at least one nucleop ever necessary. hile. In one embodiment, at least one nucleophile comprises 0039 Embodiments of various aspects described herein a thiol moiety. The dissolvable hydrogel compositions can stem in part from development of thioester hydrogels that be optionally loaded with one or more biologically and/or are not only mechanically strong, e.g., for use as a sealant or pharmacologically active agent and/or chemically modified dressing, but can also adhere to a Surface and be controllably to contain or couple to the active agent(s). removed or dissolved on-demand later by contacting the 0041. The dissolvable hydrogel compositions, kits and/or hydrogels with a thiolate composition, to allow for gradual methods described herein can be used in any application re-exposure of a Surface, e.g., for further examination and/or where a Surface or void (e.g., a physical or environmental treatment. In one embodiment, a thioester hydrogel derived surface/void or a biological surface/void) needs to covered, from multi-thiol-containing linear, branched, and/or den filled, and/or sealed. In some embodiments, the dissolvable dritic macromolecules (e.g., but not limited to multi-thiol hydrogel compositions, kits, and/or methods described containing peptide dendrimers, and/or dendrons) and acti herein can be used in any application where a Surface or Void vated ester-containing linear, branched and/or dendritic requires temporary and/or immediate treatment, covering macromolecules (e.g., but not limited to activated ester and/or structural Support, which can be removed later to containing poly(ethylene glycol)) was developed and expose the Surface or void for additional care and/or man assessed for its mechanical properties, adhesive strength, agement (e.g., but not limited to, examination, drug treat and controlled dissolution in the presence of a thiolate ment, and/or Surgical treatment). In these embodiments, a composition (e.g., a thiolate solution) when it was applied on new composition, but not necessarily a new dissolvable US 2016/02877.45 A1 Oct. 6, 2016

hydrogel composition described herein, can be applied on Wiley and Sons, New York, the contents of which are the exposed surface, if necessary. incorporated herein by reference. 0042. Accordingly, in some embodiments, the dissolv 0048. As used herein, the term “thioester hydrogel” refers able hydrogel compositions, kits and methods of uses to a hydrogel comprising thioester linkages/bonds through described herein can be used for clinical treatments, e.g., but out the hydrogel. A thioester hydrogel can be a hydrogel not limited to, Sealing, treating, and/or repairing wounds, comprising crosslinkable macromolecules or polymers held treatment of burns or other traumatized or degenerative together by thioester linkages connecting between the cross tissue, or repair or replacement of tissues or organs. In some linkable macromolecules or polymers, or a hydrogel pos embodiments, the dissolvable hydrogel compositions, kits sessing thioester linkages which are not formed from a and/or methods described herein can be used at a void, crosslinking reaction between the crosslinkable macromol wound or injury site, e.g., but not limited to, opthalmologi ecules or polymers, but are conferred by the thioester groups cal, orthopedic, cardiovascular, pulmonary, skin, burn, or inherently present in at least some of the crosslinkable urinary wounds and/or injuries, including those created macromolecules or polymers. during Surgery as well as drug delivery and tumor removal. 0049. A thioester hydrogel is a polymeric network com In some embodiments, the dissolvable hydrogel composi prising at least about two or more thioester linkages, includ tions, kits and/or methods described herein can be used as a ing, e.g., at least about two, at least about five, at least about sealant, glue, dressing, and/or coating for Surgical proce 10, at least about 20, at least about 30, at least about 40, at dures where the site of the wound is not easily accessible least about 50, at least about 60, at least about 70, at least and/or when Sutureless Surgery is desirable. about 80, at least about 90, at least about 100, at least about 0043. While the dissolvable hydrogel compositions 500, at least about 1000 or more thioester linkages. The described herein can exist in any form or part of a wound number of the thioester linkages in a thioester hydrogel can management device, in Some embodiments, the dissolvable vary with the number of reactive functional groups present hydrogel compositions can be formulated for uses as ban in the crosslinkable macromolecules or polymers, or the dages, Sealants, dressing, glues, coatings, coverings, and/or number of thioester present in the macromolecules or poly scaffolds, which, if needed, can be subsequently dissolved mers to be crosslinked. by adding an aqueous solution of a thiol or other nucleophile 0050. In some embodiments, the thioester linkages within revealing the originally-covered site. The dissolvable hydro a thioester hydrogel can be contributed from or conferred by gel compositions can be applied to a target tissue site in any at least some of the crosslinkable macromolecules or poly formulation, e.g., but not limited to, a spray, liquid, foam, mers comprising the thioester linkages. For example, a and/or preformed structure. thioester hydrogel can be derived from multi-amine-con 0044. In some embodiments, the dissolvable hydrogel taining linear, branched and/or dendritic macromolecules compositions, kits, and/or methods described herein can be (e.g., but not limited to multi-amine-containing peptide used to form a three-dimensional scaffold, gel, matrix or dendrimers, and/or dendrons) and activated ester-thioester template (e.g., of any shapes and/or sizes) for cell growth. containing linear, branched and/or dendritic macromol ecules (e.g., but not limited to activated ester-thioester Dissolvable Hydrogels or Dissolvable Hydrogel Layers containing poly(ethylene glycol)). Alternatively, a thioester Described Herein hydrogel can be derived from multi-amine- and thioester 0045. In one aspect, provided herein relates to composi containing linear, branched and/or dendritic macromol tions comprising a dissolvable thioester hydrogel. As used ecules (e.g., but not limited to multi-amine- and thioester herein, the term “hydrogel generally refers to a hydrophilic containing peptide dendrimers, and/or dendrons) and gel regardless of the state of hydration, and therefore activated ester containing linear, branched and/or dendritic includes, for example, hydrogels that are in a dehydrated or macromolecules (e.g., but not limited to activated ester anhydrous state or in a state of partial hydration. Hydrogels containing poly(ethylene glycol)). In another embodiment, a are generally polymers characterized by their hydrophilicity thioester hydrogel can be derived from multi-amine- and (e.g., capacity to absorb large amounts of fluid Such as water thioester-containing linear, branched and/or dendritic mac or wound exudate) and insolubility in water. Thus, they are romolecules (e.g., but not limited to multi-amine- and thio capable of Swelling in water while generally preserving their ester-containing peptide dendrimers, and/or dendrons) and shape. Stated another way, in some embodiments, a hydrogel activated ester-thioester-containing linear, branched and/or is a polymeric material, which exhibits the ability to swell in dendritic macromolecules (e.g., but not limited to, activated water and to retain a fraction of water within the structure ester-thioester-containing poly(ethylene glycol)). without dissolving. 0051. In some embodiments, thioester hydrogels are 0046) Without wishing to be limited, the hydrophilicity of “thioester-crosslinked hydrogels.” The term “thioester hydrogels is generally due to groups such as hydroxyl, crosslinked hydrogel” refers to a hydrogel comprising cross carboxyl, carboxamide, amines, Sulphonate and esters, linkable macromolecules or polymers held together by thio among others. On contact with water, the hydrogel assumes ester linkages connecting between the crosslinkable a swollen hydrated state that results from a balance between macromolecules or polymers. In these embodiments, the the dispersing forces acting on hydrated chains and cohesive thioester linkages within the thioester-crosslinked hydrogels forces that do not prevent the penetration of water into the are resulted from covalent interaction between the cross polymer network. The cohesive forces are most often the linkable macromolecules or polymers. For example, the result of crosslinking, but may result from electrostatic, thioester linkages within a thioester-crosslinked hydrogel hydrophobic or dipole-dipole interactions. can result from reacting a first crosslinkable macromolecule 0047. Additional information about hydrogels are or polymer comprising at least two thiols with a second described in Hydrogels, Kirk-Othmer Encyclopedia of crosslinkable macromolecule or polymer comprising cross Chemical Technology, 4th Edition, vol. 7, pp. 783-807, John linking moieties (e.g., but not limited to N-Succinimidyl US 2016/02877.45 A1 Oct. 6, 2016

moiety and/or activated ester groups) such that a crosslink 0055. In some embodiments, thioester hydrogels can be ing reaction between the first and second crosslinkable hydrolytically stable across a range of various pH values. In macromolecules or polymers forms thioester linkages. In Some embodiments, thioester hydrogels can be hydrolyti Some embodiments, the first and/or second crosslinkable cally stable at pH in a range of about 0 to about 14, in a range macromolecules or polymers do not inherently possess any of about 0 to about 12, in a range of about 0 to about 9, or thioester groups/bonds. in a range of about 0 to about 7. Hydrolysis of small 0.052. In accordance with embodiments of various molecule thioesters has been previously reported in the aspects described herein, the thioester hydrogels are dissolv context of the origins of life that small molecule thioesters able. As used herein, the term “dissolvable' refers to the such as CHC(O)SCH (with a molecule weight of about 90 capability of a hydrogel to partially or completely transform Da or 90 g/mol) hydrolyze ~10,000 times faster at high pH into a flowable state. For example, in Some embodiments, (e.g., above pH -7) and low pH (e.g., below pH -3) and are the dissolvable thioester hydrogels can be transformed into relatively stable at pH -3 to -7. That is, small molecule a solution upon contact with a nucleophile as described thioesters (e.g., with a molecular weight of no more than 500 herein. In some embodiments, the dissolution process is Da) are hydrolytically unstable at a pH below 3 or above 7. reversible, i.e., a hydrogel dissolved into a solution can Surprisingly, in accordance with various embodiments reform from the solution. In other embodiments, the disso described herein, a thioester hydrogel, which generally has lution process is not reversible. high water content, is hydrolytically stable at pH from 0 to 0053. In accordance with embodiments of various at least about 9 (FIG. 7). Without wishing to be bound by aspects described herein, at least a portion of the thioester theory, this significant increase in stability of a thioester linkages within a thioester hydrogel network can react with hydrogel can be, at least in part, a result of the polymer chain a nucleophile that is selected to cause dissociation of the backbone stabilizing the thioester bond, since hydrolysis of polymeric network and thus dissolution of at least a portion a thioester hydrogel would require the polymer chain to of the thioester hydrogel. The term “nucleophile' is recog change conformation or rearrange in space. As the chains are nized in the art, and as used herein generally means a generally confined to an area via a hydrogel, a conforma chemical moiety having a reactive pair of electrons. Any tional change or rearrangement of polymer chains can molecule or ion with electrons available for donation to become less favorable. another molecule, e.g., a free pair of electrons or at least one 0056. In some embodiments, thioester hydrogels are pi bond, can be considered as a nucleophile. Examples of adhesive. For example, the thioester hydrogel can adhere to nucleophiles include, without limitations, uncharged mol a tissue, e.g., even in the presence of wound exudate and/or ecules or moieties such as water, amines, thiols, mercaptains blood. In these embodiments, the thioester hydrogel can and alcohols, and charged moieties Such as alkoxides, thio adhere to a tissue, e.g., tissue at or Surrounding a wound, and lates, carbanions, and a variety of organic and inorganic be subsequently dissolved by adding a thiolate compound, anions. e.g., for wound management. 0054. In one embodiment, the nucleophile selected for 0057. In some embodiments, a thioester hydrogel can be use in dissolution of a dissolvable thioester hydrogel a hydrogel comprising a network of crosslinkable macro described herein includes a thiol moiety. Examples of mol molecules or polymers covalently held together by linkages ecules comprising at least one thiol moiety include, but are comprising a thioester moiety. For example, in some not limited to linear, branched and/or dendritic multi-thiol embodiments, a thioester hydrogel can be derived or formed macromolecules, poly(ethylene glycol) thiol, thiol-contain from a first water-soluble macromolecule or polymer com ing glycerol, thiol-containing polyglycerol, thiol-containing prising at least two thiol moieties and a second water-soluble peptides, cysteine, cystine, alkyl ester of cysteine, alkyl ester macromolecule or polymer comprising at least two cross of cystine, MeSCHSH, (R)/(S)-3-methyl-3-sulfanylhexan linking moieties that can react with the thiol moieties of the 1-ol, Ethanethiol, 1-Propanethiol, 2-Propanethiol, Buta first water-soluble macromolecule or polymer, to form at nethiol, tert-Butyl mercaptan, Pentanethiols, Thiophenol, least two thioester crosslinks. In some embodiments, a Dimercaptosuccinic acid. Thioacetic acid, 5-mercapto-4H thioester hydrogel can be derived or formed from a first 1.2.4 triazol-3-ol, 2-mercaptoacetamide, 2-Mercaptoetha water-soluble macromolecule or polymer comprising at least nol, 1.2-Ethanedithiol, Ammonium thioglycolate, Cysteam two thioester moieties and a second water-soluble macro ine, Methyl thioglycolate. Thiolactic acid, 1-Mercapto-2- molecule or polymer comprising at least two crosslinking propanol, 2-methoxyethanethiol. 3-Mercapto-1-propanol, moieties that can crosslink with the first water-soluble 2,3-Dimercapto-1-propanol. 1-Thioglycerol, Mercaptosuc macromolecule. In some embodiments, a thioester hydrogel cinic acid, 4-ethyl-5-mercapto-4H-1,2,4-triazol-3-ol, N-Car can be derived or formed from a first water-soluble macro bamoyl-L-cysteine, 2-Methyl-3-sulfanylpropanoic acid, molecule or polymer comprising at least two nucleophilic 4-mercaptobutyric acid, N-Acetylcysteamine, 3-Methyl-1- moieties that can crosslink with at least two crosslinking butanethiol, 1.5-Pentanedithiol, 4-Chlorothiophenol, moieties of a second water-soluble macromolecule or poly 4-Aminothiophenol, Benzyl mercaptan, 2-furanmeth mer comprising at least two thioester moieties. In some anethiol, 3-mercaptohexanol, furfuryl thiol, a disulfide com embodiments, a thioester hydrogel can be derived or formed plex of one or more of the aforementioned thiol-containing from a first water-soluble macromolecule or polymer com molecules, derivatives of the aforementioned thiol-contain prising at least two nucleophilic moieties that can crosslink ing molecules, and any combinations thereof. Without wish with at least two crosslinking moieties of a second water ing to be bound by theory, the thiol moiety can react with soluble macromolecule or polymer Such that the resulting thioester moieties within the hydrogel based on thioester hydrogel contains thioester moieties. thiol exchange, resulting in dissolution of at least a portion 0058 As used herein, the term “crosslinkable' in the of the thioester hydrogel and optionally formation of amide context of crosslinkable macromolecules or polymers refers linkages to prevent hydrogel re-formation. to the ability of macromolecules or polymers to form at least US 2016/02877.45 A1 Oct. 6, 2016

one or more covalent bonds (crosslinks) with one another to first nor the second water-soluble macromolecule comprises form a polymeric network (hydrogel) under a certain con poly(ethylene glycol) in its backbone structure. dition. 0065. As used herein, the term “linear refers to a mac 0059. As used herein, the term “water-soluble' refers to romolecule having a backbone that is substantially free of the ability of crosslinkable macromolecules or polymers branching. The term “substantially free of branching as described herein (prior to a crosslinking reaction to form a used herein means that the macromolecule backbone is hydrogel) to dissolve in a water-based solution under a either not substituted with branches or is substituted with no certain condition (e.g., temperature, pH, and/or pressure). In more than 3 branches per 1000 carbon atoms. The term Some embodiments, the water-based solution is water, a “substantially free of branching can also mean that the buffered solution (e.g., phosphate buffered saline (PBS)), macromolecule backbone has no more than 2, no more than saline, or salt solution of pH in the range from 4 to 10. 1, no more than 0.1, or no more than 0.01 branches per 1000 0060. As used interchangeably herein, the terms “mac carbon atoms. romolecule' and “polymer refer to a natural and/or syn 0066. The terms “branching” and “branches' as used thetic molecule with a molecular weight of at least about 200 herein refers to a side chain comprising at least one or more Da, at least about 500 Da, at least about 1 kDa or more, e.g., carbon atoms, including, e.g., at least two, at least three, at at least about 2 kDa, at least about 3 kDa, at least about 4 least four, at least five, at least six, at least seven, at least kDa, at least about 5 kDa, at least about 10 kDa, at least eight, at least nine, at least 10, at least 15, at least 20, at least about 20 kDa, at least about 30 kDa, at least about 40 kDa, 25, at least 50, at least 75, at least 100, or more carbonatoms. at least about 50 kDa or more. In some embodiments, the The side chain can be linear, branched, comb-like, and macromolecule (or polymer) can comprise repeating struc dendritic-like as defined herein. The side chain can comprise tural units. one or more (e.g., one, two, three, four or more) functional groups selected from the group consisting of hydrogen, 0061. The first water-soluble macromolecule and/or the straight or branched alkyl, cycloalkyl, aryl, olefin or alkene, second water-soluble macromolecule can independently alkyne, silyl, alkylsilyl, arylsilyl alkylaryl or arylalkyl chain have a backbone in any structure, e.g., but not limited to, of 1-50 carbons, fluorocarbon, and any combinations linear, branched, comb-like, dendritic-like including, e.g., thereof, wherein each alkyl, cycloalkyl, aryl, olefin, silyl, dendrimers, dendrons and hyperbranched polymers, or any alkylsilyl, arylsilyl alkylaryl, fluorocarbon, or arylalkyl combinations thereof. chain can be optionally substituted internally or terminally 0062. In some embodiments, the first and the second by one or more hydroxyl, hydroxyether, carboxyl, car water-soluble macromolecules can both have substantially boxyester, carboxyamide, amino, mono- or di-substituted the same or similar type of structure. For example, both the amino, thiol, thioester, Sulfate, Sulfonate, phosphate, phos first and the second water-soluble macromolecules can have phonate, halogen Substituents, and any combinations substantially linear structures, or both can have substantially thereof. The terms “branching and “branches' do not dendritic-like structures, or both can have structures com include hydroxyl and acetate groups. prising a combination of linear and dendritic-like structures. 0067. As used herein, the term “branched refers to a In some embodiments, the first and the second water-soluble macromolecule having a backbone with one or more Sub macromolecules can have different type of structures, e.g., stituent side chains or branches. A branched macromolecule one can have a linear structure, while another can have a can encompass a comb-like macromolecule and a dendritic dendritic-like structure. In some embodiments, the first like macromolecule. water-soluble macromolecule or the second water-soluble 0068. As used herein, the term “comb-like” refers to a macromolecule can comprise a substantially linear structure. macromolecule having a backbone with multiple trifunc In some embodiments, the first water-soluble macromol tional branchpoints from each of which a linear side chain or ecule or the second water-soluble macromolecule can com branch emanates. The linear side chain can be of any length, prise a dendritic-like structure. In some embodiments, the e.g., comprising at least one or more carbon atoms, includ first water-soluble macromolecule or the second water ing, e.g., at least two, at least three, at least four, at least five, soluble macromolecule can have a structure comprising a at least six, at least seven, at least eight, at least nine, at least combination of both linear and dendritic-like structures. 10, at least 15, at least 20, at least 25, at least 50, at least 75, 0063. In some embodiments, the first water-soluble mac at least 100, or more carbon atoms. romolecule and/or the second water-soluble macromolecular 0069. As used herein, the term “dendritic-like refers to can comprise polyesters, polyethers, polyether-esters, poly a macromolecule that is highly branched and is generally ester-amines, polythioesters, polyamino acids, polyure defined by three components: a central core or a focal point thanes, polycarbonates, polyamino alcohols, thiols, thio an interior dendritic structure (the branches), and an exterior esters, thioester-containing polymers (e.g., thioester surface with functional surface groups. The number of containing polymers described herein), crosslinking branch points increases upon moving from the central core moieties (as described in detail below) such as N-hydroxy or focal point to its surface and defines the generation of a Succinimide moiety, maleimide (MAL) moiety, or any com dendritic-like macromolecule. The dendritic-like macromol binations thereof. ecule can have Generation 1, Generation 2, Generation 3. 0064. In some embodiments, one of the first water Generation 4, Generation 5 or more. The dendritic-like soluble macromolecule and the second water-soluble mac molecules eau encompass dendrimers, dendrons, hyper romolecule can comprise polyethylene glycol) in its back branched polymers, and any combinations thereof. bone structure. In some embodiments, both of the first 0070. In some embodiments, the dendritic-like macro water-soluble macromolecule and the second water-soluble molecules can comprise "dendrimers,” which are generally macromolecule can comprise poly(ethylene glycol) in its globular monodispersed macromolecules having repeated backbone structure. In some embodiments, neither of the branching units radially emanating from a central core. See, US 2016/02877.45 A1 Oct. 6, 2016

e.g., U.S. Pat. No. 5,714,166; U.S. Pat. No. 4,289,872; U.S. for certain uses, and have been used Successfully as Sutures, Pat. No. 4435,548; U.S. Pat. No. 5,041,516; U.S. Pat. No. drug delivery carriers, and tissue engineering scaffold for 5,362,843; U.S. Pat. No. 5,154,853: U.S. Ser. No. 05/739, organ failure or tissue loss (Gilding and Reed, Polymer, 256; U.S. Pat. No. 5,602,226; U.S. Pat. No. 5,514,764; 20:1459 (1979); Mooney et al., Cell Transpl. 2:203 (1994): Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. Rev. and Lewis, D. H. in Biodegradable Polymers as Drug 1999,99, 1665-1688. Fischer, M.; Vogtle, F. Angew. Chem. Delivery Systems, Chasin, M., and Langer, R., Eds. Marcel Int. Ed. 1999, 38, 884-905. Zeng, F. Zimmerman, S. C. Dekker, New York, 1990). Some of their advantages include Chem. Rev. 1997,97, 1681-1712. Tomalia, D.A., Naylor, A. their degradability in the physiological environment to yield M.; Goddard, W. A. Angew. Chem. Int. Ed. Engl. 1990, 29. naturally occurring metabolic products and the ability to 138. These macromolecules can be synthesized using either control their rate of degradation by varying the ratio of lactic a divergent (from core to surface) (Buhleier, W.; Wehner, F. acid. In the dendritic structures the degradation can be V.; Vogtle, F. Synthesis 1987, 155-158. Tomalia, D. A.: controlled by both the type of monomer used and the Baker, H., Dewald, J.; Hall, M.: Kallos, G.; Martin, S.; generation number. Roeck, J.; Ryder, J.; Smith, P. Polymer Journal 1985, 17, 0072. In some embodiments, the dendritic-like macro 117-132. Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.: molecules can comprise “dendrons.” Dendrons are generally Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P. wedge-shaped dendrimer sections with multiple terminal Macromolecules 1986, 19, 2466. Newkome, G. R. Yao, Z. groups and a single reactive function at the focal point. Baker, G. R. Gupta, V. K. J. Org. Chem. 1985, 50, 2003.) Dendrons can undergo orthogonal reactions utilizing the or a convergent (from Surface to core) (Hawker, C. J.; focal point and Surface groups. For example, dendrons can Frechet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638–7647) be conjugated to another dendron or to another macromol approach. Compared to linear polymers, dendrimers are ecule. Examples of a dendron are shown in FIG. 1B (den highly ordered, possess high Surface area to Volume ratios, dron 1); and in FIG. 2 (dendron 1 and dendron 2). and exhibit numerous end groups for functionalization. 0073. In some embodiments, the dendritic-like macro Thus, dendrimers display several favorable physical prop molecules can comprise "hyperbranched polymers. Typi erties for both industrial and biomedical applications includ cally, hyperbranched polymers are polydisperse dendritic ing: Small polydispersity indexes (PDI), low viscosities, macromolecules that possess dendrimer-like properties but high solubility and miscibility, and adhesive properties. In are usually imperfectly branched and have an average num Some embodiments, dendrimers can include derivatives of ber of terminal functional groups, rather than a precise aromatic polyether or aliphatic amides, which may not be number of terminal functional groups. These hyperbranched ideal for in vivo uses. (Service, R. F. Science 1995, 267, polymers can be prepared in single synthetic polymerization 458–459. Lindhorst, T. K.; Kieburg, C. Angew. Chem. Int. step. Ed. 1996, 35, 1953-1956. Ashton, P. R.: Boyd, S. E.; Brown, 0074. In some embodiments, the crosslinkable polymers C. L.; Yayaraman, N.; Stoddart, J. F. Angew. Chem. Int. Ed. can be modified to Suit the need of an application, such as 1997, 1997, 732-735. Wiener, E. C.: Brechbeil, M. W.; tissue engineering applications, wound management, con Brothers, H.; Magin, R. L.; Gansow, O.A.: Tomalia, D. A.; trast agent(s) vehicles, and drug delivery vehicles. For Lauterbur, P. C. Magn. Reson. Med. 1994, 31, 1-8. Wiener, example, in some embodiments, the crosslinkable polymers E. C.; Auteri, F. P.; Chen, J. W.; Brechbeil, M. W. Gansow, can comprise a biological recognition unit for cell recogni O. A.; Schneider, D. S.; Beldford, R. L.; Clarkson, R. B.: tion, e.g., but not limited to a peptide sequence and/or a Lauterbur, P. C. J. Am. Chem. Soc. 1996, 118, 7774-7782. growth factor. By way of example only, a biological recog Toth, E.; Pubanz, D.; Vauthey, S.; Helm, L.; Merbach, A. E. nition unit for cell recognition can be attached to the end Chem. Eur. J. 1996, 2, 1607-1615. Adam, G. A.; Neuerburg, groups or within the crosslinkable polymers. An example of J.; Spuntrup, E.; Muhler, A.; Scherer, K. Gunther, R. W. J. a biological recognition unit for cell recognition includes a Magn. Reson. Imag. 1994, 4, 462-466. Bourne, M. W.; tripeptide arginine-glycine-aspartic (RGD), which can be Margerun, L.; Hylton, N.; Campion, B., Lai, J. J.: Dereugin, added to the crosslinkable polymers, e.g., to improve inter N.: Higgins, C. B. J. Magn. Reson. Imag. 1996, 6, 305-310. action of the polymers with cells, tissues, and/or bones. Miller, A. D. Angew. Chem. Int. Ed. 1998, 37, 1768-1785. Barrera et al. described the synthesis of a polylactic acid) Kukowska-Latallo, J. F.; Bielinska, A. U.; Johnson, J.; (pLAL) containing a low concentration of N-epsilon.-car Spinder, R.; Tomalia, D. A.; Baker. J. R. Proc. Natl. Acad. bobenzoxy-(L)-lysine units. The polymers were chemically Sci. 1996, 93, 4897-4902. Hawthorne, M. F. Angew. Chem. modified through reaction of the lysine units to introduce Int. Ed. 1993, 32, 950-984. Qualmann, B.; Kessels M. M.: arginine-glycine-aspartic acid peptide sequences or other Musiol H.; Sierralta W. D.; Jungblut P. W.; L., M. Angew. growth factors to improve polymer-cell interactions (Barrera Chem. Int. Ed. 1996, 35, 909-911). Biodendrimers are a et al., J. Am. Chem. Soc., 115:11010 (1993), U.S. Pat. No. class of dendritic macromolecules having Substantially all of 5,399.665 to Bartera et al.). In some embodiments, the the building blocks known to be biocompatible or degrad crosslinkable polymers can be introduced with at least one able to natural metabolites in vivo, for example, but not or more functionalities, for example, without limitations, limited to glycerol, lactic acid, glycolic acid, Succinic acid, polyamino acids, peptides, carbohydrates, etc. in order to ribose, adipic acid, malic acid, glucose, citric acid, and any improve the biocompatibility and other material properties combinations thereof. of the polymers. 0071. In some embodiments, the dendritic-like crosslink 0075 First Water-Soluble Crosslinkable Macromolecule able polymers described herein can comprise polyesters, or Polymer: polyethers, polyether-esters, and polyamino acids, copoly 0076. The first water-soluble macromolecule or polymer mers thereof, or any combinations thereof. For example, comprises at least two or more nucleophilic moieties, poly(glycolic acid), poly(lactic acid), and their copolymers including, at least about three, at least about four, at least are synthetic polyesters that have been approved by the FDA about five or more nucleophilic moieties. In some embodi US 2016/02877.45 A1 Oct. 6, 2016 10 ments, the nucleophilic moieties are selected to react with a ecule can also comprise at least one or more thioester second-water soluble macromolecule to from a thioester linkages that form part of the backbone structure of the hydrogel. As used herein, the term “nucleophilic moiety’ macromolecule. For example, in one embodiment, the first refers to an atom, a molecule or a functional group having water-soluble macromolecule comprises at least three amine at least one reactive pair of electrons. Any atom, molecule or moieties (as nucleophilic moieties), wherein the macromol functional group with electrons available for donation to ecule further comprises thioester linkages forming part of another atom, molecule or functional group, e.g., a free pair the backbone structure of the macromolecule. of electrons or at least one pi bond, can be considered as a 0078. The first water-soluble macromolecule or polymer nucleophilic moiety. Examples of nucleophilic moieties comprises at least two or more thiol moieties, including, at include, without limitations, amines, thiols, alcohols, and least about three, at least about four, at least about five or any combinations thereof. more thiol moieties. The thiol moieties can be part of the 0077. The nucleophilic moieties can be part of the side side group or side chain of the first water-soluble macro group or side chain of the first water-soluble macromolecule, molecule, the terminal group of the first water-soluble the terminal group of the first water-soluble macromolecule, macromolecule, or a combination thereof. In one embodi or a combination thereof. In one embodiment, the first ment, the first water-soluble macromolecule comprises at water-soluble macromolecule comprises at least four thiol least four thiol moieties. moieties (as nucleophilic moieties). Alternatively, in another 0079. In some embodiments, the first water-soluble mac embodiment, the first water-soluble macromolecule com romolecule can have a chemical structure of formula (I) prises at least three amine moieties (as nucleophilic moi selected from the group consisting of chemical structure eties). In some embodiments, the water-soluble macromol (i)-structure (xii). S-en-N-N, (i) (ii)

------Q

(iii)

pi

Q

------Q US 2016/02877.45 A1 Oct. 6, 2016 11

-continued (iv) (v) QR R R Q RQ Q Q 2, ( iii. R Q () ) R. R.

(vi)

(vii) (viii)

US 2016/02877.45 A1 Oct. 6, 2016 12

-continued (ix) (x)

R. R. Q QR RN-4- R. R. Q QN^g ox^oQ R. R. Q Q f Q- leC

(2) R R. R. Q- leC (2.

R R () QR

(xi) (xii) RQ

chR so

Q XQ Q xor k al R\s pi 4 No R. R. R R QR (2) indicates text missing or illegible when filed and any combinations thereof. wherein each alkyl, cycloalkyl, aryl, olefin, silyl alkylsilyl, 0080 Q can be any atom or a group of atoms (e.g., at least arylsilyl, alkylaryl, fluorocarbon, or arylalkyl chain can be two atoms or more) provided that it can form a bond (e.g., optionally substituted internally or terminally by one or a single bond, a double bond, or a triple bond) with its more hydroxyl, hydroxyether, carboxyl, carboxyester, car neighboring atoms or groups of atoms. In some embodi boxyamide, amino, mono- or di-substituted amino, thiol, ments, Q can be independently selected from the group thioester, Sulfate, phosphate, phosphonate, halogen Substitu consisting of O, S, Se, NH, CH, and any combination ents, and any combinations thereof thereof. In some embodiments, the first water-soluble mac I0083. In some embodiments, R can comprise an oligomer romolecule can comprise at least two Q atoms or groups, or polymer of a biocompatible material, e.g., but not limited wherein the Q atoms or groups can be the same or different to, poly(ethylene glycol) and/or poly(ethylene oxide); poly from at least one of the others. (hydroxy acid); a carbohydrate; a protein; a polypeptide; an 0081 R can be any atom or a group of atoms (e.g., at least amino acid; a nucleic acid; a nucleotide; a polynucleotide; a two atoms or more) provided that it can form a bond (e.g., DNA segment; a RNA segment; a lipid; a polysaccharide; an a single bond, a double bond, or a triple bond) with its antibody; a pharmaceutical agent, an epitope for a biological adjacent atom. R can be linear, branched, aromatic, cyclic, receptor; or any combinations thereof. In some embodi comb-like, or dendritic-like as defined herein. In some ments, R does not include poly(ethylene glycol). embodiments, the first water-soluble macromolecule can comprise at least two R groups, wherein the R groups can be I0084. In some embodiments, R can comprise an oligomer the same or different from at least one of the others. In some or polymer of a biocompatible material. As used herein, the embodiments where at least two R groups are in Substan term “biocompatible” refers to a material exhibiting essen tially the same structure, at least one R group can be different tially no cytotoxicity or immunogenicity while in contact from another R group. 0082 In some embodiments, R can be independently with body fluids or tissues. The biocompatible material can selected from the group consisting of a hydrogen, straight or be biodegradable or non-biodegradable. As used herein, the branched alkyl, cycloalkyl, aryl, olefin or alkene, alkyne, term “biodegradable” refers to the ability of a polymeric silyl, alkylsilyl, arylsilyl, alkylaryl or arylalkyl chain of 1-50 material to erode or degrade in Vivo to form Smaller chemi carbons, fluorocarbon, and any combinations thereof, cal fragments. Degradation may occur, for example, by US 2016/02877.45 A1 Oct. 6, 2016

enzymatic, chemical or physical processes. Non-limiting second water-soluble macromolecule to form a gel. For examples of biodegradable polymeric materials can include example, m, n, X, and y can each independently be an integer polyesters, polyamides, polyethers, polycarbonates, polyan of 0 or greater, including, e.g., at least one, at least two, at hydrides, polyorthoesters, polycaprolactone, polyester least three, at least four, at least five, at least six, at least amides, polycyanoacrylate, polyetherester, poly(phos seven, at least eight, at least nine, at least 10, at least 20, at phates), poly(phosphonates), poly(phosphites), polyhydric least 25, at least 50, at least 75, at least 100, at least 250, at alcohol esters, blends and copolymers thereof. As used least 500, at least 750, at least 1000, at least 1500 or more. herein, the term “non-biodegradable' refers to the ability of In some embodiments, m, n, X, and y can each be indepen a polymeric material to resisterosion or degradation in vivo. dently selected from an integer of 1-1000, or from an integer Thus, a non-biodegradable material can stay in vivo for a of 10-1000. significantly long amount of time, or even permanently. 0087. In some embodiments, the first water-soluble mac Non-limiting examples of degradation-resistant polymeric romolecule can be a dendritic-like macromolecule as defined materials can include polyethylene, polypropylene, polytet herein. In one embodiment, the first water-soluble macro rafluoroethylene, polyurethanes, silicon, polyacrylates, eth molecule can be a dendron. ylene-vinyl acetates (and other acyl-substituted cellulose 0088. In one embodiment, the first water-soluble macro acetates), polystyrenes, polyvinyl oxides, polyvinyl fluo molecule has a chemical structure of formula (II), wherein rides, poly(Vinyl imidazoles), chlorosulphonated polyole the formula (II) is represented as follows:

(II) SH

HN O O

N H N -N- SH

O --> O

-N-1-44 N HN O

HS NH

SH

fins, polyethylene oxides, polyvinyl alcohols (PVA), any 0089 Additionally or alternatively, the first water-soluble art-recognized degradation-resistant polymers, or any com macromolecule can comprise at least two thioester linkages binations thereof. or more, including, at least about three, at least about four, 0085. In one embodiment, R can comprise poly(ethylene at least about five or more thioester linkages. In one embodi glycol) and/or poly(ethylene oxide); ment, the first water-soluble macromolecule comprises at I0086 m, n, x, and y can each independently be any least three or more thioester moieties. The thioester linkages integer of Zero or greater (e.g., at least one or more) provided can form part of the backbone structure of the first water that the first water-soluble macromolecule has a molecular soluble macromolecule. For example, the first water-soluble weight of at least about 200 Da or more (e.g., at least about macromolecule can have a chemical structure of formula 1 kDa, at least about 2 kDa or more) and can react with the (III), wherein the formula (III) is represented as follows: US 2016/02877.45 A1 Oct. 6, 2016 14

(0093. Second Water-Soluble Macromolecule Comprising (III) at Least Two Crosslinking Moieties: CIHHN 0094. In some embodiments, the second water-soluble macromolecule comprises at least two crosslinking moieties that can form a linkage with the nucleophilic moieties of the first water-soluble macromolecule to enable formation of a l S thioester hydrogel comprising at least two thioester bonds (—S C=O ). In some embodiments, the second water O soluble macromolecule comprises at least two crosslinking HO S moieties that can react with the thiol moieties (—SH) of the N1 NHHC, first water-soluble macromolecule to enable formation of a O thioester hydrogel comprising at least two thioester bonds O S (—S C=O ). For example, the second water-soluble macromolecule can comprise at least two or more crosslink ing moieties, including, at least about three, at least about four, at least about five or more crosslinking moieties. The NHHCI crosslinking moieties can be part of the side group or side chain of the second water-soluble macromolecule, the ter 0090 Synthesis of the first water-soluble macromolecule minal group of the second water-soluble macromolecule, or of formula (III) from citric acid is described in Example 6. a combination thereof. In one embodiment, the second 0091. In some embodiments, the first water-soluble mac water-soluble macromolecule comprises at least two cross romolecule comprises at least two or more nucleophilic linking moieties. moieties (e.g., but not limited to thiol, amine, alcohol), 0.095 As used herein, the term “crosslinking moiety” or including at least about three, at least about four, at least “crosslinking moieties’ refers to an organic reactive atom or about five or more nucleophilic moieties, that can react with group of atoms (e.g., a group of at least two or more atoms) a second-water soluble macromolecule that contains at least that can react with the nucleophilic moieties (e.g., but not two or more thioester linkages to from a thioester hydrogel. limited to thiol (—SH), alcohol ( OH), amine ( NH) of For example, the first and the second-water soluble macro the first water-soluble macromolecule. The second water molecules can have chemical structures of formula (IV) and soluble macromolecule can comprise any art-recognized (V), respectively, wherein the formula (IV) and (V) are crosslinking moieties, e.g., but not limited to, 1-Ethyl-3-3- represented as follows: dimethylaminopropylcarbodiimide hydrochloride (EDC or

(IV)

H N NH2 O O

-e-N-1-44 N HN O

HN

(V) O O O O N -- O sus N O No ~~ n--> O1 O O O

0092 Syntheses of the first and second water-soluble EDAC), hydroxybenzotriazole (HOBT), N-Hydroxysuccin macromolecules of formula (IV) and (V) are described in imide (NHS), N-Hydroxysuccinimide ester (NHS ester), Examples 1 and 8, respectively. imidoester, maleimide, haloacetyl (e.g., iodoacetyl or bro US 2016/02877.45 A1 Oct. 6, 2016

moacetyl), hydrazide, alkoxyamine, photoreactive cross 0098. In some embodiments, at least one of the cross linking moieties (e.g., but not limited to phenyl azide, and linking moieties of the second water-soluble macromolecule diazirine), 2-(1H-7-AZabenzotriazol-1-yl)-1,1,3,3-tetram can comprise N-Hydroxysuccinimide (NHS) and/or ethyl uronium hexafluorophosphate methanaminium maleimide (MAL) moieties. In some embodiments, the (HATU), silanization, alkyl halide, aldehyde, amino, bromo second water-soluble macromolecule can further comprise or iodoacetyl, carboxyl, hydroxyl, epoxy, ester, silane, and at least two thioester linkages within the backbone structure any combinations thereof. of the macromolecule. 0099. In some embodiments, at least one of the cross 0096. In some embodiments, at least one of the cross linking moieties of the second water-soluble macromolecule linking moieties of the second water-soluble macromolecule can comprise a NHS ester, e.g., but not limited to Succin can comprise a N-Hydroxysuccinimide (NHS) moiety. In imidyl Valerate (SVA), succinimidyl carbonate (SC), suc Some embodiments, the second water-soluble macromol cinimidylglutarate (SG). Succinimidyl Succinate (SS). Suc ecule can further comprise at least two thioester linkages cinimidyl carboxymethyl (SCM), succinimidyl propionate within the backbone structure of the macromolecule. (SPA), and any combinations thereof. In one embodiment, at 0097. In some embodiments, at least one of the cross least one of the crosslinking moieties of the second water linking moieties of the second water-soluble macromolecule soluble macromolecule comprises a Succinimidyl Valerate. can comprise a maleimide (MAL) moiety. In some embodi 0100. In some embodiments, the second water-soluble ments, the second water-soluble macromolecule can further macromolecule can have a chemical structure of formula comprise at least two thioester linkages within the backbone (VI) selected from the group consisting of chemical struc structure of the macromolecule. tures (xiii)-(x1).

(xiii) O Q R. R. O N Q O

O Sr.'s-n'sR. R. Q s O (xiv) O Q R. R. Nulls--4.No Q sh-xy's Qa -Q -O R R ) O (xv) O O R. R. Q Q O Q N

Q Q R. R. (xvii) O O R R Q R. R. Q N1 O -x Q -*. Q x's- N s Q R. R. R R O

(xvii) O O R. R. Q R. R. Q O Q Q N s N1 y Q (-1. y O1 Q R. R. & WR R O O iii. (xviii) O O R. R. R. R. Y. N Q Q Q Q N s

O s'''R Q Q (-r-‘’sI R O US 2016/02877.45 A1 Oct. 6, 2016 16

-continued (xix) O 7 R R. Q R. R. Q R R O Nt \-Q Q Q -ex. O san's-sa-'sa'sR R 8 R. R. y R R iN 7 O (XX)

(xxi)

(xxii) US 2016/02877.45 A1 Oct. 6, 2016 17

-continued

(xxiii)

(xxiv) US 2016/02877.45 A1 Oct. 6, 2016 18

-continued

(XXv) (xxvi)

(xxvii) US 2016/02877.45 A1 Oct. 6, 2016 19

-continued

(xxviii)

(XXix) US 2016/02877.45 A1 Oct. 6, 2016 20

-continued

(XXX)

(XXXi)

OReferrer-1' RR Q Q Q Q Q RR 3O US 2016/02877.45 A1 Oct. 6, 2016 21

-continued

(XXXii)

K.y R-fso R > O RR Q R. R. Q R. R. Q RR O xix.6-rret------O Q O

2, i.

(XXXiii) US 2016/02877.45 A1 Oct. 6, 2016 22

-continued

(XXXiv)

(XXXv)

R O. iN O Ry Q NY QRYÉ, R o O N O US 2016/02877.45 A1 Oct. 6, 2016 23

-continued

(XXXvi)

(XXXvii)

US 2016/02877.45 A1 Oct. 6, 2016 25

-continued (xl) O V Rican O

Q Q

O848 R. RRR -tory Q N Q Q Q R N-noQ /, ohn-Q-roded.R. R. R. R. O S Q ---N k, O (FR l, . pi R R Q y-Q R1 Ri Q Q 4N/

fO and any combinations thereof. thioester, Sulfate, phosphate, phosphonate, halogen Substitu 0101 Q can be any atom or a group of atoms (e.g., at least ents; and any combinations thereof. two atoms or more) provided that it can form a bond (e.g., 0104. In some embodiments, R can comprise an oligomer a single bond, a double bond, or a triple bond) with its or polymer of a biocompatible material, e.g., but not limited neighboring atoms or groups of atoms. In some embodi to, poly(ethylene glycol) and/or poly(ethylene oxide); poly ments, Q can be independently selected from the group (hydroxy acid); a carbohydrate; a protein; a polypeptide; an consisting of O, S, Se, NH, CH, and any combination thereof. In some embodiments, the second water-soluble amino acid; a nucleic acid; a nucleotide; a polynucleotide; a macromolecule can comprise at least two Qatoms or groups, DNA segment; a RNA segment; a lipid; a polysaccharide; an wherein the Q atoms or groups can be the same or different antibody; a pharmaceutical agent, an epitope for a biological from at least one of the others. receptor; or any combinations thereof. 0102 R can be any atom or a group of atoms (e.g., at least 0105 m, n, x, y, and Z can each independently be any two atoms or more) provided that it can form a bond (e.g., integer of 0 or greater (e.g., at least 1 or greater) provided a single bond, a double bond, or a triple bond) with its that the first water-soluble macromolecule has a molecular adjacent atom. R can be linear, branched, aromatic, cyclic, weight of at least about 200 Da or more (e.g., at least about comb-like, or dendritic-like as defined herein. In some embodiments, the second water-soluble macromolecule can 1 kDa, at least about 2 kDa or more) and can react with the comprise at least two R groups, wherein the R groups can be first water-soluble macromolecule to form a gel. For the same or different from at least one of the others. In some example, m, n, x, y, and Z can each independently be an embodiments where at least two R groups are in Substan integer of Zero or greater, including, e.g., at least one, at least tially the same structure, at least one R group can be different two, at least three, at least four, at least five, at least six, at from another R group. least seven, at least eight, at least nine, at least 10, at least 0103) In some embodiments, R can be independently 20, at least 25, at least 50, at least 75, at least 100, at least selected from the group consisting of a hydrogen, straight or 250, at least 500, at least 750, at least 1000, at least 1500 or branched alkyl, cycloalkyl, aryl, olefin or alkene, alkyne, more. In some embodiments, m, n, x, y, and Z can each be silyl, alkylsilyl, arylsilyl, alkylaryl or arylalkyl chain of 1-50 independently selected from an integer of 1-1000, or from an carbons, fluorocarbon, and any combinations thereof, integer of 10-1000. wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, 0106. In some embodiments, the second water-soluble arylsilyl, alkylaryl, fluorocarbon, or arylalkyl chain can be macromolecule can be a linear macromolecule as defined optionally substituted internally or terminally by one or herein. For example, in some embodiments, the second more hydroxyl, hydroxyether, carboxyl, carboxyester, car water-soluble macromolecule can have the following chemi boxyamide, amino, mono- or di-substituted amino, thiol, cal structure (xiii), wherein R is hydrogen: US 2016/02877.45 A1 Oct. 6, 2016 26

70 mmHg, at least about 80 mmHg, including, e.g., at least O about 90 mmHg, at least about 100 mmHg, at least about Q R. R. O. 150 mmHg, at least about 200 mmHg, at least about 250 mmHg, at least about 300 mmHg, at least about 350 mmHg N Q O or more. In some embodiments, the thioester hydrogel when Sr. st-*. NN used as a sealant in a blood vessel can withstand an arterial O R. R. Q pressure of at least about 80 mmHg, at least about 100 O mmHg, at least about 120 mmHg, at least about 150 mmHg, at least about 200 mmHg. Thioester hydrogels can be 0107. In these embodiments, Q can be oxygen. In these adapted for various mechanical strengths to provide appro embodiments, X can be an integer of four. In one embodi priate treatment of different types of wounds. ment, the second water-soluble macromolecule is poly(eth 0112. In some embodiments, the thioester hydrogel ylene glycol) disuccinimidyl Valerate, e.g., with a molecular described herein can be transparent. The term “transparent weight of about 3400 Da. The molecular weight of the as used herein refers to a hydrogel material which can poly(ethylene glycol) disuccinimidyl Valerate can vary with transmit an average of greater than 30% or more (including, the chain length of the poly(ethylene glycol). e.g., greater than 40%, greater than 50%, greater than 60%, 0108. In some embodiments, the second water-soluble greater than 70%, greater than 80%, greater than 90%, macromolecule can have a chemical structure of formula (V) greater than 95% or more) of incident visible light across the shown as follows: visible light spectrum.

(V) O O O O N --- O sus N O No ~~ n--> O1 O O O

0109. In some embodiments, the second water-soluble 0113. In some embodiments, the thioester hydrogels macromolecule can have a chemical structure of formula described herein are hydrophilic. As used herein, the term (VII) shown as follows: “hydrophilic' in reference to a hydrogel means that the

(VII) x-r-rror-3

0110. In some embodiments, the thioester hydrogel hydrogel can interact with water molecules by electrostatic described herein can be entirely or partially flexible. As used interaction and/or hydrogen bonds. For example, a hydro herein, the term “flexible' generally refers to a material philic hydrogel can attract and absorb water from a Sur being capable of bending or flexing Such that it is pliant and rounding environment and Swell to a larger volume. A yieldable in response to a change in Surrounding condition hydrophilic hydrogel can be water-soluble or water-in (e.g., an external force or pressure), without causing any soluble. In accordance with embodiments of various aspects macroscopic breaking. A flexible material can generally alter described herein, the thioester hydrogel can be dissolved in geometric shape and/or Volume to accommodate a change in an aqueous solution comprising a thiolate compound, but remain hydrolytically stable in water or a salt Solution at a Surrounding condition and/or to conform to the shape of an pH value in a range from about 3 to at least about 9. object brought in contact with it without losing its integrity. Hydrophilicity of the hydrogel can, in part, depend on the Thus, the term “flexible” when used in reference to the hydrophilicity of the crosslinkable polymers that form the thioester hydrogel described herein refers to a hydrogel hydrogel. In some embodiments, a hydrophilic thioester being capable of Swelling without losing its integrity when hydrogel is a hydrogel comprising hydrophilic crosslinkable it is exposed to an aqueous condition and/or being conformal polymers, e.g., crosslinkable polymers comprising polar to the shape of a surface or void to which the thioester and/or charged functional groups, rending them to Soluble in hydrogel is applied. water. Examples of hydrophilic crosslinkable polymers can 0111. In some embodiments, the thioester hydrogel include, but are not limited to, poly(ethylene glycol), poly described herein can be capable of withstanding a fluid (ethylene oxide), poly(glycerol), poly(vinyl acetate), poly pressure of at least about 2 mmHg, including, e.g., at least (vinyl pyrrolidone), poly(propylene glycol), poly(vinyl alco about 5 mmHg, at least about 10 mmHg, at least about 20 hol), polysiloxane, maleic anhydride copolymers, mmHg, at least about 30 mmHg, at least about 40 mmHg, at polyethers, copolymers thereof, and any combinations least about 50 mmHg, at least about 60 mmHg, at least about thereof. US 2016/02877.45 A1 Oct. 6, 2016 27

0114. In some embodiments, the thioester hydrogel reference to an alkyl group means an alkyl group in which described herein can be elastic. As used herein, the term a lower alkyl group, Such as methyl, ethyl or propyl, is "elastic' refers to a hydrogel having low Young's modulus attached to a linear alkyl chain. Exemplary alkyl groups and high yield strain compared with other types of poly include methyl, ethyl, i-propyl. n-butyl, t-butyl, n-pentyl, meric materials. heptyl, octyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl 0115. In some embodiments, the thioester hydrogel and hexadecyl. Useful alkyl groups include branched or described herein can be viscoelastic. As used herein, the straight chain alkyl groups of six to 50 carbon, and also term “viscoelastic’ refers to a hydrogel exhibiting both include the lower alkyl groups of one to about four carbons elastic and Viscous characteristics. For example, a Viscoelas and the higher alkyl groups of about 12 to about 16 carbons. tic hydrogel can at least partially return to its original form I0120. As used herein, the term “alkenyl' or “alkene' when an applied stress is released, and the response is refers to an alkyl group containing at least one carbon time-dependent. In dynamic mechanical characterization, carbon double bond. The alkenyl group can be optionally the level of Viscoelasticity is proportional to the damping substituted with one or more “alkyl group substituents.” coefficient measured by the tan (delta) of the material. The Exemplary alkenyl groups include vinyl, allyl, n-pentenyl, tan (delta) is generally the ratio of the Viscous dissipative decenyl, dodecenyl, tetradecadienyl, heptadec-8-en-1-yland loss modulus to the elastic storage modulus. High tan (delta) heptadec-8,11-dien-1-yl. values can indicate a high viscous component in the material I0121. As used herein, the term “alkynyl' or “alkyne' behavior and hence a strong damping to any perturbation refers to an alkyl group containing a carbon-carbon triple will be observed. The measurement of these moduli is bond. The alkyne group can be optionally substituted with described in An Introduction to Rheology, by Barnes, H. A., one or more “alkyl group Substituents.” Exemplary alkynyl Hutton, J. F., and Walters, K.; Elsevier, Amsterdam (1997). groups include ethynyl, propargyl, n-pentynyl, decynyl and 0116. In some embodiments, the thioester hydrogels dodecynyl. Useful alkynyl groups include the lower alkynyl described herein are at least 50% or more mechanically groups. stronger than a disulfide-crosslinked hydrogel (e.g., 8-arm I0122. As used herein, the term "cycloalkyl refers to a PEG-SH (20 kDa)) described in Sinko, P. J. et al. Bioma non-aromatic mono- or multicyclic ring system of about four terials, 2011, 32, 1204-1217) of the same weight percent. to about 10 carbon atoms. The cycloalkyl group can be For example, in one embodiment, the ~10 wt % thioester optionally partially unsaturated. The cycloalkyl group can hydrogel described herein has a storage modulus of about be also optionally Substituted with an aryl group Substituent, 6000 Pa, while a ~10 wt % disulfide-crosslinked hydrogel oxo and/or alkylene. Representative monocyclic cycloalkyl has a storage modulus of about 3000 Pa. In some embodi rings include cyclopentyl, cyclohexyl and cycloheptyl. Use ments, the thioester hydrogel described herein can have a ful multicyclic cycloalkyl rings include adamantyl, octahy storage modulus of at least about 3000 Pa or higher, includ dronaphthyl, decalin, camphor, camphane, and noradaman ing, e.g., at least about 4000 Pa, at least about 5000 Pa, at tyl. least about 6000 Pa, at least about 7000 Pa, at least about 8000 Pa, at least about 9000 Pa, at least about 10000 Pa, at I0123. As used herein, the term “aryl refers to an aro least about 20000 Pa, at least about 30000 Pa, at least about matic carbocyclic radical containing about 6 to about 10 40000 Pa or higher. carbon atoms. The aryl group can be optionally Substituted with one or more aryl group Substituents, which can be the 0117 The thioester hydrogel can form any shape, e.g., a same or different, where “aryl group substituent includes film, a sheet, a coating, or a three-dimensional construct, alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, alkoxy, ary e.g., a hollow and/or Solid structure. In some embodiments, loxy, aralkoxy, carboxy, aroyl, halo, nitro, trihalomethyl, the thioester hydrogel can form a film, a sheet, a coating, or cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, a layer and termed as “dissolvable hydrogel layer herein. acyloxy, acylamino, aroylamino, carbamoyl, alkylcarbam 0118. In some embodiments, the thioester hydrogel can oyl, dialkylcarbamoyl, rylthio, alkylthio, alkylene and further comprise at least one or more bioactive agents —NRR", where R and R' are each independently hydrogen, described herein. In some embodiments, the thioester hydro alkyl, aryl and aralkyl. Exemplary aryl groups include gel can further comprise at least two or more, including, e.g., substituted or unsubstituted phenyl and substituted or unsub 2, 3, 4, 5, 6 or more bioactive agents described herein. stituted naphthyl. 0119 Definitions of some chemical functional groups 0.124. As used herein, the term “acyl refers to an alkyl used herein are defined as follows. As used herein, the term CO— group, wherein alkyl is as previously described. “alkyl refers to an aliphatic hydrocarbon group which can Exemplary acyl groups comprise alkyl of 1 to about 30 be straight or branched having one to about 60 carbon atoms carbon atoms. Exemplary acyl groups also include acetyl, in the chain, and which preferably have about six to about propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl. 50 carbons in the chain. “Lower alkyl refers to an alkyl group having one to about nine carbon atoms. “Higher 0.125. As used herein, the term “aroyl means an aryl alkyl refers to an alkyl group having about 10 to about 20 CO— group, wherein aryl is as previously described. Exem carbon atoms. The alkyl group can be optionally Substituted plary aroyl groups include benzoyl and 1- and 2-maphthoyl. with one or more alkyl group substituents which can be the I0126. As used herein, the term “alkoxy' refers to an same or different, where “alkyl group substituent includes alkyl-O-group, wherein alkyl is as previously described. halo, amino, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alky Exemplary alkoxy groups include methoxy, ethoxy, lthio, arylthio, aralkyloxy, aralkylthio, carboxy, alkoxycar n-propoxy, i-propoxy, n-butoxy, and heptoxy. bonyl, oxo and cycloalkyl. There can be optionally inserted I0127. As used herein, the term “aryloxy' refers to an along the alkyl chain one or more oxygen, silicon, Sulfur, or aryl-O-group, wherein the aryl group is as previously Substituted or unsubstituted nitrogen atoms, wherein the described. Exemplary aryloxy groups include phenoxy and nitrogen substituent is lower alkyl. “Branched when used in naphthoxy. US 2016/02877.45 A1 Oct. 6, 2016 28

0128. As used herein, the term “alkylthio’ refers to an integer from Zero to about 50, —(CH2)n-N(R)—(CH2)m- alkyl-S— group, wherein alkyl is as previously described. wherein each of m and n is independently an integer from Exemplary alkylthio groups include methylthio, ethylthio. Zero to about 50 and R is hydrogen or alkyl, methylenedioxy i-propylthio and heptylthio. CH2-O ) and ethylenedioxy ( O—(CH2)2-O ). An 0129. As used herein, the term “arylthio’ refers to an alkylene group can have about two to about three carbon aryl-S— group, wherein the aryl group is as previously atoms and can further have 6-50 carbons. described. Exemplary arylthio groups include phenylthio 0144. As used herein, the term “halo' or “halide” refers and naphthylthio. to fluoride, chloride, bromide, or iodide. 0130. As used herein, the term “aralkyl refers to an (0145 As used herein, the term “fluorocarbon includes aryl-alkyl-group, wherein aryl and alkyl are as previously fluoroalkyl, fluorocycloalkyl, and fluoroether groups. described. Exemplary aralkyl groups include benzyl, phe 0146. As used herein, the term “silyl refers to hydro nylethyl and naphthylmethyl. carbyl derivatives of the silyl group: R'Si, wherein R' can 0131. As used herein, the term “aralkyloxy' refers to an be hydrogen, alkyl, aryl, or any combinations thereof. aralkyl-O-group, wherein the aralkyl group is as previ ously described. An exemplary aralkyloxy group is benzy Dissolvable Hydrogel Compositions Comprising a loxy. Dissolvable Hydrogel Layer Described Herein 0.132. As used herein, the term “aralkylthio’ refers to an 0.147. In another aspect, provided herein relates to a aralkyl-S— group, wherein the aralkyl group is as previ dissolvable hydrogel composition comprising at least one ously described. An exemplary aralkylthio group is benzyl layer of the dissolvable hydrogel described herein. In some thio. embodiments, the dissolvable hydrogel layer can function as 0133. As used herein, the term “dialkylamino” refers to an adhesive layer, allowing the dissolvable hydrogel com an —NR'R" group, wherein each of R and R" is indepen position to adhere to a surface (e.g., a tissue Surrounding a dently an alkyl group as previously described. Exemplary wound) and be controllably removed from the tissue surface, alkylamino groups include ethylmethylamino, dimethyl when needed at a later time, by addition of a thiolate amino, and diethylamino. compound. In some embodiments, the dissolvable hydrogel 0134. As used herein, the term “alkoxycarbonyl refers to layer can further comprise a bioactive agent described herein an alkyl-O CO— group. Exemplary alkoxycarbonyl that can be released from the hydrogel layer to the adhered groups include methoxycarbonyl, ethoxycarbonyl, buty tissue. Examples of bioactive agents can include, but are not loxycarbonyl, and t-butyloxycarbonyl. limited to, pharmaceutical agents, drugs, cells, gases and 0135. As used herein, the term “aryloxycarbonyl refers gaseous precursors, synthetic organic molecules, proteins, to an aryl-O-CO— group. Exemplary aryloxycarbonyl enzymes, growth factors, vitamins, steroids, polyanions, groups include phenoxy- and naphthoxy-carbonyl. nucleosides, nucleotides, polynucleotides, nanoparticles, 0136. As used herein, the term “aralkoxycarbonyl refers diagnostic agents, genetic materials, and any combinations to an aralkyl-O CO— group. An exemplary aralkoxycar thereof. Additional information about bioactive agents is bonyl group is benzyloxycarbonyl. described below in section “Bioactive agents.” 0.137 As used herein, the term “carbamoyl refers to an 0.148. In some embodiments, the dissolvable hydrogel HN CO— group. composition can be present as a thin sheet or layer. In some 0.138. As used herein, the term “alkylcarbamoyl refers to embodiments, the dissolvable hydrogel composition can be a R'R''N CO group, wherein one of R" and R' is hydro present as a thin sheet or layer Supported by a sheet Support gen and the other of R" and R' is alkyl as previously member to provide mechanical strength. The sheet Support described. member for the hydrogel can, for example, be a thin scrim 0.139. As used herein, the term “dialkylcarbamoyl refers or net structure, for example formed of a synthetic and/or to R'R''N CO - group, wherein each of R" and R is natural polymer Such as polyethylene or polypropylene. The independently alkyl as previously described. sheet support member for the dissolvable hydrogel can be 0140. As used herein, the term “acyloxy' refers to an disposed on the Surface of the dissolvable hydrogel compo acyl-O-group, wherein acyl is as previously described. sition that is directed away from a surface (e.g., a wound or 0141. As used herein, the term “acylamino” refers to an lesion) in use. Alternatively or additionally, the sheet Support acyl-NH- group, wherein acyl is as previously described. member can be embedded within the hydrogel polymer. The 0142. As used herein, the term “aroylamino” refers to an sheet support member can, if desired, extend beyond the aroyl-NH-group, wherein aroyl is as previously described. margins of the hydrogel composition, and can be provided 0143. As used herein, the term “alkylene' refers to a with a skin-adhesive portion to further secure the dissolvable straight or branched bivalent aliphatic hydrocarbon group hydrogel composition to the skin. The skin-adhesive portion having from one to about 30 carbon atoms. The alkylene can be hydrogel in nature (for example a plasticized tacky group can be straight, branched, or cyclic. The alkylene hydrogel, which can be the same as or different from the group can be also optionally unsaturated and/or Substituted hydrogel provided on the Support member), or may be with one or more “alkyl group substituents.” There can be another type of skin adhesive selected from the many skin optionally inserted along the alkylene group one or more adhesives known in the wound dressings art. The Support oxygen, Sulphur, or Substituted or unsubstituted nitrogen member can be or can comprise a sheet member as defined atoms, wherein the nitrogen Substituent is alkyl as previ in WO 2007/113452, the content of which is incorporated ously described. Exemplary alkylene groups include meth herein by reference. In some embodiments, the Support ylene (—CH2-), ethylene (—CH2-CH2-), propylene member can comprise or be a “fibrous absorbent sheet (—(CH2)3-), cyclohexylene ( C6H10-), —CH=CH member as defined in WO 2007/113452 and/or can com CH=CH-, -CH=CH-CH2-, -(CF2)n(CH2)m-, prise one or more other sheet members defined as “other wherein n is an integer from about 1 to about 50 and m is an absorbent sheet members’ in WO 2007/113452. US 2016/02877.45 A1 Oct. 6, 2016 29

0149. In some embodiments, the dissolvable hydrogel a mesh patch (the patch includes two layers of an inert composition can be a multi-layer composite comprising at synthetic mesh, generally made of polypropylene, and is least one layer of the dissolvable hydrogel described herein described in U.S. Pat. No. 6,280,453) that includes a fila and at least one additional layer Such as additional hydrogel ment to stiffen and maintain the device in a flat configura layer(s), and/or other polymer(s), and/or other sheet Support tion; (f) VISILEX mesh (from C.R. Bard, Inc.), which is a members. By way of example only, in some embodiments, polypropylene mesh that is constructed with monofilament a multi-layer hydrogel composition can comprise at least polypropylene; (g) other meshes available from C.R. Bard, one layer of the dissolvable hydrogel described herein Inc. which include PERFIX Plug, KUGEL Hernia Patch, 3D overlaid by at least one or more drug-releasing layers and/or MAX mesh, LHI mesh, DULEX mesh, and the VEN a breathable (air and/or moisture permeable) polymeric film TRALEX Hernia Patch; and (h) other types of polypropyl (e.g., but not limited to, polyurethane film) as the top layer. ene monofilament hernia mesh and plug products include The drug-releasing layer(s) can comprise a pharmaceutically HERTRA mesh 1, 2, and 2A, HERMESH 3, 4 & 5 and active agent described herein entrapped in a hydrogel and/or HERNIAMESH plugs T1, T2, and T3 from Herniamesh polymeric matrix. The pharmaceutically active agent can be USA, Inc. (Great Neck, N.Y.). physically entrapped in the hydrogel and/or polymeric 0153. In some embodiments, the dissolvable hydrogel matrix, and/or conjugated to matrix-forming monomers that composition can constitute a dressing, bandage, glue, seal form the hydrogel and/or polymeric matrix. ant, coating, and/or covering for a wound, tissue Void or 0150. In some embodiments, the dissolvable hydrogel lesion. The dissolvable hydrogel composition can, after composition can be provided with a protectant layer (e.g. of removal of any protectant layer as appropriate, be applied to non-stick paper or plastic, such as siliconised paper or the wound directly so that the dissolvable hydrogel layer can plastic) to protect one or both surfaces of the hydrogel adhere to tissue Surrounding the wound, thus contacting composition prior to use. and/or protecting the wound and Surrounding tissues. While 0151. While not necessary, in some embodiments, the not necessary, in Some embodiments, additional conven dissolvable hydrogel composition can further comprise a tional bandages, cloths or other protective fabrics or mate degradable or non-degradable mesh to be used in combina rials can be subsequently applied to further encase the tion with the dissolvable hydrogel to provide additional dissolvable hydrogel composition. adhesion to a tissue site. Further, the combination of the 0154) In some embodiments, these compositions can be mesh and the dissolvable hydrogel layer can provide for formulated to treat, Seal, and/or adhere various tissues, for improved strength, which can be desirable when the area of example, but not limited to, dura mater, cardiovascular tissue repair is large. Such as a tissue plane or a hernie repair. tissue, ducts, bladders, lung tissue, liver, other parenchymal 0152 Meshes to be used in combination with the dis organs, bones, skeletal muscles, skin, as well as Soft tissues. solvable hydrogel layer include, but are not limited to, In some embodiments, these compositions can be formu commercially available products. Examples of films and lated to treat patients suffering from a variety of internal or meshes include INTERCEED (Johnson & Johnson, Inc.), topical conditions, including, but not limited to, lacerations, PRECLUDE (W.L. Gore), and POLYACTIVE (poly(ether tears, wounds, ulcers, astamoses, and Surgical procedures. In ester) multiblock copolymers (Osteotech, Inc., Shrewsbury, Some embodiments, the compositions can be formulated for N.J.), based on poly(ethylene glycol) and poly(butylene use in any indication or application where a Suture or staple terephthalate), and SURGICAL absorbable hemostat gauze is being used. In some embodiments, the dissolvable hydro like sheet from Johnson & Johnson. Another mesh is a gel composition can be formulated to form a sealant and/or prosthetic polypropylene mesh with a bioresorbable coating glue for use where the site of the wound is not easily called SEPR AMESH Biosurgical Composite (Genzyme accessible or where sutureless Surgery is desired, including, Corporation, Cambridge, Mass.). One side of the mesh is e.g., but not limited to urinary tract Surgery (e.g., neph coated with a bioresorbable layer of sodium hyaluronate and rotomy closure, urethral repair, hypospadia repair), pulmo carboxymethylcellulose, providing a temporary physical nary Surgery (e.g., sealing parenchymal & bronchial leaks, barrier that separates the underlying tissue and organ Sur bronchopleural fistula repair, persistent air leak repairs), faces from the mesh. The other side of the mesh is uncoated, gastrointestinal tract and stomach Surgery (e.g., parotid allowing for complete tissue ingrowth similar to bare poly cutaneous fistula, tracheo-oesophageal fistula, peptic ulcer propylene mesh. In one embodiment, the fibrosis-inducing repair), joint Surgery (e.g., cartilage repair, meniscal repair), agent may be applied only to the uncoated side of SEP heart Surgery (e.g., cardiac ventricular rupture repair), brain RAMESH and not to the sodium hyaluronate/carboxymeth Surgery (e.g., dural defect repairs), ear Surgery (e.g., ear ylcellulose coated side. Other films and meshes include: (a) drum perforation), and post-Surgical drainage reduction BARD MARLEX mesh (C.R. Bard, Inc.), which is a very (e.g., mastectomy, axillary dissection). The ease of applica dense knitted fabric structure with low porosity; (b) mono tion, as well as the ability to quickly form a gel to seal a wet filament polypropylene mesh such as PROLENE available or dry wound, and the ability to dissolve upon addition of a from Ethicon, Inc. Somerville, N.J. (sec, e.g., U.S. Pat. Nos. thiolate compound, if needed, to release the hydrogel com 5,634,931 and 5,824,082)); (c) SURGISIS GOLD and SUR position at a later time point from the wound can provide GISIS IHM soft tissue graft (both from Cook Surgical, Inc.) better management of a wound (e.g., delicate tissue) without which are devices specifically configured for use to reinforce any further unnecessary tissue damage and can thus promote Soft tissue in repair of inguinal hernias in open and laparo wound healing. scopic procedures; (d) thin walled polypropylene Surgical 0.155. In some embodiments, the dissolvable hydrogel meshes such as are available from Atrium Medical Corpo composition can be formulated to form a cell construct or ration (Hudson, N.H.) under the trade names PROLITE, scaffold or matrix or gel, e.g., for organ/tissue repair or PROLITE ULTRA, and LITEMESH; (e) COMPOSIX her replacement. In these embodiments, the dissolvable hydro nia mesh (C.R. Bard, Murray Hill, N.J.), which incorporates gel composition can further comprise cells. The cells can be US 2016/02877.45 A1 Oct. 6, 2016 30 incorporated into the dissolvable hydrogel layer and/or form a long or a short-term implantable medical device. In additional layers such as additional hydrogel layer(s) and/or Some embodiments, the composition can further comprise a polymer matrices, if any. biologically and/or pharmaceutically active agent described 0156 By way of example only, islets of Langerhans (the herein (e.g., but not limited to, drugs, peptides, nucleic acids, insulin producing cells of the pancreas) can be embedded in and small molecules) sufficient for effective site-specific or the dissolvable hydrogel and/or the dissolvable hydrogel systemic drug delivery (Gutowska et al., J. Biomater. Res., composition, which can then be transplanted into a subject 29, 811-21 (1995) and Hoffman, J. Controlled Release, 6, to regulate blood Sugar level in a diabetic Subject. Accord 297-305 (1987)). The biologically and/or pharmaceutically ingly, microencapsulation of tissue-specific cells into the active agents can be physically mixed, embedded in, dis dissolvable hydrogel and/or the dissolvable hydrogel com persed in, covalently attached, or adhered to the hydrogel position can be used to treat a number of disease states, e.g., matrix and/or the crosslinkable polymers that form the due to cell dysfunction, including, but not limited to, Par hydrogel matrix by covalent interaction (e.g., but not limited kinson's disease (e.g., L-dopamine cells), liver disease (e.g., to, hydrogen bonds) or non-covalent interaction (e.g., van hepatocyte cells), and diabetes (e.g., islets of Langerhans). der Waals interaction, electrostatic interaction, physical 0157 Additional examples of cells that can be incorpo adsorption, and/or physical entrapment). When biologically rated in the dissolvable hydrogel composition include but and/or pharmaceutically active agent(s) described herein is are not limited to hepatocytes and bile duct cells, islet cells attached to the hydrogel matrix and/or the crosslinkable of the pancreas, parathyroid cells, thyroid cells, cells of the polymers that form the hydrogel matrix by covalent bonds, adrenal-hypothalmic-pituitary axis including hormone-pro Sustained release of the active agent can be provided by ducing gonadal cells, epithelial cells, nerve cells, heart means of hydrolysis of the covalent bond between the active muscle cells, blood vessel cells, lymphatic vessel cells, agent and the polymer backbone as well as by the site of the kidney cells, and intestinal cells, cells forming bone and active agent in the hydrogel structure (e.g., interior VS. cartilage, Smooth and skeletal muscle. Besides these types of exterior). In some embodiments, the pendent groups on the cells, stem cells and/or derived stem cells (e.g., induced hydrogel structure can be pH sensitive such as carboxylic pluripotent stem cells) can also be used in the dissolvable acid groups which further controls the pH dependent disso hydrogel composition. For example, stem cells and/or lution rate. derived stem cells can be incorporated in the dissolvable 0160. In some embodiments of various aspects described hydrogel composition and be Subsequently converted to a herein, the dissolvable hydrogels (or the dissolvable hydro desired specific cell type according to methods known in the gel layers) as described herein can be used with vacuum art. The cells can be obtained from a patient’s body (autolo assisted closure. Vacuum assisted closure (also known as gous cells), from a donor (allogeneic cells) and/or from vacuum therapy, vacuum sealing or negative pressure established cell lines. wound therapy) generally employs vacuum assisted drain 0158. In some embodiments, the dissolvable hydrogel age to remove blood and/or serous fluid from a wound, burn composition can be formulated to form temporary scaffold area or operation site. This technique can promote healing in ing, e.g., for cellular growth (e.g., in vitro, in Vivo, and in acute or chronic wound and/or burns. See, e.g., Xie et al. situ) and implantation. The dissolvable hydrogel composi “The clinical effectiveness of negative pressure would tion or the dissolvable hydrogel can be formed prior to therapy: a systematic review,” Journal of Wound Care implantation or in situ by crosslinking the crosslinkable (2010) Vol. 19 (11): 490-495. polymers. The dissolvable hydrogel composition or the 0.161 Accordingly, in some embodiments, the dissolv dissolvable hydrogel can adhere to the tissue after implan able hydrogel compositions described herein can further tation, thus preventing the dissolvable hydrogel composition comprise a film for covering the dissolvable hydrogel or or the dissolvable hydrogel from moving away from the dissolvable hydrogel layer described herein, and a drainage implanted site over time and allowing cells to adhere to the tube connected to an opening of the film such that blood or hydrogel for cellular growth and/or tissue regeneration. The fluid exudate from a wound can be removed via the drainage dissolvable hydrogel or the dissolvable hydrogel composi tube in the presence of vacuum or Sub-atmospheric pressure. tion as a temporary scaffolding can then be dissolved by The film can provide a sealing to tissue Surrounding a wound addition of a thiolate compound at an appropriate time, e.g., and thus allow Sub-atmospheric pressure to be applied to a after there is sufficient cellular growth within the hydrogel local wound environment. and/or tissue integration with the dissolvable hydrogel com 0162 The vacuum or sub-atmospheric pressure can be position or the dissolvable hydrogel. In some embodiments, applied to a wound, burn area, or operation site continuously the dissolvable hydrogel composition can further comprise a or intermittently, depending on the type of wound or burn bioactive agent described herein, e.g., but not limited to being treated. The vacuum or Sub-atmospheric pressure can angiogenesis-inducing factors (e.g., vascular endothelial be created using any art-recognized device or apparatus, growth factors) and/or differentiation factors, to enhance including, e.g., wall Suction apparatus, Surgical Vacuum vascularization and/or differentiation of the growing cell bottles, and/or any commercial systems designed for mass following implantation. vacuum assisted closure. In some embodiments, such device 0159. In some embodiments, the crosslinkable polymers or apparatus can provide controlled levels of continuous or used to form the dissolvable hydrogel described herein can intermittent Sub-atmospheric pressure ranging from about have pendent heteroatom and/or functional groups (e.g., but 25 mmHg to about 400 mmHg or from about 25 mmHg to not limited to amine, carboxylic acid) that allow control of 200 mmHg. physical properties, derivatization of the polymers with at 0163. In some embodiments, the vacuum device or appa least one bioactive agent, e.g., but not limited to a drug, ratus can comprise a vacuum generator and optionally a and/or alteration of the biodegradability of the polymers. In container to collect blood or fluid exudate from a wound. Some embodiments, a dissolvable hydrogel composition can The vacuum device or apparatus can be designed to Suit the US 2016/02877.45 A1 Oct. 6, 2016

needs of different situations (e.g., but not limited to hospital from one or both of the first crosslinkable polymers and the setting, home use, and/or during transportation in an ambu second crosslinkable polymers that comprise a thioester lance). linkage or functional group in their molecular structure. In Applications of the Dissolvable Hydrogels and/or Dissolv these embodiments, the first crosslinkable polymers and/or able Hydrogel Compositions Described Herein and Methods the second crosslinkable polymers can be covalently linked of Uses together via any art-recognized chemical reactions, includ 0164. The dissolvable hydrogels, dissolvable hydrogel ing, e.g., but not limited to an amine-ester reaction. compositions, and/or kits described herein can be used in any biomedical applications where adherence of the hydro 0167. In another aspect, the method comprises (a) con gels to a surface (e.g., a tissue surface, a wound Surface, tacting a wound in a subject with a hydrogel composition and/or a non-biological Surface) followed by a Subsequent comprising a dissolvable hydrogel layer, wherein the dis release of the hydrogel from the surface is desirable. Where Solvable hydrogel layer comprises linear, branched, and/or the Surface is a delicate Surface, e.g., a tissue Surface or a dendritic crosslinkable polymers held together by thioester wound Surface, release or removal of an adhesive hydrogel linkages formed between the first crosslinkable polymer and from the Surface by a physical force, e.g., mechanical the second crosslinkable polymer, and (b) allowing the debridement and/or Surgical incision can be undesirable, as dissolvable hydrogel layer to adhere to tissue Surrounding it can potentially create undesirable damage and/or trauma the wound. In some embodiments, the method further com to the Surface. In accordance with embodiments of various prises dissolving the dissolvable hydrogel layer by adding a aspects described herein, the dissolvable hydrogel described nucleophile, thereby releasing the hydrogel layer from the herein, while adhesive to a tissue surface, can be dissolved wound. In one embodiment, the nucleophile can comprise a by addition of a thiolate compound, thus releasing the thiolate compound or molecule. In some embodiments, the dissolvable hydrogel off the surface and allowing the surface first crosslinkable polymers and the second crosslinkable to be re-exposed. Exemplary applications that can be ben polymers do not necessarily possess thioester linkage or efited from the reversibility of the dissolvable hydrogel or functional group in their molecular structures. In these dissolvable hydrogel composition include, but are not lim embodiments, thioester linkages present within a dissolvable ited to, wound management, tissue and/or organ repair/ hydrogel can result or be formed from covalent interaction regeneration, temporary cell scaffolding, drug delivery, and/ between the first crosslinkable polymers and the second or any combinations thereof. crosslinkable polymers. For example, the thioester linkages (0165. As used herein, the phrase “reversibility of the present within a dissolvable hydrogel can result from react dissolvable hydrogel refers to ability of converting the ing a first crosslinkable polymer comprising at least two dissolvable hydrogel described herein to a solution or any thiols with a second crosslinkable polymer comprising flowable state by addition of a nucleophile, e.g., a thiolate crosslinking moieties (e.g., but not limited to N-Succinim compound. Without wishing to be bound by theory, conver idyl moiety and/or activated ester groups), wherein neither sion of the dissolvable hydrogel described herein to a of the crosslinkable polymers has any thioester bonds in flowable state or a solution is based on thioester-thiol their molecular structure. exchange reaction. However, the flowable state or the solu 0168 Without wishing to be bound by theory, a thioester tion docs not necessarily need to be able to re-form a thiol exchange between thioester linkages in the dissolvable hydrogel. For example, the thioester-thiol exchange reaction hydrogel layer and thiols in the thiolate compound leads to can prevent hydrogel re-formation after dissolving the dissolution of the dissolvable hydrogel layer. In some hydrogel to solution. embodiments, the thiol-thioester exchange can also result in 0166 In some embodiments, the dissolvable hydrogels, formation of an amide linkage, thereby preventing re-for dissolvable hydrogel compositions, and/or kits described mation of the first dissolvable hydrogel. herein can be used to improve wound management where existing dressings and/or sealants applied on a wound are 0169. In some embodiments, the hydrogel composition removed by physical force Such as mechanical debridement comprising the dissolvable hydrogel layer can be pre-formed and/or Surgical incision. Accordingly, methods for wound prior to contacting the wound. Upon the contact, the dis management in a Subject are also provided herein. In one Solvable hydrogel layer can adhere to the tissue surrounding aspect, the method comprises (a) contacting a wound in a the wound. Subject with a hydrogel composition comprising a dissolv 0170 In alternative embodiments, the dissolvable hydro able hydrogel layer, wherein the dissolvable hydrogel layer gel layer can form in situ between other components (e.g., comprises first linear, branched, and/or dendritic crosslink a sheet Support member, a protectant layer, a mesh) of a able polymers and second linear, branched, and/or dendritic hydrogel composition described herein and the wound, and crosslinkable polymers covalently held together, wherein adhere to the tissue surrounding the wound, thus attaching the first crosslinkable polymers and/or the second crosslink the other components of the hydrogel composition to the able polymers comprise at least one thioester linkage or wound. In these embodiments, the method can further functional group in their molecular structures; and (b) allow comprise forming a dissolvable hydrogel layer between ing the dissolvable hydrogel layer to adhere to tissue Sur other components of a hydrogel composition described rounding the wound. In some embodiments, the method herein and the wound by contacting the wound and the other further comprises dissolving the dissolvable hydrogel layer components of the hydrogel composition with a solution or by adding a nucleophile, thereby releasing the hydrogel a spray comprising a first water-soluble crosslinkable poly layer from the wound. In one embodiment, the nucleophile mer and a second water-soluble crosslinkable polymer, can comprise a thiolate compound or molecule. In these wherein the first and the second crosslinkable polymers embodiments, at least Some of the thioester linkages present become covalently held together to form a thioester hydro within a dissolvable hydrogel network can be contributed gel. US 2016/02877.45 A1 Oct. 6, 2016 32

0171 In some embodiments, the first crosslinkable poly 0177. In another example where the hydrogel composi mers and/or the second crosslinkable polymers can comprise tion comprises a bioactive agent for treatment of a wound, at least one thioester linkage or functional group in their the dissolvable hydrogel layer can be dissolved whenever molecular structures. replenishment of the bioactive agent in the hydrogel com 0172. In some embodiments, the first crosslinkable poly position or administration of a different bioactive agent is mers and the second crosslinkable polymers become held required. Accordingly, in Some embodiments, the method together by thioester linkages formed between the first can further comprise contacting the exposed wound, upon crosslinkable polymer and the second crosslinkable poly release or removal of the prior hydrogel composition from mer. In these embodiments, the first crosslinkable polymers the wound, to another hydrogel composition comprising the and the second crosslinkable polymers do not necessarily same bioactive agent or a different bioactive agent. possess thioester linkage or functional group in their 0178. In other embodiments, the dissolvable hydrogel molecular structures. In these embodiments, thioester link layer can be remained on the wound until the wound stops ages present within a dissolvable hydrogel can result or be bleeding and/or is completely healed before the dissolvable formed from covalent interaction between the nucleophilic hydrogel layer is dissolved. moieties of the first crosslinkable polymers and the cross linking moieties of the second crosslinkable polymers. For 0179 Accordingly, the time duration between the step of example, the thioester linkages present within a dissolvable contacting the wound with a hydrogel composition and the hydrogel can result from reacting a first crosslinkable poly step of dissolving the dissolvable hydrogel layer to release mer comprising at least two thiols with a second crosslink the hydrogel composition from the wound can vary, for able polymer comprising crosslinking moieties (e.g., but not example, from about 30 minutes to about weeks or months. limited to N-succinimidyl moiety and/or activated ester In Some embodiments, the time duration can vary from groups). about one hour to about one month, from about three hours 0173. In various aspects described herein, the dissolvable to about two weeks, from about six hours to about one week, hydrogel layer described herein can form and adhere to the from about 12 hours to about four days, or from about 24 tissue Surrounding the wound within seconds to minutes, hours to about three days e.g., within about one second to 60 minutes, within about 0180. As used herein, the term “dissolving refers to one second to about 30 minutes, within about one second to converting the dissolvable hydrogel layer to a liquid state, a about 15 minutes, within about one second to about 10 solution or any flowable state. The term “flowable state' as minutes, or within about one second to about five minutes. used herein refers to a state of a material having a consis 0.174 While not necessary, in some embodiments, the tency or viscosity that permits the material to flow, e.g., with hydrogel composition can further comprise a degradable or the aid of a gentle wash or rinse. In some embodiments, the non-degradable mesh, as discussed earlier, to be used in dissolvable hydrogel layer is dissolved by addition of a combination with the dissolvable hydrogel to provide addi thiolate compound to form a solution. tional adhesion to a tissue site. Further, the combination of 0181. In some embodiments of various aspects described the mesh and the dissolvable hydrogel layer can provide for herein, the dissolvable hydrogels (or the dissolvable hydro improved strength, which can be desirable when the area of gel layers) as described herein can be used with vacuum tissue repair is large. Such as a tissue plane or a hernie repair. assisted closure as described earlier. For example, a dissolv 0.175. In some embodiments, the dissolvable hydrogel able hydrogel (or dissolvable hydrogel layer) described and/or the hydrogel composition comprising a dissolvable herein can be applied to a wound, where the dissolvable hydrogel layer described herein can be used, for example as hydrogel (or dissolvable hydrogel layer) can then be covered a sealant, along with Suture or staples to further close or with a film to which a vacuum hose is connected. Accord secure a wound. When used in this manner, the sealant can ingly, in Some embodiments of various aspects described provide a leak tight barrier for liquids or air. herein, the method can further comprise applying vacuum or 0176 The dissolvable hydrogel layer of the hydrogel providing a sub-atmospheric pressure to the wound, after the composition can be dissolved at any appropriate time (e.g., dissolvable hydrogel layer has adhered to the tissue sur determined by a skilled practitioner Such as a physician or rounding the wound. In some embodiments, the method can Surgeon) after it is adhered to the tissue Surrounding the further comprise, prior to application of vacuum to the wound. By way of example only, in Some embodiments, the wound, covering the dissolvable hydrogel (or dissolvable wound can be contacted with the hydrogel composition, e.g., hydrogel layer) with a film or a thin material, to which a to stop the bleeding, and/or provide temporary treatment of drainage tube is connected. The film can provide a sealing to the wound, where immediate medical attention is not easily tissue Surrounding a wound and thus allow Sub-atmospheric accessible such as in a military field, in the wild, in a rural pressure to be applied to a local wound environment. area, at home, and/or during transportation. In these embodi 0182. The vacuum or sub-atmospheric pressure can be ments, the dissolvable hydrogel layer can be remained on the applied to a wound, burn area, or operation site continuously wound until the Subject gains access to more definitive or intermittently, depending on the type of wound or burn medical care and/or treatment, e.g., in a clinic or hospital. being treated. The vacuum or Sub-atmospheric pressure can Then, the medical practitioner can dissolve the dissolvable be created using any art-recognized device or apparatus, hydrogel layer by addition of a thiolate compound, thereby including, e.g., wall Suction apparatus, Surgical Vacuum releasing the hydrogel composition from the wound, for bottles, and/or any commercial systems designed for example, for examination and/or treatment. Accordingly, in vacuum assisted closure. In some embodiments, such device Some embodiments, the method can further comprise Sub or apparatus can provide controlled levels of continuous or jecting the re-exposed wound, upon release of the hydrogel intermittent Sub-atmospheric pressure ranging from about composition from the wound, to a treatment and/or exami 25 mmHg to about 400 mmHg or from about 25 mmHg to nation. 200 mmHg. US 2016/02877.45 A1 Oct. 6, 2016

0183. When it is desired to remove the dissolvable hydro buffered solution. When the thiolate compound is applied to gel composition from the wound (e.g., when it is time to the dissolvable hydrogel layer adhered to a biological tissue, change the wound dressing or bandage, or for examination the pH of the aqueous buffered solution is desired to be and/or treatment), the vacuum or Sub-atmospheric pressure maintained at a physiological pH, e.g., between pH ~6 and applied to the wound can be turned off. A nucleophile pH -8. described herein (e.g., a thiolate compound or molecule) can 0187. Without wishing to be bound by theory, addition of be applied to the dissolvable hydrogel (e.g., by injection) to the thiolate compound to the dissolvable hydrogel layer dissolve the hydrogel, which can then be removed from the results in a thioester-thiol exchange (or used interchangeably wound using vacuum. The film or thin material, if present, herein with the term “thiol-thioester exchange'). Thiol can be also removed. Alternatively, the film or thin material thioester exchange in water, where a thiol replaces a thiol in can be removed prior to adding a nucleophile (e.g., a thiolate a thioester, is known to occur readily in Solution with Small compound or molecule) to the dissolvable hydrogel adhered molecules. For example, adding an equivalent number of to the wound and subsequent removal of the dissolved free thiols to a solution of thioester Small molecules (e.g., hydrogel with a vacuum. Accordingly, in some embodiments thiol: thioester stoichiometric ratio is about 1:1) is sufficient of various aspects described herein, the method can further to lead to thiol-thioester exchange. However, thiol-thioester comprise, upon dissolving the dissolvable hydrogel or exchange in macromolecule assemblies, e.g., hydrogel sys hydrogel layer, removing at least the dissolved hydrogel tems, has not been explored. Surprisingly, thioester cross from the wound with vacuum. In some embodiments, blood, linked hydrogels (also termed “dissolvable hydrogels' fluid exudate, and/or particulates present on the wound described herein” are shown to be unexpectedly stable. As Surface can also be removed by vacuum during removal of shown in FIG. 7, when the equivalent number of thiols the dissolved hydrogel. In some embodiments, the vacuum added to a thioester hydrogel was four (based on the number assisted closure can be repeated. thioester linkages), there was almost no change in mechani 0184. A Thiolate Compound or Molecule: cal properties over a period of at least about 60 minutes. 0185. A thiolate compound or molecule for use to dis Thiol-thioester exchange reactions appeared to occur very Solve the dissolvable hydrogel layer can be a compound or slowly or insignificantly. That is, adding an equivalent molecule comprising a thiol group (-SH). In some embodi number of free thiols to a thioester crosslinked hydrogel is ments, the thiolate compound is a small molecule, e.g., less not sufficient to allow significant thiol-thioester exchange to than 1 kDa, less than 500 Da, less than 400 Da, less than 300 occur. Instead, the thioester crosslinked hydrogel is dis Da, less than 200 Da, less than 100 Da or lower. In some solved upon addition of an excess of free thiols (e.g., as embodiments, a thiolate compound is a water-soluble mac shown in FIG. 4). These combined data indicate that the romolecule greater than 500 Da. Examples of thiolate com thioester exchange reaction in a thioester crosslinked hydro pounds include, without limitations, linear, branched and/or gel is generally slow and unfavorable unless an excess of dendritic multi-thiol macromolecules, poly(ethyleneglycol) free thiols is used. Without wishing to be bound by theory, thiol, thiol-containing glycerol, thiol-containing polyglyc as the polymer chains are generally confined to an area via erol, thiol-containing polypeptides, cysteine, cystine, alkyl the crosslinked hydrogel, a conformational change or rear ester of cysteine, alkyl ester of cystine, MeSCH2SH, (R)/ rangement of polymer chains can become less favorable. (S)-3-methyl-3-sulfanylhexan-1-ol, Ethanethiol, 1-Propa 0188 Further, as shown in FIG. 4, the rate of hydrogel nethiol, 2-Propanethiol, Butanethiol, tert-Butyl mercaptan, dissolution can increase with concentration of the thiolate Pentanethiols. Thiophenol, Dimercaptosuccinic acid. Thio compound and/or the pH of the media in which the thiolate acetic acid, 5-mercapto-4H-1.2.4 triazol-3-ol, 2-mercap compound is dispersed. toacetamide, 2-Mercaptoethanol. 1.2-Ethanedithiol, Ammo 0189 Accordingly, the concentration of the thiolate com nium thioglycolate, CySteamine, Methyl thioglycolate, pound added can, in part, depend on the number of thioester Thiolactic acid, 1-Mercapto-2-propanol, 2-methoxy linkages present in the dissolvable hydrogel layer, pH of the ethanethiol, 3-Mercapto-1-propanol. 2,3-Dimercapto-1-pro media in which the thiolate compound is dispersed, and/or panol. 1-Thioglycerol, Mercaptosuccinic acid, 4-ethyl-5- a desirable rate of hydrogel dissolution. To provide excess mercapto-4H-1,2,4-triazol-3-ol, N-Carbamoyl-L-cysteine, thiols relative to available thioester linkages, the stoichio 2-Methyl-3-sulfanylpropanoic acid, 4-mercaptobutyric acid, metric ratio (e.g., mole ratio) of the total thiol groups added N-Acetylcysteamine, 3-Methyl-1-butanethiol, 1.5-Pentan to the total thioester linkages present in the dissolvable edithiol, 4-Chlorothiophenol, 4-Aminothiophenol, Benzyl hydrogel described herein should be greater than 1:1, greater mercaptan, 2-furanmethanethiol, 3-mercaptohexanol, furfu than 2:1, greater than 3:1, greater than 4:1, greater than 5:1, ryl thiol, derivatives thereof, a disulfide complex of one or greater than 10:1, greater than 20:1, greater than 25:1, more of the aforementioned compounds, and any combina greater than 50:1 or higher. In some embodiments, the tions thereof. In some embodiments, the thiolate compound thiolate compound is provided as a Saturated Solution. The is selected such that it is inert and does not react with the term "saturated solution' as used herein refers to a solution tissue, or cause any adverse or undesirable effect to the of the thiolate compound present in an amount that reaches tissue. In some embodiments, the thiolate compound also the point at which no more of the thiolate compound can be encompasses a mixture of thiolate compounds described dissolved in the Solution and any additional amounts will herein. appear as a separate phase. The method need not be limited 0186 The thiolate compound can be formulated in any to a fully saturated thiolate solution but can include a form to Suit the application format, e.g., but not limited to Substantially saturated or near Saturated thiolate solution or spraying and/or injection and/or bath. In some embodiments, concentrated thiolate solution. the thiolate compound can be formulated as a Solution, a 0190. As used herein, the term “wound” refers to physi spray, powder, or any combinations thereof. In one embodi cal disruption of the continuity or integrity of tissue structure ment, the thiolate compound is provided in an aqueous caused by a physical (e.g., mechanical) force, a biological US 2016/02877.45 A1 Oct. 6, 2016 34

(e.g., thermic or actinic force), or a chemical means. In one adhesion formation requires a second operative procedure to embodiment, the term “wound’ encompasses wounds of the remove adhesion, further complicating the treatment. Given skin. The term "wound also encompasses contused the wide-spread occurrence of post-Surgical adhesions, a wounds, as well as incised, stab, lacerated, open, penetrat number of approaches have been attempted for preventing ing, puncture, abrasions, grazes, burns, frostbites, corro adhesions (Stangel et al., “Formation and Prevention of sions, wounds caused by ripping, scratching, pressure, Postoperative Abdominal Adhesions”. The Journal of burns, and biting, and other types of wounds. In some Reproductive Medicine, Vol. 29, No. 3, March 1984 (pp. embodiments, the term "wound encompasses ulcerations 143-156), and diZerega, “The Cause and Prevention of (e.g., ulcers), or ulcers of the skin. In some embodiments, the PostSurgical Adhesions', published by Pregnancy Research term "wound also includes Surgical wounds. Branch, National Institute of Child Health and Human 0191 The wound can be acute or chronic. As used herein, Development, National Institutes of Health, Building 18, the term "chronic wound” refers to a wound that does not Room 101, Bethesda, Md. 20205.) fully heal even after a prolonged period of time (e.g., two to 0196. Exemplary approaches for prevention of post-sur three months or longer). Chronic wounds, including pressure gical adhesion include 1) systemic administration of ibu Sores, venous leg ulcers and diabetic foot ulcers, can simply profen (e.g., see Singer, U.S. Pat. No. 4.346,108), 2) paren be described as wounds that fail to heal. Whilst the exact teral administration of antihistamines, corticosteroids, and molecular pathogenesis of chronic wounds is not fully antibiotics, 3) intraperitoneal administration of dextran solu understood, it is acknowledged to be multi-factorial. As the tion and of polyvinylpyrrolidone solution, 4) systemic normal responses of resident and migratory cells during administration of oxyphenbutaZone, a non-steroidal anti acute injury become impaired, these wounds are character inflammatory drug that acts by inhibiting prostaglandin ized by a prolonged inflammatory response, defective production, and 5) administration of linear synthetic and wound extracellular matrix (ECM) remodeling and a failure natural polymers (Hubell 6060582: Fertil. Steril., 49:1066: of re-epithelialization. Steinleitner et al. (1991) “Poloxamer 407 as an Intraperito 0.192 The wound can be an internal wound, e.g. where neal Barrier Material for the Prevention of PostSurgical the external structural integrity of the skin is maintained, Adhesion Formation and Reformation in Rodent Models for Such as in bruising or internal ulceration, or external Reproductive Surgery.” Obstetrics and Gynecology, 77(1): wounds, particularly cutaneous wounds, and consequently 48 and Leach et al. (1990) “Reduction of postoperative the tissue can be any internal or external bodily tissue. In adhesions in the rat uterine horn model with poloxamer some embodiment the tissue is skin (such as human skin), 407, Am. J. Obstet. Gynecol., 162(5):1317. Linsky et al., i.e. the wound is a cutaneous wound. Such as a dermal or 1987 "Adhesion reduction in a rabbit uterine horn model epidermal wound. using TC-7. J. Reprod. Med., 32:17, Diamond et al., 1987 0193 Wounds can be classified in one of two general "Pathogenesis of adhesions formation/reformation: applica categories, partial thickness wounds or full thickness tions to reproductive surgery,” Microsurgery, 8:103). wounds. A partial thickness wound is limited to the epider 0.197 For example, formation of post-surgical adhesions mis and Superficial dermis with no damage to the dermal involving organs of the peritoneal cavity and the peritoneal blood vessels. A full thickness wound involves disruption of wall is undesirable result of abdominal surgery. This occurs the dermis and extends to deeper tissue layers, involving frequently and arises from Surgical trauma. During the disruption of the dermal blood vessels. The healing of the operation, serosanguinous (proteinaceous) exudate is partial thickness wound occurs by simple regeneration of released which tends to collect in the pelvic cavity (Holtz, epithelial tissue. Wound healing in full thickness wounds is G., 1984). If the exudate is not absorbed or lysed within a more complex. short period of time, it becomes ingrown with fibroblasts, 0194 In some embodiments, the wound is selected from with Subsequent collagen deposition occurs leading to adhe the group consisting of cuts and lacerations, Surgical inci S1O.S. sions or wounds, punctures, grazes, scratches, compression 0.198. In some embodiments, the method described herein wounds, abrasions, friction wounds (e.g. nappy rash, friction can be used to prevent formation of adhesions between blisters), decubitus ulcers (e.g. pressure or bed Sores), ther injured tissues by introducing a barrier comprising the mal effect wounds (burns from cold and heat sources, either dissolvable hydrogel and/or the hydrogel composition com directly or through conduction, convection, or radiation, and prising a dissolvable hydrogel layer described herein electrical sources), chemical wounds (e.g. acid or alkali between the injured tissues. This polymeric barrier can as a burns) or pathogenic infections (e.g. viral, bacterial or sheet or coating on the exposed injured tissue to prevent fungal) including open or intact boils, skin eruptions, blem surgical adhesions (Urry et al., Mat. Res. Soc. Symp. Proc. ishes and acne, ulcers, chronic wounds, (including diabetic 292, 253-64 (1993)). This polymeric barrier can be control associated wounds Such as lower leg and foot ulcers, venous lably dissolved over a time course by addition of an appro leg ulcers and pressure Sores), skin graft/transplant donor priate amount of a thiolate compound that allows for normal and recipient sites, immune response conditions, e.g. pso healing to occur without formation of adhesions/scars etc. riasis and eczema, stomach or intestinal ulcers, oral wounds, (0199. In some embodiments, the wound to be contacted including a ulcers of the mouth, damaged cartilage or bone, and/or treated by the hydrogel composition comprising a amputation wounds, corneal lesions, and any combinations dissolvable hydrogel layer described herein can include skin thereof. lacerations. Skin lacerations are tears in the skin produced 0.195 Adhesion formation is a major post-surgical com by accidents, trauma, or as a result of a Surgical procedure. plication. The incidence of clinically significant adhesion is Lacerations often require treatment in order to close the hole about 5 to 10 percent with some cases as high as 100 percent. in the skin, stop bleeding, and/or prevent infection. Depend Among the most common complications of adhesion for ing on degree of lacerations, different formats of the dis mation are obstruction, infertility, and pain. Occasionally, Solvable hydrogel compositions (e.g., bandage, glue, seal US 2016/02877.45 A1 Oct. 6, 2016

ant, and/or coating) can be used to treat skin lacerations. For dard suture procedures, the dissolvable hydrogels described example, minor lacerations in the skin can be treated using herein (e.g., in a form of tissue adhesive and/or glue) can be an adhesive hydrogel bandage to cover the wound. However, used to repair the wound. This type of treatment can be larger lacerations may require a dissolvable hydrogel glue to simple, quick and safe, and correspond to the requirement of help seal the wound. For example, a dissolvable hydrogel a quick restoration of the integrity of the globe to avoid composition in a form of glue can be used to treat lacerations further complications. deeper than 0.25 inches having a jagged edge or loose flap 0203 Besides an easy and fast application on the wound, of tissue. The location of the laceration can also affect the the criteria for an adhesive are to 1) bind to the tissue form of treatment. For example, it can be more desirable to (necrosed or not, very often wet) with an adequate adhesion treat a skin laceration on a joint using glue because adhesive force, 2) be non-toxic, 3) be biodegradable or resorbable, 4) bandage can tend to limit mobility of the joint. The use of be sterilizable and 5) not interfere with the healing process. glues to treat skin lacerations can also reduce the chance of Various alkyl-cyanoacrylates are available for the repair of scar formation. small perforations. However, the monomers of these “super 0200. In some embodiments, the wound to be contacted glues', in particular those with short alkyl chains, can be and/or treated by the hydrogel composition comprising a toxic. They also polymerize too quickly leading to applica dissolvable hydrogel layer described herein can include liver tions that might be difficult and, once polymerized, the lacerations. Lacerations of the liver can occur from trauma Surface of the glue is rough and hard which can result in or as a result of a Surgical procedure. The liver is a highly patient discomfort and a need to wear contact lens. Even vascularized organ and bleeds profusely when lacerated or though cyanoacrylate is tolerated as a corneal sealant, a traumatized. Liver lacerations are generally difficult to number of complications have been reported including cata repair owing to the nature of liver tissue. Liver tissue has ract formation, corneal infiltration, glaucoma, giant papillary very weak cohesive strength, and, consequently, Sutures and conjunctivitis, and symblepharon formation. Furthermore, Staples are not satisfactory because they may pull through in more than 60% of the patients, additional Surgical inter the liver tissue. The lack of satisfactory wound treatment vention was needed. methods for liver lacerations combined with the fact that it 0204 Other glues have also been developed, for example, is difficult to reach the veins that feed the liver renders liver adhesive hemostats, based on fibrin, being usually consti lacerations particularly serious. In fact, severe lacerations of tuted of fibrinogen, thrombin and factor XIII, as well as the liver often result in the patient’s death due to bleeding. systems with fibrinogen and photosensitizers activated with 0201 In some embodiments, the hydrogel composition light. However, autologous products (time consuming in an (e.g., in a form of a sealant) comprising a dissolvable emergency) or severe treatments of the non-autologous hydrogel described herein can be used in lung Surgery to products before clinical use are needed to avoid any con decrease or eliminate some of the problematic aspects of tamination to the patient. An ideal sealant for corneal lung Surgery. Such as treatment of pneumothorax and pull perforations should 1) not impair normal vision, 2) quickly monary leaks. Types of lung Surgery include, without limi restore the intraocular pressure, IOP, 3) maintain the struc tations, lobectomy, lung biopsy, lung-tissue removal, pneu tural integrity of the eye, 4) promote healing, 5) adhere to monectomy, thoracoscopy, and thoracotomy. Risks moist tissue surfaces, 6) possess Solute diffusion properties associated with lung Surgery include wound infection, post which are molecular weight dependent and favorable for Surgical internal bleeding, air leaks through the lung wall, normal cornea function, 7) possess rheological properties pain or numbness at the incision site, and inflammation of that allow for controlled placement of the polymer on the the lungs (pneumonia). Further, air leakage is frequently wound, and 8) polymerize under mild conditions. observed after thoracic procedures, such as pulmonary 0205. In some embodiments, the dissolvable hydrogel resection and decortication. The dissolvable hydrogel can be and/or the hydrogel composition comprising a dissolvable used as a sealant to create an air-tight seal so as to prevent hydrogel described herein can be used for sealing a retinal or reduce severe complications, such as bronchopleural hole. Existing techniques used for the treatment of retinal fistulas and/or infection resulting from extended chest tube holes such as cryotherapy, diathermy and photocoagulation drainage, extended recovery time, and/or postoperative mor are unsuccessful in the case of complicated retinal detach bidity related to pulmonary Surgery. ment, partly because of the delay in the application and/or 0202 In some embodiments, the dissolvable hydrogel the weak strength of the chorioretinal adhesion. Cyanoacry and/or the hydrogel composition comprising a dissolvable late retinopexy is previously discussed for use in special hydrogel described herein can be used for sealing cornea cases and shown that the chorioretinal adhesion can be perforation. Corneal perforations afflict a fraction of the stronger and last longer than the earlier techniques. As noted population and are produced by a variety of medical con previously with regard to corneal perforation treatment, the ditions (e.g., but not limited to, infection, inflammation, extremely rapid polymerization of cyanoacrylate glues (for Xerosis, neurotrophication, and/or degeneration) and/or trau example, risk of adhesion of the injector to the retina), the mas (e.g., but not limited to, chemical, thermal, Surgical, and difficulty to use them in aqueous conditions and the toxicity penetrating). Unfortunately, corneal perforations often lead are some of the inconvenience and/or risks associated with to loss of vision and a decrease in an individual’s quality of the method of using cyanoacrylate glues. While the polym life. Depending on the type and the origin of the perforation, erization can be slowed down by adding iophendylate to the different treatments are currently available from suturing the monomers, the reaction still occurs in two to three seconds. wound to a cornea graft. However, this is a difficult Surgical Risks of retinal tear at the edge of the treated hole can also procedure given the delicate composition of the cornea and be observed because of the hardness of cyanoacrylate once the severity of the wound, which increase the likelihood for polymerized. leakage and severe astigmatism after Surgery. In some 0206. In some embodiments, the dissolvable hydrogel embodiments where perforations cannot be treated by stan and/or the hydrogel composition comprising a dissolvable US 2016/02877.45 A1 Oct. 6, 2016 36 hydrogel described herein can be used for sealing a corneal ureter and bladder after surgical removal of his prostate transplant. In a corneal transplant the Surgeon usually makes gland. Failures can be caused by myriad factors, including approximately 16 Sutures around the transplant to secure the poor Surgical technique (e.g., Sutures that were not inserted new cornea in place. A sutureless procedure by using the correctly; and/or knots that were tied too tightly rendering dissolvable hydrogel and/or the hydrogel composition com the ends ischaemic). In some embodiments, use of the prising a dissolvable hydrogel described herein can be dissolvable hydrogel as sealants and/or methods of use desirable, as 1) sutures can provide a site for infection, 2) the described herein can decrease or eliminate some of the sutured cornea can take three months to heal before the causes of failed prostatectomy urethral-bladder anastomosis sutures need to be removed, and/or 3) the strain applied to procedures. the new corneatissue from the Sutures can distort the cornea. 0207. In some embodiments, the dissolvable hydrogel 0210. In some embodiments, the dissolvable hydrogel and/or the hydrogel composition comprising a dissolvable and/or the hydrogel composition comprising a dissolvable hydrogel described herein can be used in oculoplastics or hydrogel described herein can be used as sealants and/or oculoplastic Surgery. For example, blepharoplasty incisions tissue scaffold in the methods described herein to repair blepharoplasty is an operation to remove excess skin, fat and cartilage, meniscus and/or disk. Cartilaginous tissues play muscle from around the eyes to correct droopy eyelids and important roles in contributing to load Support and energy bagginess under the eyes. It can be performed on the upper dissipation in the joints of the musculoskeletal system. lids and lower lids, at the same time or separately. The These tissues include articular cartilage, which is predomi operation may be done using either conventional or laser nantly an avascular, and alympharic tissue with very low techniques. For Surgery on the upper eyelids, cuts are made cell-density. As a result, articular cartilage has limited capac into the natural lines and creases in the lid, and into the ity for self-repair following injury or aging. Degeneration of laughter lines at the corner of the eye. For Surgery on the cartilage in the meniscus, intervertebral disks, or joints can lower eyelids, a cut is usually made just below the eyelashes. lead to severe and debilitating pain in patients. Injuries to This means the Scars lull along the eye's natural folds, these tissues are often retained for many years and may concealing them as much as possible. Excess fat, muscle and eventually lead to more severe secondary damage. See loose skin are removed, and the cut is currently closed using Moskowitz, R. W., Osteoarthritis: diagnosis and medical/ Sutures. If only fat is being removed, sometimes the cut is Surgical management. 2nd ed., W.B. Saunders Company: made on the inside of the lower eyelid, leaving no visible 1984. Today, more than one million knee, hip, and shoulder scar. A dissolvable hydrogel described hereinformulated as joint Surgical procedures are performed annually in the a tissue adhesive can provide a means to secure the cuts United States as a consequence of trauma or a lifetime of made during Surgery. wear and tear. See Praemer, A.; Furner, S.; Rice, D. P. 0208. In some embodiments, the dissolvable hydrogel Musculoskeletal Conditions in the United States, American and/or the hydrogel composition comprising a dissolvable Academy of Orthopedic Surgeons: Rosemont, Ill., 1999. hydrogel described herein can be used as sealants using the Despite the large number of patients suffering from cartilage methods described herein in gastrointestinal anastomosis degeneration, the only existing treatment options for carti procedures. Gastrointestinal anastomosis is the technique of lage degeneration include chronic administration of anti joining two pieces of bowel together. There are many inflammatory agents, total joint replacement, osteotomy, techniques for gastro-intestinal anastomosis, including both and/or allograft transplantation, each of which leads to mechanical stapled techniques and hand-Sutured procedures. mixed long-term results. The technique may involve a simple end-end anastomosis of 0211. In some embodiments, the dissolvable hydrogel two pieces of jejunum, a more complex colo-anal anasto and/or the hydrogel composition comprising a dissolvable mosis, or a biliary enteric join. One of the problems with hydrogel described herein can be used as sealants and/or techniques employing Sutures or staples is that leakage may glues using the methods described herein in tissue plane occur around the Sutures or staples. See, for example, Bruce applications. For example, the dissolvable hydrogel and/or et al. Br. J. Surg. 88:1157-1168 (2001) reporting leakage the hydrogel composition comprising a dissolvable hydrogel rates of 5-8%. Accordingly, the dissolvable hydrogel as described herein can be applied between two planes of tissue sealants and methods of use described herein can be used to to seal them together. Over time the dissolvable hydrogel Supplement the Sutures or staples used in intestinal anasto can be controllably dissolved by addition of a thiolate moses, providing a better seal that can reduce leakage. The compound as new tissue grows into the area. Example consequences of a failed anastomosis are severe and fre applications include, but are not limited to, a number of quently life-threatening. Although failures can be caused by cosmetic and tissue restoration Surgeries. In some embodi myriad factors, including poor Surgical technique (e.g., ments, the dissolvable hydrogel and/or the hydrogel com sutures that were not inserted correctly, knots that were tied position comprising a dissolvable hydrogel described herein too tightly rendering the ends ischaemic, and/or incorrect can be used when the procedures involve significant tissue use of a staple gun), in Some embodiments, use of the plane separation that may result in formation of seroma with dissolvable hydrogel as sealants and/or methods of use associated complications. Such as infection, e.g., general described herein can decrease or eliminate some of the Surgery procedures, such as mastectomies and lumpecto causes of failed gastrointestinal anastomosis procedures. mies, and/or plastic Surgery procedures, such as abdomino 0209. In some embodiments, the dissolvable hydrogel plastys, rhytidectomy or rhinoplastys, mammaplasty and and/or the hydrogel composition comprising a dissolvable reconstruction, forehead lifts and buttocks lifts, as well as hydrogel described herein can be used as sealants using the skin grafts, biopsy closure, cleft-palate reconstruction, her methods described herein in prostatectomy urethral-bladder nia repair, lymph node resection, groin repair, Caesarean anastomosis procedures. Prostatectomy urethral-bladder section, laparoscopic trocar repair, vaginal tear repair, and anastomosis is the technique of joining together a patients hand Surgery. US 2016/02877.45 A1 Oct. 6, 2016 37

0212. Adhesion formation is a major post-Surgical com sentative procedures include, for example, coronary artery plication. The incidence of clinically significant adhesion is bypass grafts, coronary angioplasty, diagnostic cardia cath about 5 to 10 percent with some cases as high as 100 percent. eterization, carotid endarterectomy, and valve repair. An Among the most common complications of adhesion for additional use of the dissolvable hydrogel and/or the hydro mation are obstruction, infertility, and pain. Occasionally, gel composition comprising a dissolvable hydrogel adhesion formation requires a second operative procedure to described herein as sealants can include repair of cardiac remove adhesion, further complicating the treatment. Given tissue after a myocardial infarction. The dissolvable hydro the wide-spread occurrence of post-Surgical adhesions, a gel and/or the hydrogel composition comprising the dissolv number of approaches have been attempted for preventing able hydrogel described herein can be applied to the adhesions (Stangel et al., “Formation and Prevention of infarcted tissue to provide structural Support to the weak Postoperative Abdominal Adhesions”. The Journal of ened tissue. For example, the dissolvable hydrogel described Reproductive Medicine, Vol. 29, No. 3, March 1984 (pp. herein can act as a sleeve for the cardiac tissue. 143-156), and diZerega, “The Cause and Prevention of 0217. In some embodiments, the dissolvable hydrogel PostSurgical Adhesions', published by Pregnancy Research and/or the hydrogel composition comprising a dissolvable Branch, National Institute of Child Health and Human hydrogel described herein can be used as adhesive, coating, Development, National Institutes of Health, Building 18, sealants and/or glues using the methods described herein to Room 101, Bethesda, Md. 20205.) repair a dura tissue. Dura tissue is a fibrous membrane 0213 Exemplary approaches for prevention of post-sur covering the brain and the spinal cord and lining the inner gical adhesion include 1) systemic administration of ibu surface of the skull. Existing methods of dural repair involve profen (e.g., see Singer, U.S. Pat. No. 4.346,108), 2) paren the application of interrupted Sutures and the use of dural teral administration of antihistamines, corticosteroids, and replacement materials (duraplasty), which is a meticulous antibiotics, 3) intraperitoneal administration of dextran Solu Surgery and Suffers from the limitation that pinholes pro tion and of polyvinylpyrrolidone solution, 4) systemic duced by Surgical needles can cause leakage. Moreover, administration of oxyphenbutaZone, a non-steroidal anti intraoperative dehydration can shrink the dura creating a inflammatory drug that acts by inhibiting prostaglandin difficult closure since it is difficult to approximate the edges production, and 5) administration of linear synthetic and with sutures. In older patients, the dura can be often more natural polymers (Hubell 6060582: Fertil. Steril., 49:1066: Susceptible to tearing when stretched and/or Sutured because Steinleitner et al. (1991) “Poloxamer 407 as an Intraperito the dura can be thin and fragile. Adhesives such as fibrin neal Barrier Material for the Prevention of PostSurgical have been used for repair of dura tissue, but have had limited Adhesion Formation and Reformation in Rodent Models for success. See “Glue in the Repair of Dural Defects in Reproductive Surgery.” Obstetrics and Gynecology, 77(1): Craniofacial Resections. J. Latyngology and Otology 106: 48 and Leach et al. (1990) “Reduction of postoperative 356-57 (1992); Kjaergard et al., “Autologous Fibrin Glue adhesions in the rat uterine horn model with poloxamer Preparation and Clinical Use in Thoracic Surgery.” Eur. J. 407, Am. J. Obstet. Gynecol., 162(5):1317. Linsky et al., Cardio-Thorc. Surg. 6: 52-54 (1992); Thompson et al., 1987 "Adhesion reduction in a rabbit uterine horn model “Fibrin Glue: A Review of Its Preparation, Efficacy, and using TC-7. J. Reprod. Med., 32:17, Diamond et al., 1987 Adverse Effects as a Topical Hemostat, Drug Intelligence "Pathogenesis of adhesions formation/reformation: applica and Clinical Pharmacy 22: 946-52 (1988); and Brennan, tions to reproductive surgery, Microsurgery, 8:103). “Fibrin Glue.” Blood Reviews 5: 240-44 (1991). The dis 0214 For example, formation of post-Surgical adhesions Solvable hydrogels as sealants and methods of use described involving organs of the peritoneal cavity and the peritoneal herein can be used to repair the dura after a craniotomy or wall is undesirable result of abdominal surgery. This occurs laminectomy and/or prevent postoperative leakage of cere frequently and arises from Surgical trauma. During the brospinal fluid. See Preul et al. Neurosurgery 53:1189-1199 operation, serosanguinous (proteinaceous) exudate is (2003) and Balance, Calif. in Some Points in the Surgery of released which tends to collect in the pelvic cavity (Holtz, the Brain and Its Membranes. London, Macmillan & Co. G., 1984). If the exudate is not absorbed or lysed within a Injection Site Wound. short period of time, it becomes ingrown with fibroblasts, 0218. In some embodiments, the dissolvable hydrogel with Subsequent collagen deposition occurs leading to adhe and/or the hydrogel composition comprising a dissolvable S1O.S. hydrogel described herein can be used in the methods 0215. In some embodiments, the method described herein described herein to deliver a bioactive agent Such as growth can be used to prevent formation of adhesions between factor. For example, the dissolvable hydrogel and/or the injured tissues by introducing a barrier comprising the hydrogel composition comprising a dissolvable hydrogel dissolvable hydrogel and/or the hydrogel composition com described herein can comprise a bioactive agent described prising a dissolvable hydrogel layer described herein herein and be used as a patch to cover an infracted tissue in between the injured tissues. This polymeric barrier can as a a myocardial infarction to help reduce loss of tissue func sheet or coating on the exposed injured tissue to prevent tion. In some embodiments, the dissolvable hydrogel and/or Surgical adhesions, and can be controllably dissolved over a the hydrogel composition comprising a dissolvable hydrogel time course by gradual addition of an appropriate amount of described herein can be used for vascular applications where a thiolate compound that allows for normal healing to occur the dissolvable hydrogel and/or the hydrogel composition without formation of adhesions/scars etc. described herein can be loaded with site-specific angiogen 0216. In some embodiments, the dissolvable hydrogel esis factor(s), e.g., but not limited to, vascular endothelial and/or the hydrogel composition comprising a dissolvable growth factor, platelet derived growth factor, and/or other hydrogel described herein can be used as sealants and/or angiogenesis factors. The dissolvable hydrogel and/or the glues using the methods described herein to repair, close hydrogel composition used as a vascular graft/patch can be and/or secure vascular and/or cardiovascular tissue. Repre used to bypass, replace, and/or repair a part of the diseased/ US 2016/02877.45 A1 Oct. 6, 2016

dysfunctional blood vessel. In some embodiments, the dis are amenable for use in the pharmaceutical compositions of Solvable hydrogel and/or the hydrogel composition compris the dissolvable hydrogel described herein. Pharmaceutically ing a dissolvable hydrogel described herein can form an active agent include, but are not limited to, chemotherapeu implant comprising an angiogenesis antagonist, e.g., for tic agents, such as radiosensitizers, receptor inhibitors and inhibiting undesired angiogenesis in a specific site, such as agonists or other anti-neoplastic agents; immune modula tumor, cancer, retinopathy, or the like. tors, anti-inflammatory agents, and bioactive agents, such as 0219 Vascular endothelial growth factor is a secreted cytokines, growth factors, or steroids with or without the angiogenic mitogen whose target cell specificity appears to co-incorporation of tumor or pathogen antigens to increase be restricted to vascular endothelial cells. The resulting the anti-neoplastic response as a means of vaccine develop angiogenesis properties may also be induced using platelet ment; local anesthetic agents; antibiotics; or nucleic acids as derived growth factor, tissue treatment factor, and the like. a means of local gene therapy. The phrase “vascular endothelial growth factor” refers 0223) Accordingly, methods for site-specific or systemic broadly to all members of the vascular endothelial growth delivery of a bioactive agent are provided herein. For factor family, which may comprise polynucleotides, poly example, the method comprises: a) implanting at a target site peptides encoded by such polynucleotides that facilitate in the body of a patient in need thereof a dissolvable angiogenesis, and the like. U.S. Pat. No. 6,040,157 to Hu et hydrogel and/or a hydrogel composition comprising a dis al. (hereby incorporated by reference) discusses general solvable hydrogel layer described herein, wherein a thera characteristics and specific properties of vascular endothe peutically effective amount of a biologically or pharmaceu lial growth factor and is incorporated herein by reference. tically active agent is incorporated into the dissolvable Notably, VEGF has at least four different forms of 121, 165, hydrogel and/or the hydrogel composition; b) allowing the 189 and 206 amino acids due to alternative splicing, which dissolvable hydrogel layer to adhere to the target site; and c) are designated as VEGF121, VEGF165, VEGF189, and dissolving the dissolvable hydrogel layer by addition of a VEGF206, respectively. In some embodiments, the growth thiolate compound, thereby releasing the hydrogel compo factor can be added to the dissolvable hydrogel described sition from the target site. In some embodiments, the thiolate herein at the time of implantation. In some embodiments, the compound can be added by injection, e.g., via a syringe growth factors can be introduced into the tissue site, e.g., and/or catheter, and/or by spraying, e.g., on a skin Surface. vascular graft, followed by treatment with the dissolvable 0224. The dissolvable hydrogel and/or the hydrogel com hydrogel and/or composition described herein. position comprising a dissolvable hydrogel described herein 0220. The dissolvable hydrogel and/or the hydrogel com can also be used in cosmetic applications using the methods position comprising a dissolvable hydrogel described herein described herein. In some embodiments, the dissolvable can be utilized to diagnose disease, promote healing and/or hydrogel and/or compositions (e.g., adhesives) can be used prevent disease or disorder by targeting or concentrating a alone or in combination with a void filler, where the cross bioactive agent such as a drug to local and regional areas. linkable polymers can be injected under the skin to form the 0221. In some embodiments, the dissolvable hydrogel dissolvable hydrogel in situ. Alternatively, the dissolvable and/or the hydrogel composition comprising a dissolvable hydrogel and/or the hydrogel composition comprising a hydrogel described herein can also be used for a variety of dissolvable hydrogel described herein (e.g., adhesives) can applications including, but not limited to, production of be applied as a topical cosmetic or therapeutic composition, micro- and nanoparticles. Such materials can be used to used, e.g., in connection with creams, shampoos, Soaps, Sun repair an injured tissue, organ, bone, or genetic defect. Other screen, lotions to moisturize the tissue, and oils, for derma uses of the dissolvable hydrogel and/or composition tological purposes, cleansing, and the like. The dissolvable described herein provided herein include treatment of early, hydrogel and/or the hydrogel composition comprising a late or previously treated malignancies, pre-treatment of dissolvable hydrogel described herein (e.g., adhesives) can malignancies or other condition as a sensitizer to augment also be used with agents such as rapamycin or analogs e.g., therapy of another agent such as with radiation sensitizers, everolimus or blolimus, which can help minimize scaring avoidance of locoregional lymph node metastasis, augmen after plastic Surgery performed on the face, body, or other tation of local wound healing and decrease in infection, external skin area. manipulation of structure and abnormal scar formation, 0225. In some embodiments, the dissolvable hydrogel delivery of drugs, cytokines or Steroids-into, for example, and/or the hydrogel composition comprising a dissolvable joint capsules-insulin, glucagon, or genetically missing hydrogel layer described herein can be injected or placed in enzymes and for the treatment of post-operative pain. In one Vivo as a Void filling composition or used as a sealant/ embodiment, the dissolvable hydrogel and/or the hydrogel adhesive alone or in combination with natural polymers, composition comprising a dissolvable hydrogel described e.g., but not limited to, collagen, hyaluronic acid, gelatin, herein can be used to treat cancer. For example, the dissolv heparin, fibrin and/or heparin sulfate. Voids that can be filled able hydrogel and/or the hydrogel composition comprising a using the dissolvable hydrogel and/or composition described dissolvable hydrogel described herein can be used to treat herein include, without limitations, a nasal airway, or an various malignancies, e.g., but not limited to, lung, colon, organ of the gastro-intestinal track, for example, in order to prostate, pancreas, ovarian, sarcoma, mesothelioma, or arrest localized bleeding and/or promote healing following breast cancer at all stages. trauma, injury, or Surgery. 0222. The dissolvable hydrogel and/or the hydrogel com 0226. In some embodiments, the dissolvable hydrogel position comprising a dissolvable hydrogel described herein and/or the hydrogel composition comprising a dissolvable can be used to deliver any agent at a specific site. The agent hydrogel layer described herein can be used where the site can be in any pharmaceutically acceptable form of an agent, of the wound is not easily accessible or when sutureless including pharmaceutically acceptable salts. A large number Surgery is desired, e.g., but not limited to, in cardiovascular of pharmaceutically active agents are known in the art and Surgery, urinary tract Surgery (e.g., nephrotomy closure, US 2016/02877.45 A1 Oct. 6, 2016 39 urethral repair, hypospadia repair), pulmonary Surgery (e.g., eties. In some embodiments, the first crosslinkable polymer sealing parenchymal & bronchial leaks, bronchopleural fis can comprise thioester moieties. tula repair, persistent air leak repairs), gastrointestinal tract 0230. The first crosslinkable polymer and the second and stomach Surgery (e.g., parotid cutaneous fistula, tracheo crosslinkable polymer can each be independently formu oesophageal fistula, peptic ulcer repair), joint Surgery (e.g., lated in a form selected from the group consisting of a spray, cartilage repair, meniscal repair), heart Surgery (e.g., cardiac a foam, a gel, a solution, a powder, and any combinations Ventricular rupture repair), brain Surgery (e.g., dural defect thereof. repairs), ear Surgery (e.g., ear drum perforation), and post 0231. In some embodiments, the kit can further comprise Surgical drainage reduction (e.g., mastectomy, axillary dis at least one reagent. For example, a reagent can include a section) and alveolar osteitis (“dry socket’) and related reconstitution buffer if the components of the crosslinkable post-Surgical oral indications, and post-Surgical drainage polymers are provided as a powder. Additionally or alter reduction (mastectomy, axillary dissection). natively, a reagent can include an antiseptic agent, e.g., for 0227. In cardiovascular surgery, the dissolvable hydrogel cleaning a wound before treatment. and/or the hydrogel composition comprising a dissolvable 0232. In some embodiments, the at least two components hydrogel layer described herein can be used as sealants, for of the crosslinkable polymers can be provided in a dual example, for needle holes, Suture lines, diffuse and nonspe barrel Syringe. In these embodiments, the at least two cific bleeding, anastomotic bleeding, friable tissue bleeding, components of the crosslinkable polymers can be mixed aortic dissections, Ventricular ruptures, and fistulas. together by passing through a mixing tip, which can be releasably attached to the outlet of the dual-barrel syringe. Kits 0233. In some embodiments of the kits described herein, 0228 Kits, e.g., for use in the methods described herein the kit can further comprise a bioactive agent described or in any applications described herein are also provided. In herein. In some embodiments, the bioactive agent can be one aspect, a kit comprises a) at least one or a plurality of incorporated into the pre-formed dissolvable hydrogel (e.g., two or more) pre-formed dissolvable hydrogel com described herein or in at least one component of the cross position(s) described herein and b) a thiolate compound. linkable polymers. In other embodiments, the bioactive Thus, a user can directly apply the pre-formed dissolvable agent can be provided in a separate container. hydrogel composition to a target site (e.g., a wound). 0234. In some embodiments of the kits described herein, 0229. In another aspect, a kit comprises a) at least two the thiolate compound can be formulated in a form selected components of the crosslinkable polymers to be applied to a from the group consisting of a spray, a foam, a solution, a target site (e.g., a wound) to form a dissolvable hydrogel gel, a powder, and any combinations thereof. Non-limiting described herein in situ at the target site, wherein the examples of the thiolate compound can include linear, crosslinkable polymers are each at least about 200 Da or branched and/or dendritic multi-thiol macromolecules, poly higher (e.g., at least about 500 Da, at least about one kDa or ethylene glycol) thiol, thiol-containing glycerol, thiol-con higher), and b) a thiolate compound. In some embodiments, taining peptides, cysteine, cystine, alkyl ester of cysteine, at least two components of the crosslinkable polymers can alkyl ester of cystine, McSCH2SH, (R)/(S)-3-methyl-3- include a) a first water-soluble linear, branched, and/or sulfanylhexan-1-ol, Ethanethiol, 1-Propanethiol, 2-Propa dendritic crosslinkable polymer comprising at least two thiol nethiol, Butanethiol, tert-Butyl mercaptan, Pentanethiols, moieties, and b) a second water-soluble linear, branched, Thiophenol, Dimercaptosuccinic acid. Thioacetic acid, and/or dendritic crosslinkable polymer that can react with 5-mercapto-4H-1,2,4-triazol-3-ol, 2-mercaptoacetamide, the first crosslinkable polymer to form a dissolvable and 2-Mercaptoethanol. 1.2-Ethanedithiol, Ammonium thiogly adhesive hydrogel, wherein the second crosslinkable poly colate, Cysteamine, Methyl thioglycolate. Thiolactic acid, mer comprises at least two crosslinking moieties that are 1-Mercapto-2-propanol, 2-methoxyethanethiol. 3-Mer capable of tenting with the thiol moieties of the first cross capto-1-propanol. 2,3-Dimercapto-1-propanol, 1-Thioglyc linkable polymer to form thioester linkages between the first erol, Mercaptosuccinic acid, 4-ethyl-5-mercapto-4H-1,2,4- and the second crosslinkable polymers. In other embodi triazol-3-ol, N-Carbamoyl-L-cysteine, 2-Methyl-3- ments, at least two components of the crosslinkable poly Sulfanylpropanoic acid, 4-mercaptobutyric acid, mers can include a) a first water-soluble linear, branched, N-Acetylcysteamine, 3-Methyl-1-butanethiol, 1.5-Pentan and/or dendritic crosslinkable polymer comprising at least edithiol, 4-Chlorothiophenol, 4-Aminothiophenol, Benzyl two thioester moieties, and b) a second water-soluble linear, mercaptan, 2-Furanmethanethiol, 3-Mercaptohexanol, Fur branched, and/or dendritic crosslinkable polymer that can furyl thiol, derivatives thereof, a disulfide complex of one or react with the first crosslinkable polymer to form a dissolv more thereof, and any combinations thereof. able and adhesive thioester hydrogel, wherein the second 0235. In some embodiments of various aspects described crosslinkable polymer comprises at least two crosslinking herein, the kits can further comprise component(s) for moieties for crosslinking with the first crosslinkable poly performing vacuum assisted closure. Exemplary compo mer. In other embodiments, at least two components of the nents can include, but are not limited to a film or thin crosslinkable polymers can include a) a first water-soluble material (e.g., to seal the wound and create a Sub-atmo linear, branched and/or dendritic crosslinkable polymer that spheric pressure at the local wound environment), a drainage can react with the second crosslinkable polymer to form a tube that can be connected to a vacuum source or generator, dissolvable and adhesive thioester hydrogel, wherein the a vacuum device or apparatus, a container (e.g., to collect first crosslinkable polymer comprises at least two nucleop dissolved hydrogel, blood, fluid exudate and/or any other hilic moieties (e.g., but not limited to, thiol, alcohol, amine) particulates/materials present on the wound Surface), and for crosslinking with the second crosslinkable polymer, and any combinations thereof. b) a second water-soluble linear, branched and/or dendritic 0236. In addition to the above-mentioned components, crosslinkable polymer comprises at least two thioester moi the kit can include informational material. The informational US 2016/02877.45 A1 Oct. 6, 2016 40 material can be descriptive, instructional, marketing or other 0241 Examples of covalently crosslinked dissolvable material that relates to the methods described herein and/or hydrogels can be formed by reacting a crosslinkable poly the use/storage of the dissolvable hydrogel composition mer comprising activated esters (such as an N-hydroxysuc and/or components of the crosslinkable polymers. For cinimide) with another crosslinkable polymer comprising example, the informational material describes methods to thiols. Alternatively, covalently crosslinked dissolvable thio form a dissolvable hydrogel using the components of the ester hydrogels can be formed by reacting a crosslinkable crosslinkable polymers provided in the kit; and/or methods polymer comprising maleimide (MAL) moieties with thio to dissolve the dissolvable hydrogel. The kit can also include ester linkages within its structure, with another crosslinkable a delivery device. polymer comprising thiols. Another example of covalently 0237. In some embodiments, the informational material, crosslinked dissolvable thioester hydrogels can be formed e.g., instructions, is provided in printed matter, e.g., a printed by reacting a crosslinkable polymer comprising activated text, drawing, and/or photograph, e.g., a label or printed esters (such as an N-hydroxysuccinimide) with another sheet. However, the informational material can also be crosslinkable polymer comprising nucleophilic moieties provided in other formats, such as Braille, computer read with thioester linkages within its structure. Another example able material, video recording, or audio recording. In of covalently crosslinked dissolvable thioester hydrogels another embodiment, the informational material of the kit is can be formed by reacting a crosslinkable polymer compris a link or contact information, e.g., a physical address, email ing activated esters (such as an N-hydroxysuccinimide) with address, hyperlink, website, or telephone number, where a thioester linkages within its structure with another cross user of the kit can obtain substantive information about the linkable polymer comprising nucleophilic moieties (e.g., but formulation and/or its use in the methods described herein. not limited to, alcohol, amine). In some embodiments, the informational material can also Bioactive Agents, Biologically and/or Pharmaceutically be provided in any combination of formats. Active Agents that can be Used in the Dissolvable Hydrogel 0238. In some embodiments, the kit contains separate and/or Compositions Described Herein containers, dividers or compartments for the pre-formed 0242. In some embodiments, the dissolvable hydrogel dissolvable hydrogel or components of the crosslinkable and/or the composition comprising the dissolvable hydrogel polymers and informational material. For example, the pre (e.g., as a layer) can comprise at least one bioactive agent, formed dissolvable hydrogel or components of the cross including, e.g., at least two, at least three, at least four or linkable polymers can be contained in at least one bottle, more bioactive agents. In some embodiments, the bioactive vial, or syringe, and the informational material can be (s) can be incorporated into the dissolvable hydrogel contained in a plastic sleeve or packet. In other embodi described herein, and/or other additional layers, if any, ments, the separate elements of the kit are contained within present in the composition. The bioactive agent(s) can be a single, undivided container. For example, the pre-formed covalently conjugated to the polymeric structure of the dissolvable hydrogel or components of the crosslinkable hydrogel and/or physically entrapped within the hydrogel. polymers is contained in at least one bottle, vial or syringe 0243 In some embodiments, the bioactive agent(s) can that has attached thereto the informational material in the be incorporated into the dissolvable hydrogel described form of a label. herein, and/or other additional layers, if any, present in the 0239. In some embodiments, the kit includes a plurality, composition in an amount between about 0.01% and about e.g., a pack, of individual containers, each containing one or 80% by weight, or between about 1% and about 30%. One more units of the pre-formed dissolvable hydrogel or com of skill in the art can determine an appropriate loading ponents of the crosslinkable polymers. For example, the kit amount of active agent according to various applications and includes a plurality of Syringes, ampules, foil packets, or purposes. blister packs, each containing a single-use unit of the pre 0244. A “bioactive agent” refers to an agent that is formed dissolvable hydrogel or components of the cross capable of exerting a biological effect in vitro and/or in vivo. linkable polymers. The containers of the kits can be air tight The biological effect can be therapeutic in nature. As used and/or waterproof. herein, “bioactive agent” refers also to a substance that is used in connection with an application that is diagnostic in Exemplary Synthesis of Dissolvable Hydrogels Described nature. Such as in methods for diagnosing the presence or Herein absence of a disease in a patient. The bioactive agents can be 0240. To prepare a dissolvable hydrogel described herein, neutral or positively or negatively charged. Examples of linear, branched, and/or dendritic-like crosslinkable poly Suitable bioactive agents include pharmaceuticals and drugs, mers are crosslinked (e.g., by a covalent bond). For example, cells, gases and gaseous precursors (e.g., O2), Synthetic the linear, branched and/or dendritic polymers can be made organic molecules, proteins, enzymes, growth factors, Vita crosslinkable by chemical modification to have two or more mins, steroids, polyanions, nucleosides, nucleotides, poly functional groups that are capable of reacting with func nucleotides, nanoparticles, and diagnostic agents, such as tional groups present on other linear, branched and/or den contrast agents for use in connection with magnetic reso dritic crosslinkable polymers—in one embodiment, thiol nance imaging, ultrasound, positron emission tomography (—SH) groups on a first crosslinkable polymer and an (PET), X-ray computed tomography or other imaging N-hydroxysuccinimide (NHS) or other activated ester on a modalities. second crosslinkable polymer. Each functional group on a 0245 “Genetic material refers generally to nucleotides multifunctionally linear, branched and/or dendritic cross and polynucleotides, including, but not limited to, deoxyri linkable polymer is capable of covalently binding with bonucleic acid (DNA), any types of ribonucleic acid (RNA) another crosslinkable polymer, thereby effecting crosslink molecules (e.g., but not limited to, siRNA, mRNA, modified ing between the polymers and formation of the dissolvable RNA, or any combinations thereof), peptide nucleic acid hydrogel described herein. (PNA), and any combinations thereof. The genetic material US 2016/02877.45 A1 Oct. 6, 2016 can be made by Synthetic chemical methodology known to ciprofloxacin and norfloxacin; (13) tetracycline antibiotic one of ordinary skill in the art, or by the use of recombinant anti-infectives, including but not limited to doxycycline, technology, or by a combination of the two. The DNA and minocycline, and tetracycline; (14) antituberculosis antimy RNA can optionally comprise unnatural or synthetic nucleo cobacterial anti-infectives including but not limited to iso tides or analogs and can be single or double Stranded. niazid (INH), and rifampin; (15) antiprotozoal anti-infec "Genetic material' refers also to sense and anti-sense DNA tives, including but not limited to atovaquone and dapsone; and RNA, that is, a nucleotide sequence that is complemen (16) antimalarial antiprotozoal anti-infectives, including but tary to a specific sequence of nucleotides in DNA and/or not limited to chloroquine and pyrimethamine; (17) anti RNA. retroviral anti-infectives, including but not limited to rito 0246. Examples of bioactive agents for use in the dis navir and Zidovudine; (18) antiviral anti-infective agents, solvable hydrogel and/or compositions described herein including but not limited to acyclovir, ganciclovir, interferon include, without limitations, medicaments; vitamins; min alpha, and rimantadine; (19) alkylating antineoplastic eral Supplements; Substances used for the treatment, preven agents, including but not limited to carboplatin and cisplatin: tion, diagnosis, cure or mitigation of disease or illness; or (20) nitrosourea alkylating antineoplastic agents, including substances which attest the structure or function of the body; but not limited to carmustine (BCNU); (21) antimetabolite or pro-drugs, which become biologically active or more antineoplastic agents, including but not limited to metho active after they have been placed in a predetermined trexate; (22) pyrimidine analog antimetabolite antineoplastic physiological environment. In some embodiments, bioactive agents, including but not limited to fluorouracil (5-FU), agent(s) include, but are not limited to, growth factors. Such gemcitabine, or ceftazidine, aminoglycodi meroperium, or as members of the transforming growth factor (TGF) gene ticarcillin and tobramycin; (23) hormonal antineoplastics, family (e.g., TGF-31, TGF-B2, and TGF-B3), fibroblast including but not limited to goserelin, leuprolide, and growth factors (FGFs), platelet derived growth factors tamoxifen; (24) natural antineoplastics, including but not (PDGFs), epidermal growth factors (EGFs), connective tis limited to aldesleukin, interleukin-2, docetaxel, etoposide Sue activated peptides (CTAPs), osteogenic factors, bone (VP-16), interferon alpha, paclitaxel, and tretinoin (ATRA); morphogenetic proteins (for example, BMP-1, BMP-2, (25) antibiotic natural antineoplastics, including but not BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9); limited to bleomycin, actinomycin, daunorubicin, doxoru heparin-binding growth factors (for example, fibroblast bicin, and mitomycin; (26) Vinca alkaloid natural antine growth factor (FGF), epidermal growth factor (EGF), plate oplastics, including but not limited to vinblastine and Vin let-derived growth factor (PDGF), insulin-like growth factor cristine; (27) autonomic agents, including but not limited to (IGF)); Inhibins (for example, Inhibin A, Inhibin B); growth nicotine; (28) anticholinergic autonomic agents, including differentiating factors (for example, GDF-1); and Activins but not limited to benztropine and trihexyphenidyl: (29) (for example, Activin A, Activin B, Activin AB), vascular antimuscarinic anticholinergic autonomic agents, including endothelium growth factor (VEGF); hormones, e.g., but not but not limited to atropine and oxybutynin; (30) ergot limited to, insulin, glucagon, and estrogen; therapeutic alkaloid autonomic agents, including but not limited to agents or drugs, e.g., but not limited to wound-healing bromocriptine; (31) cholinergic agonist parasympathomi agents, anti-inflammatory steroids, and chemotherapeutics; metics, including but not limited to pilocarpine; (32) cho antimicrobial agents; an anesthetic; and biologically active linesterase inhibitor parasympathomimctics, including but analogs, fragments, and derivatives of Such growth factors; not limited to pyridostigmine; (33) alpha-blocker sympatho and any combinations thereof. lytics, including but not limited to praZosin; (34) beta 0247. In some embodiments, the bioactive agent(s) can blocker sympatholytics, including but not limited to be pharmaceutically active agent(s). Non-limiting examples atenolol; (35) adrenergic agonist sympathomimetics, includ of the pharmaceutically active agent(s) can include (1) ing but not limited to albuterol and dobutamine; (36) car nonsteroidal anti-inflammatory drugs (NSAIDs) analgesics, diovascular agents, including but not limited to aspirin including but not limited to diclofenac, ibuprofen, ketopro (ASA), plavix (Clopidogrel bisulfate) etc.; (37) beta-blocker fen, and naproxen; (2) opiate agonist analgesics, including antianginals, including but not limited to atenolol and pro but not limited to codeine, Vancomycin, ceftazidime, fenta pranolol; (38) calcium-channel blocker antianginals, includ nyl, hydromorphone, and morphine; (3) Salicylate analge ing but not limited to nifedipine and Verapamil: (39) nitrate sics, including but not limited to aspirin (ASA) (or enteric antianginals, including but not limited to isosorbide dinitrate coated ASA); (4) H1-blocker antihistamines, including but (ISDN); (40) cardiac glycoside antiarrhythmics, including not limited to clemastine and terfenadine; (5) H2-blocker but not limited to digoxin; (41) class I anti-arrhythmics, antihistamines, including but not limited to cimetidine, including but not limited to lidocaine, mexiletine, phenytoin, famotidine, nizadine, and ranitidine; (6) anti-infective procainamide, and quinidine; (42) class II antiarrhythmics, agents, including but not limited to mupirocin; (7) antian including but not limited to atenolol, metoprolol, propra aerobic anti-infectives, including but not limited to chloram nolol, and timolol; (43) class III antiarrhythmics, including phenicol metronidazole and clindamycin; (8) antifungal but not limited to amiodarone; (44) class TV antiarrhyth antibiotic anti-infectives, including but not limited to mics, including but not limited to diltiazem and Verapamil; amphotericin B, clotrimazole, fluconazole, and ketocon (45) alpha-blocker antihypertensives, including but not lim azole; (9) macrollide antibiotic anti-infectives, including but ited to praZosin; (46) angiotensin-converting enzyme inhibi not limited to azithromycin and erythromycin; (10) miscel tor (ACE inhibitor) antihypertensives, including but not laneous beta-lactam antibiotic anti-infectives, including but limited to captopril and enalapril; (47) beta blocker antihy not limited to aztreonam and imipenem; (11) penicillin pertensives, including but not limited to atenolol, meto antibiotic anti-infectives, including but not limited to naf prolol, nadolol, and propanolol; (48) calcium-channel cillin, oxacillin, penicillin G, and penicillin V; (12) qui blocker antihypertensive agents, including but not limited to nolone antibiotic anti-infectives, including but not limited to diltiazem and nifedipine; (49) central-acting adrenergic anti US 2016/02877.45 A1 Oct. 6, 2016 42 hypertensives, including but not limited to clonidine and not limited to desmopressin, goserelin, oxytocin, and vaso methyldopa; (50) diuretic antihypertensive agents, including pressin (ADH); (90) progestins, including but not limited to but not limited to amiloride, furosemide, hydrochlorothiaz medroxyprogesterone, norethindrone, and progesterone; ide (HCTZ), and spironolactone; (51) peripheral vasodilator (91)thyroid hormones, including but not limited to levothy antihypertensives, including but not limited to hydralazine roxine; (92) immunobiologic agents, including but not lim and minoxidil; (52) antilipemics, including but not limited to ited to interferon beta-1b and interferon gamma-1b; (93) gemfibrozil and probucol; (53) bile acid sequestrant anti immunoglobulins, including but not limited to immune lipemics, including but not limited to cholestyramine; (54) globulin IM, IMIG, IGIM and immune globulin IV, IVIG, HMG-CoA reductase inhibitor antilipemics, including but IGIV; (94) amide local anesthetics, including but not limited not limited to lovastatin and pravastatin; (55) inotropes, to lidocaine; (95) ester local anesthetics, including but not including but not limited to amrinone, dobutamine, and limited to benzocaine and procaine; (96) musculoskeletal dopamine; (56) cardiac glycoside inotropes, including but corticosteroid anti-inflammatory agents, including but not not limited to digoxin; (57) thrombolytic agents or enzymes, limited to beclomethasone, betamethasone, cortisone, dex including but not limited to alteplase (TPA), anistreplase, amethasone, hydrocortisone, and prednisone; (97) muscu streptokinase, and urokinase; (58) dermatological agents, loskeletal anti-inflammatory immunosuppressives, includ including but not limited to colchicine, isotretinoin, metho ing but not limited to azathioprine, cyclophosphamide, and trexate, minoxidil, tretinoin (ATRA); (59) dermatological methotrexate; (98) musculoskeletal nonsteroidal anti-in corticosteroid anti-inflammatory agents, including but not flammatory drugs (NSAIDs), including but not limited to limited to betamethasone and dexamethasone; (60) antifun diclofenac, ibuprofen, ketoprofen, ketorlac, and naproxen; gal topical antiinfectives, including but not limited to (99) skeletal muscle relaxants, including but not limited to amphotericin B, clotrimazole, miconazole, and nystatin: baclofen, cyclobenzaprine, and diazepam; (100) reverse (61) antiviral topical anti-infectives, including but not lim neuromuscular blocker skeletal muscle relaxants, including ited to acyclovir, (62) topical antineoplastics, including but but not limited to pyridostigmine; (101) neurological agents, not limited to fluorouracil (5-FU); (63) electrolytic and renal including but not limited to nimodipine, riluzole, tacrine and agents, including but not limited to lactulose; (64) loop ticlopidine; (102) anticonvulsants, including but not limited diuretics, including but not limited to furosemide: (65) to carbamazepine, gabapentin, lamotrigine, phenytoin, and potassium-sparing diuretics, including but not limited to valproic acid; (103) barbiturate anticonvulsants, including triamterene; (66) thiazide diuretics, including but not limited but not limited to phenobarbital and primidone; (104) ben to hydrochlorothiazide (HCTZ); (67) uricosuric agents, Zodiazepine anticonvulsants, including but not limited to including but not limited to probenecid; (68) enzymes clonazepam, diazepam, and lorazepam; (105) anti-parkiso including but not limited to RNase and DNase; (69) immu nian agents, including but not limited to bromocriptine, noSupressive agents, including but not limited to levodopa, carbidopa, and pergolide; (106) anti-vertigo cyclosporine, steroids, methotrexate, tacrolimus, Sirolimus, agents, including but not limited to meclizine; (107) opiate rapamycin; (70) antiemetics, including but not limited to agonists, including but not limited to codeine, fentanyl. prochlorperazine; (71) salicylate gastrointestinal anti-in hydromorphone, methadone, and morphine; (108) opiate flammatory agents, including but not limited to Sulfasala antagonists, including but not limited to naloxone; (109) Zine; (72) gastric acid-pump inhibitor anti-ulcer agents, beta-blocker anti-glaucoma agents, including but not limited including but not limited to omeprazole; (73) H2-blocker to timolol, (110) miotic anti-glaucoma agents, including but anti-ulcer agents, including but not limited to cimetidine, not limited to pilocarpine; (111) ophthalmic aminoglycoside famotidine, nizatidine, and ranitidine; (74) digestants, antiinfectives, including but not limited to gentamicin, neo including but not limited to pancrelipase; (75) prokinetic mycin, and tobramycin; (112) ophthalmic quinolone anti agents, including but not limited to erythromycin; (76) infectives, including but not limited to ciprofloxacin, nor opiate agonist intravenous anesthetics including but not floxacin, and ofloxacin; (113) ophthalmic corticosteroid limited to fentanyl; (77) hematopoietic antianemia agents, anti-inflammatory agents, including but not limited to dex including but not limited to erythropoietin, filgrastim amethasone and prednisolone; (114) ophthalmic nonsteroi (G-CSF), and sargramostim (GM-CSF); (78) coagulation dal anti-inflammatory drugs (NSAIDs), including but not agents, including but not limited to antihemophilic factors limited to diclofenac; (115) antipsychotics, including but not 1-10 (AHF 1-10); (79) anticoagulants, including but not limited to clozapine, haloperidol, and risperidone; (116) limited to warfarin, heparin (important for heparin bound benzodiazepine anxiolytics, sedatives and hypnotics, includ polymers and cardiopulmonary bypass pump circuits), arga ing but not limited to clonazepam, diazepam, lorazepam, troban each works by a different mechanism and is oxazepam, and prazepam; (117) psychoStimulants, includ metabolized differently: (80) growth receptor inhibitors, ing but not limited to methylphenidate and pemoline; (118) including but not limited to erlotinib and gefetinib; (82) antitussives, including but not limited to codeine; (119) abortifacients, including but not limited to methotrexate: bronchodilators, including but not limited to theophylline; (83) antidiabetic agents, including but not limited to insulin; (120) adrenergic agonist bronchodilators, including but not (84) oral contraceptives, including but not limited to estro limited to albuterol: (121) respiratory corticosteroid anti gen and progestin; (85) progestin contraceptives, including inflammatory agents, including but not limited to dexam but not limited to levonorgestrel and norgestrel; (86) estro ethasone; (122) antidotes, including but not limited to flu gens including but not limited to conjugated estrogens, mazenil and naloxone; (123) heavy metal antagonists/ diethylstilbestrol (DES), estrogen (estradiol, estrone, and chelating agents, including but not limited to penicillamine; estropipate); (87) fertility agents, including but not limited (124) deterrent Substance abuse agents, including but not to clomiphene, human chorionic gonadatropin (HCG), and limited to disulfiram, naltrexone, and nicotine; (125) with menotropins; (88) parathyroid agents including but not drawal Substance abuse agents, including but not limited to limited to calcitonin; (89) pituitary hormones, including but bromocriptine; (126) minerals, including but not limited to US 2016/02877.45 A1 Oct. 6, 2016 iron, calcium, and magnesium; (127) vitamin B compounds, Suppressants including but not limited to phenyl-propa including but not limited to cyanocobalamin (vitamin B12) nolamine hydrochloride or caffeine; (k) expectorants includ and niacin (vitamin B3); (128) vitamin C compounds, ing but not limited to guaifenesin; (1) antacids including but including but not limited to ascorbic acid; (129) vitamin D not limited to aluminum hydroxide and magnesium hydrox compounds, including but not limited to calcitriol: (130) ide; (m) biologicals including but not limited to peptides, antiparasitic compounds including but not limited to met polypeptides, proteins and amino acids, hormones, interfer ronidazole; (131) bronchodilators, including but not limited ons or cytokines, and other bioactive peptidic compounds, to salmeterol, and beta agonists; (132) leukotriene blockers/ including but not limited to interleukins 1-18 including modifiers including montelukast or zileuton; (133) inhaled mutants and analogues, RNase, DNase, luteinizing hormone steroids including but not limited to fluticaSone, beclom releasing hormone (LHRH) and analogues, gonadotropin ethasone, or budesonide. Anti-bleeding (hemostatic) agents releasing hormone (GnRH), transforming growth factor-. including but not limited to protamine and antihelminth, beta. (TGF-beta), fibroblast growth factor (FGF), tumor radiation sensitizers, and other drugs including but not necrosis factor-alpha & beta (TNF-alpha & beta), nerve limited to racin and cyclosporine are also included. Addi growth factor (NGF), growth hormone releasing factor tional anticancer drugs including but not limited to pycn (GHRF), epidermal growth factor (EGF), fibroblast growth idione as well as anti-Myc inhibitors. Nanoparticles can factor homologous factor (FGFHF), hepatocyte growth fac comprise silver or silver salts for antibacterial activity. tor (HGF), insulin growth factor (IGF), invasion inhibiting 0248. In addition to the foregoing, the following phar factor-2 (IIF-2), bone morphogenetic proteins 1-7 (BMP maceutically active agents can also be used in the dissolv 1-7), Somatostatin, thymosin-alpha-1, gamma-globulin, able hydrogels and/or compositions described herein, which superoxide dismutase (SOD), complement factors, hCH, include, but are not limited to, chlorhexidine; estradiol tPA, calcitonin, ANF, EPO and insulin; and (n) anti-infective cypionate in oil; estradiol Valerate in oil; flurbiprofen; flur agents including but not limited to antifungals, anti-bacte biprofen Sodium; ivermectin; levodopa, nafarelin; and rials (including, e.g., silver nanoparticles), anti-virals, anti Somatropin. Further, the following drugs can also be used: helminths, antiseptics and antibiotics. Additional agents pycnidione, cyclosporine, recombinant beta-glucan: bovine include hemoglobin, oxygen, nitric oxide, silver or other immunoglobulin concentrate; bovine Superoxide dismutase; noble metals or ions thereof (e.g., silver nanoparticles, rods, the formulation comprising fluorouracil, epinephrine, and crystals and other structures or silver salts). Additional bovine collagen; recombinant hirudin (r-Hir), HIV-1 immu agents include drugs that have renal toxicity and cardio nogen; human anti-TAC antibody; recombinant human toxicity, wherein the delivery with the particles assists in growth hormone (r-hGH); recombinant human hemoglobin reducing the renal or cardiotoxicity by delivering the drugs (r-Hb); recombinant human mecasermin (r-IGF-1); recom in a targeted manner to a tissue site other than kidneys or the binant interferon beta-1a; lenograstim (G-CSF); olanzapine; heart. recombinant thyroid stimulating hormone (r-TSH); and 0250 Examples of specific drugs that can be used topotecan. Further still, the following intravenous products include, but are not limited to asparaginase; bleomycin; can be used: acyclovir Sodium; aldesleukin; atenolol; bleo buSulfan; capecitabine; carboplatin: carmustine, chlorambu mycin Sulfate, human calcitonin; salmon calcitonin; carbo cil; cisplatin; cyclophosphamide; cytarabine; dacarbizine; platin; carmustine; dactinomycin, daunorubicin HCl, doc dactinomycin; daunorubicin; dexraZOxane; docetaxel, doxo etaxel; doxorubicin HCl; epoetin alfa: etoposide (VP-16); rubicin; erlotinibil/gefictinib: etoposide; floxuridine; fludara fluorouracil (5-FU); ganciclovir Sodium; gentamicin Sulfate; bine; fluoruracil; gemcitabine; 10-hydrocamptothecin, interferon alpha; leuprolide acetate; meperidine HCl; metha hydroxyurea; idarubicin; ifosfamide; irinotecan, lomustine; done HCl; methotrexate sodium; paclitaxel; ranitidine HCl; mechlorethamine; melphalan; mercaptopurine; methotrex vinblastin sulfate; and zidovudine (AZT). ate; mitomycin; mitotane; mitoxantrone; paclitaxel; pento 0249 Further examples of pharmaceutically active statin; plicamycin; pemextred procarbazine; rituximabe; agents from the above categories include: (a) anti-neoplas streptozocin, teniposid; thioguanine; thiotepa, vinplastine, tics including but not limited to androgen inhibitors, anti Vinchristine; and vinorelbineorderivates of these molecules. metabolites, cytotoxic agents, receptor inhibitors, and 0251 Examples of anticancer, antineoplastic agents are immunomodulators; (b) anti-tussives including but not lim camptothecins. These drugs are antineoplastic by virtue of ited to dextromethorphan, dextromethorphan hydrobromide, their ability to inhibit topoisomerase I. Camptothecin is a noscapine, carbetapentane citrate, and chlorphedianol plant alkaloid isolated from trees indigenous to China and hydrochloride; (c) antihistamines including but not limited analogs thereof including but not limited to 9-aminocamp to chlorpheniramine maleate, phenindamine tartrate, pyril tothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, amine maleate, doxylamine Succinate, and phenyltoloxam 10, 11-methylenedioxycamptothecin, 9-nitro 10, 11-methyl ine citrate; (d) decongestants including but not limited to enehydroxycamptothecin, 9-chloro-10, 11-methylenehy phenylephrine hydrochloride, phenylpropanolamine hydro droxycamptothecin, 9-amino-10, 11-methylenehydroxyca chloride, pseudophedrine hydrochloride, and ephedrine; (e) mptothecin, 7-ethyl-10-hydroxycamptothecin (SN-38), various alkaloids including but not limited to codeine phos topotecan, DX-8951, Lurtotecan (GII 147221C), and other phate, codeine Sulfate and morphine; (f) mineral Supple analogs (collectively referred to herein as camptothecin ments including but not limited to potassium chloride, Zinc drugs) are presently under study worldwide in research chloride, calcium carbonates, magnesium oxide, and other laboratories for treatment of colon, breast, and other cancers. alkali metal and alkaline earth metal salts; (g) ion exchange 0252) Additionally, the pharmaceutically active agent can resins including but not limited to cholestryramine: (h) be a radiosensitizer, including but not limited to metoclopr anti-arrhythmics including but not limited to N-acetylpro amide, sensamide or neusensamide (manufactured by Oxi cainamide: (i) antipyretics and analgesics including but not gene); profiromycin (made by Vion); RSR13 (made by limited to acetaminophen, aspirin and ibuprofen; (ii) appetite Allos); THYMITAQR (made by Agouron), etanidazole or US 2016/02877.45 A1 Oct. 6, 2016 44 lobenguane (manufactured by Nycomed); gadolinium tex ing but not limited to anthelmintics, antianaerobics, antibi aphrin (made by Pharmacyclics); BuldR/Broxine (made by otics, aminoglycoside antibiotics, antifungal antibiotics, NeoPharm); IPdR (made by Sparta); CR2412 (made by Cell cephalosporin antibiotics, macrollide antibiotics, miscella Therapeutic); L1X (made by Terrapin); agents that minimize neous beta-lactam antibiotics, penicillin antibiotics, qui hypoxia, and the like. The biologically active Substance can nolone antibiotics, Sulfonamide antibiotics, tetracycline anti be selected from the group consisting of peptides, polypep biotics, antimycobacterials, antituberculosis tides, proteins, amino acids, polysaccharides, growth fac antimycobacterials, antiprotozoals, antimalarial antiprotoZo tors, hormones, anti-angiogenesis factors, interferons or als, antiviral agents, anti-retroviral agents, scabicides, and cytokines, elements, and pro-drugs. In one embodiment, the biologically active Substance is a therapeutic drug or pro urinary anti-infectives; antineoplastic agents, including but drug, most preferably a drug selected from the group con not limited to alkylating agents, nitrogen mustardaklylating sisting of chemotherapeutic agents and other antineoplastics agents, nitrosourea alkylating agents, antimetabolites, including but not limited to paclitaxel, carboplatin and purine analog antimetabolites, pyrimidine analog antime cisplatin: nitrosourea alkylating antineoplastic agents, tabolites, hormonal antineoplastics, natural antineoplastics, including but not limited to carmustine (BCNU); fluorou antibiotic natural antineoplastics, and Vinca alkaloid natural racil (5-FU) and gemcitabine; hormonal antineoplastics, antineoplastics; autonomic agents, including but not limited including but not limited to goserelin, leuprolide, and to anticholinergics, antimuscarinic anticholinergics, ergot tamoxifen; receptor inhibitors including but not limited to alkaloids, parasympathomimetics, cholinergic agonist para erlotinib, gefetinib, Sunitinib, Imatinib, or anti-ckit inhibi sympathomimetics, cholinesterase inhibitor para-sympath tors (registered name is Gleevec); natural antineoplastics, omimetics, sympatholytics, alpha-blocker sympatholytics, including but not limited to aldesleukin, interleukin-2, doc beta-blocker sympatholytics, sympathomimetics, and adren etaxel, etoposide (VP-16), interferon alpha, paclitaxel, and ergic agonist sympathomimetics; cardiovascular agents, tretinoin (ATRA)carboplatin and cisplatin: nitrosourea alky including but not limited to antianginals, betablocker anti anginals, calcium-channel blocker antianginals, nitrate anti lating antineoplastic agents, including but not limited to anginals, antiarrhythmics, cardiac glycoside antiarrhyth carmustine (BCNU); fluorouracil (5-FU) and gemcitabine; mics, class I antiarrhythmics, class II antiarrhythmics, class hormonal antineoplastics, including but not limited to gos III antiarrhythmics, class N antiarrhythmics, antihyperten erelin, leuprolide, and tamoxifen; receptor inhibitors includ sive agents, alpha-blocker antihypertensives, angiotensin ing but not limited to erlotinib, gefetinib, Sunitinib, Ima converting enzyme inhibitor (ACE inhibitor) antihyperten tinib, or anti-ckit inhibitors (registered name is Gleevec); sives, beta-blocker antihypertensives, calcium-channel natural antineoplastics, including but not limited to aldesleu blocker antihypertensives, central-acting adrenergic antihy kin, interleukin-2, docetaxel, etoposide (VP-16), interferon pertensives, diuretic antihypertensive agents, peripheral alpha, paclitaxel, and tretinoin (ATRA), antibiotics, anti vasodilator antihypertensives, antilipemics, bile acid seques virals, antifungals, anesthetics, antihelminths, anti-inflam trant antilipemics, IIMG-CoA reductase inhibitor anti matories, and anticoagulants. lipemics, inotropes, cardiac glycoside inotropes, and throm 0253) In some embodiments, the bioactive agent(s) to be bolytic agents; dermatological agents, including but not delivered is dissolved in an aqueous Solution or in an limited to antihistamines, anti-inflammatory agents, corti aqueous solution containing another compound to increase costeroid anti-inflammatory agents, antipruritics/local anes the agent's solubility including but not limited to Cremaphor thetics, topical anti-infectives, antifungal topical anti-infec E/L for paclitaxel. tives, antiviral topical anti-infectives, and topical 0254 Non-limiting examples of additional pharmaceuti antineoplastics; electrolytic and renal agents, including but cally active agents include the following therapeutic catego not limited to acidifying agents, alkalinizing agents, diuret ries: anabolic agents, anesthetic agents, antacids, anti-asth ics, carbonic anhydrase inhibitor diuretics, loop diuretics, matic agents, anticholesterolemic and anti-lipid agents, anti osmotic diuretics, potassium-sparing diuretics, thiazide coagulants, anti-convulsants, anti-diarrheals, antiemetics, diuretics, electrolyte replacements, and uricoSuric agents; anti-infective agents, anti-inflammatory agents, anti-manic enzymes, including but not limited to pancreatic enzymes agents, anti-nauseants, antineoplastic agents, anti-obesity and thrombolytic enzymes; gastrointestinal agents, includ agents, anti-pyretic and analgesic agents, anti-spasmodic ing but not limited to antidiarrheals, antiemetics, gastroin agents, anti-thrombotic agents, anti-uricemic agents, anti testinal anti-inflammatory agents, salicylate gastrointestinal anginal agents, antihistamines, anti-tussives, appetite Sup anti-inflammatory agents, antacid anti-ulcer agents, gastric pressants, biologicals, cerebral dilators, coronary dilators, acid-pump inhibitor anti-ulcer agents, gastric mucosal anti decongestants, diuretics, diagnostic agents, erythropoietic ulcer agents, H2-blocker anti-ulcer agents, cholelitholytic agents, expectorants, gastrointestinal sedatives, hyperglyce agents, digestants, emetics, laxatives and stool softeners, and mic agents, hypnotics, hypoglycemic agents, ion exchange prokinetic agents; general anesthetics, including but not resins, laxatives, mineral Supplements, mucolytic agents, limited to inhalation anesthetics, halogenated inhalation neuromuscular drugs, peripheral vasodilators, psychotrop anesthetics, intravenous anesthetics, barbiturate intravenous ics, sedatives, Small molecule inhibitors, receptor enzySmes, anesthetics, benzodiazepine intravenous anesthetics, and stimulants, thyroid and anti-thyroid agents, uterine relax opiate agonist intravenous anesthetics; hematological ants, vitamins, and prodrugs. agents, including but not limited to antianemia agents, 0255 More specifically, non-limiting examples of phar hematopoietic antianemia agents, coagulation agents, anti maceutically active agents include the following therapeutic coagulants, hemostatic coagulation agents, platelet inhibitor categories: analgesics, including but not limited to non coagulation agents, thrombolytic enzyme coagulation steroidal anti-inflammatory drugs, opiate agonists and agents, and plasma Volume expanders; hormones and hor salicylates; antihistamines, including but not limited to mone modifiers, including but not limited to abortifacients, H1-blockers and H2-blockers; anti-infective agents, includ adrenal agents, corticosteroid adrenal agents, androgens, US 2016/02877.45 A1 Oct. 6, 2016 antiandrogens, antidiabetic agents, Sulfonylurea antidiabetic fungi that inhibit growth of or destroy other microbes, or agents, antihypoglycemic agents, oral contraceptives, pro genetically-engineered thereof and isolated from Such natu gestin contraceptives, estrogens, fertility agents, oxytocics, ral source. Substances of similar structure and mode of parathyroid agents, pituitary hormones, progestins, antithy action can be synthesized chemically, or natural compounds roid agents, thyroid hormones, and tocolytics; immunobio can be modified to produce semi-synthetic antibiotics. logic agents, including but not limited to immunoglobulins, 0258. Additional examples of antimicrobial agents immunosuppressives, toxoids, and vaccines; local anesthet include, but are not limited to, silver nanoparticles, rods, ics, including but not limited to amide local anesthetics and crystals, or any other structures, and/or silver salts. ester local anesthetics; musculoskeletal agents, including but not limited to anti-gout anti-inflammatory agents, corticos Pharmaceutical Compositions teroid anti-inflammatory agents, gold compound anti-in 0259. As used herein, the term “pharmaceutical compo flammatory agents, immuno-Suppressive anti-inflammatory sition” refers to a chemical compound or composition agents, nonsteroidal anti-inflammatory drugs (NSAIDs), capable of inducing a desired therapeutic effect in a Subject. salicylate anti-inflammatory agents, skeletal muscle relax In some embodiments, a pharmaceutical composition com ants, neuromuscular blocker skeletal muscle relaxants, and prises a pre-formed dissolvable hydrogel described herein. reverse neuromuscular blocker skeletal muscle relaxants; In some embodiments, a pharmaceutical composition com neurological agents, including but not limited to anticonvul prises components of the linear, branched and/or dendritic sants, barbiturate anticonvulsants, benzodiazepine anticon crosslinkable polymers described herein to be applied to a Vulsants, anti-migraine agents, anti-parkinsonian agents, target site (e.g., a wound) to form a dissolvable hydrogel anti-Vertigo agents, opiate agonists, and opiate antagonists: described herein in situ at the target site (e.g., a wound). In ophthalmic agents, including but not limited to antiglau certain embodiments, a pharmaceutical composition com coma agents, beta-blocker anti gluacoma agents, miotic prises a therapeutically effective amount of a bioactive agent anti-glaucoma agents, mydriatics, adrenergic agonist mydri described herein distributed in one or more embodiments of atics, antimuscarinic mydriatics, ophthalmic anesthetics, the dissolvable hydrogel described herein. In some embodi ophthalmic anti-infectives, ophthalmic aminoglycoside anti ments, the pharmaceutical composition can comprise a pro infectives, ophthalmic macrollide anti-infectives, ophthalmic quinolone anti-infectives, ophthalmic Sulfonamide anti-in drug of the compounds provided herein. In certain embodi fectives, ophthalmic tetracycline anti-infectives, ophthalmic ments, a pharmaceutical composition can comprise inactive anti-inflammatory agents, ophthalmic corticosteroid anti ingredients, such as, for example, carriers and excipients. inflammatory agents, and ophthalmic nonsteroidal anti-in 0260. The phrase “therapeutically effective amount” flammatory drugs (NSAIDs); psychotropic agents, including refers to the amount of a pharmaceutical composition that but not limited to antidepressants, heterocyclic antidepres elicits the biological or medicinal response in a tissue, sants, monoamine oxidase inhibitors (MAOIs), Sclerosants system, animal, individual, patient, or human that is being including but not limited to talc, alcohol or doxycyclin, sought by a researcher, Veterinarian, medical doctor or other selective serotonin re-uptake inhibitors (SSRIs), tricyclic clinician. antidepressants, antimanics, antipsychotics, phenothiazine 0261. As used herein, the term “pharmaceutically accept antipsychotics, anxiolytics, sedatives, and hypnotics, barbi able” refers to a formulation of a compound that does not turate sedatives and hypnotics, benzodiazepine anxiolytics, significantly abrogate the biological activity, a pharmaco sedatives, and hypnotics, and psychoStimulants; respiratory logical activity and/or other properties of the compound agents, including but not limited to antitussives, broncho when the formulated compound is administered to a Subject. dilators, adrenergic agonist bronchodilators, antimuscarinic In certain embodiments, a pharmaceutically acceptable for bronchodilators, expectorants, mucolytic agents, respiratory mulation does not cause significant irritation to a Subject. anti-inflammatory agents, leukotriene modifiers and respi 0262. As used herein, pharmaceutically acceptable ratory corticosteroid anti-inflammatory agents; toxicology derivatives of a compound include, but are not limited to, agents, including but not limited to antidotes, heavy metal salts, esters, enol ethers, enol esters, acetals, ketals, orthoe antagonists/chelating agents, Substance abuse agents, deter sters, hemiacetals, hemiketals, acids, bases, Solvates, rent Substance abuse agents, and withdrawal Substance hydrates, PEGylation, or prodrugs thereof. Such derivatives abuse agents; minerals; and vitamins, including but not can be readily prepared by those of skill in this art using known methods for Such derivatization. The compounds limited to vitamin A, vitamin B, Vitamin C, vitamin D, produced can be administered to animals or humans without Vitamin E, and vitamin K. Substantial toxic effects and are either pharmaceutically 0256 In some embodiments, the pharmaceutically active active or prodrugs. Pharmaceutically acceptable salts agents can include an antimicrobial agent. The term “anti include, but are not limited to, amine salts, such as but not microbial agent” as used herein refers to any entity with limited to chloroprocaine, choline, N,N'-dibenzyl-ethylene antimicrobial activity, i.e. the ability to inhibit or reduce the diamine, ammonia, diethanolamine and other hydroxyalky growth and/or kill a microbe, for example, bacteria. In lamines, ethylenediamine, N-methylglucamine, procaine, various embodiments, the antimicrobial agent can be a N-benzyl-phenethylamine, 1-para-chloro-benzyl-2-pyrroli compound (e.g., antibiotics or antiseptic agent) indicated for din-1-ylmethyl-benzimidazole, diethylamine and other treatment of a bacterial infection in a human or veterinary alkylamines, piperazine and tris(hydroxymethyl)-amin Subject. omethane; alkali metal salts, such as but not limited to 0257. In some embodiments, an antimicrobial agent can lithium, potassium and sodium; alkali earth metal salts. Such be an antibiotic. As used herein, the term “antibiotic' is art as but not limited to barium, calcium and magnesium; recognized and includes antimicrobial agents naturally pro transition metal salts, such as but not limited to Zinc, and duced by microorganisms such as bacteria (including Bacil other metal salts. Such as but not limited to Sodium hydrogen lus species), actinomycetes (including Streptomyces) or phosphate and disodium phosphate, and also including, but US 2016/02877.45 A1 Oct. 6, 2016 46 not limited to, salts of mineral acids, such as but not limited 0264. As used herein, the term “administer” refers to the to hydrochlorides and Sulfates; and salts of organic acids, placement of a composition into a subject by a method or Such as but not limited to acetates, lactates, malates, tar route which results in at least partial localization of the trates, citrates, ascorbates. Succinates, butyrates, Valerates composition at a desired site such that desired effect is and fumarates. Pharmaceutically acceptable esters include, produced. Examples of administration routes can include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, het but are not limited to, transdermal, topical (including buccal eroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl and Sublingual) administration and/or by Surgery. esters of acidic groups, including, but not limited to, car 0265. In some embodiments, the pharmaceutical compo boxylic acids, phosphoric acids, phosphinic acids, Sulfonic sition comprising components of the crosslinkable polymers acids, Sulfinic acids and boronic acids. Pharmaceutically can be administered to a target site (e.g., a wound) by acceptable enol ethers include, but are not limited to, deriva injection Such that a dissolvable hydrogel can form in situ at tives of formula C=C(OR) where R is hydrogen, alkyl, the target site (e.g., a wound). In some embodiments, the alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, pharmaceutical composition comprising a pre-formed dis cycloalkyl, or heterocyclyl. Pharmaceutically acceptable Solvable hydrogel can be administered to a target site (e.g., enol esters include, but are not limited to, derivatives of a wound) by direct implantation and Surgery. formula C=C(OC(O)R) where R is hydrogen, alkyl, alk 0266 Embodiments of Various Aspects Described Herein enyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, can be Defined in any of the Following Numbered Para cycloalkyl, or heterocyclyl. Pharmaceutically acceptable graphs: Solvates and hydrates are complexes of a compound with 0267. 1. A method comprising: one or more solvent or water molecules, or one to about 100, 0268 (a) contacting a wound with a hydrogel com or one to about 10, or one to about two, three, or four, solvent position comprising a dissolvable hydrogel layer, or water molecules. wherein the dissolvable hydrogel layer comprises 0263. In some embodiments, the pharmaceutical compo linear, branched, and/or dendritic crosslinkable poly sition can further comprise a pharmaceutically-acceptable mers held together by covalent bonds formed carrier. As used here, the term “pharmaceutically-acceptable between the first crosslinkable polymer and the sec carrier” means a pharmaceutically-acceptable material, ond crosslinkable polymer, wherein the dissolvable composition or vehicle. Such as a liquid or Solid filler, hydrogel layer comprises thioester linkages; and diluent, excipient, manufacturing aid (e.g., lubricant, talc 0269 (b) allowing the dissolvable hydrogel layer to magnesium, calcium or Zinc Stearate, or steric acid), or adhere to tissue Surrounding the Wound. Solvent encapsulating material, involved in carrying or 0270 2. The method of paragraph 1, further compris transporting the Subject compound from one organ, or ing dissolving the dissolvable hydrogel layer by adding portion of the body, to another organ, or portion of the body. a thiolate compound to result in a thiol-thioester Each carrier must be “acceptable' in the sense of being exchange, thereby releasing the hydrogel composition compatible with the other ingredients of the formulation and from the wound. not injurious to the patient. Some examples of materials 0271 3. A method comprising: which can serve as pharmaceutically-acceptable carriers 0272 (a) contacting a wound with a hydrogel com include: (1) Sugars, such as lactose, mannose, fructose, position comprising a dissolvable hydrogel layer, dextrose, trehalose, glucose and Sucrose; (2) starches, such wherein the dissolvable hydrogel layer comprises as corn starch and potato starch; (3) cellulose, and its linear, branched, and/or dendritic crosslinkable poly derivatives, such as Sodium carboxymethyl cellulose, meth mers held together by thioester linkages formed ylcellulose, ethyl cellulose, microcrystalline cellulose and between the first crosslinkable polymer and the sec cellulose acetate; (4) powdered tragacanth; (5) malt; (6) ond crosslinkable polymer; gelatin; (7) lubricating agents, such as magnesium Stearate, 0273 (b) allowing the dissolvable hydrogel layer to Sodium lauryl Sulfate and talc.; (8) excipients, such as cocoa adhere to tissue Surrounding the wound; and butter and Suppository waxes; (9) oils, such as peanut oil, 0274 (c) dissolving the dissolvable hydrogel layer cottonseed oil, safflower oil, sesame oil, olive oil, corn oil by adding a thiolate compound to result in a thiol and Soybean oil: (10) glycols, such as propylene glycol; (11) thioester exchange, thereby releasing the hydrogel polyols, such as glycerin, Sorbitol, mannitol and polyethyl composition from the wound. ene glycol (PEG); (12) esters, such as ethyl oleate and ethyl 0275 4. The method of any of paragraphs 1-3, wherein laurate; (13) agar, (14) buffering agents, such as magnesium the dissolvable hydrogel layer is derived from a first hydroxide and aluminum hydroxide; (15) alginic acid, (16) water-soluble linear, branched, and/or dendritic cross pyrogen-free water, (17) isotonic Saline; (18) Ringer's Solu linkable polymer comprising at least two thiol moieties tion; (19) ethyl alcohol; (20) pH buffered solutions; (21) and a second water-soluble linear, branched, and/or polyesters, polycarbonates and/or polyanhydrides; (22) dendritic crosslinkable polymer comprising at least two bulking agents, such as polypeptides and amino acids (23) crosslinking moieties that are capable of reacting with serum component, such as Scrum albumin, HDL and LDL: said at least two thiol moieties of the first crosslinkable (22) C-C alcohols, such as ethanol; and (23) other non polymer to form the thioester linkages between the first toxic compatible Substances employed in pharmaceutical and second crosslinkable polymers. formulations. Wetting agents, coloring agents, release 0276 5. The method of paragraph 1 or 2, wherein the agents, coating agents, Sweetening agents, flavoring agents, dissolvable hydrogel layer is derived from a first water perfuming agents, preservative and antioxidants can also be soluble linear, branched, and/or dendritic crosslinkable present in the formulation. The terms such as “excipient'. polymer comprising at least two thioester linkages and “carrier”, “pharmaceutically acceptable carrier' or the like a second water-soluble linear, branched, and/or den are used interchangeably herein. dritic crosslinkable polymer comprising at least two US 2016/02877.45 A1 Oct. 6, 2016 47

crosslinking moieties that are capable of forming a succinimide (NHS) moieties, maleimide (MAL) moi linkage with the first water-soluble linear, branched, eties, or any combinations thereof. and/or dendritic polymer. 0279 8. The method of any of paragraphs 1-7, wherein the branched crosslinkable polymer comprises polyes 0277 6. The method of paragraph 1 or 2, wherein the ters, polyethers, polyether-esters, polyglycerols, dissolvable hydrogel layer is derived from a first water polyamino acids, polyester-amines, polyurethanes, soluble linear, branched and/or dendritic crosslinkable polycarbonates, polyamino alcohols, thiols, amines, polymer comprising at least two nucleophilic moieties N-hydroxysuccinimide (NHS) moieties, Maleimide that are capable of forming a linkage with at least two (MAL) moieties, or any combinations thereof. crosslinking moieties of the second-water soluble lin 0280 9. The method of any of paragraphs 1-8, wherein ear, branched and/or dendritic polymer; wherein at least the dendritic crosslinkable polymer comprises polyes one of the first and second water-soluble linear, ters, polyethers, polyether-esters, polyamino acids, branched and/or dendritic crosslinkable polymers com polyester-amines, polyurethanes, polycarbonates, prises at least two thioester linkages. polyamino alcohols, thiols, amines, N-hydroxysuccin imide (NHS) moieties, Maleimide (MAL) moieties, or 0278 7. The method of any of paragraphs 1-6, wherein any combinations thereof. the linear crosslinkable polymer comprises polyesters, 0281 10. The method of any of paragraphs 1-9, polyethers, polyether-esters, polyglycerols, polyamino wherein the first crosslinkable polymer has a chemical acids, polyester-amines, polyurethanes, polycarbon structure selected from the group consisting of structure ates, polyamino alcohols, thiols, amines, N-hydroxy (i)-structure (xii) shown as follows: S-S-N-N, (i) (ii)

------Q l

(iii) , r US 2016/02877.45 A1 Oct. 6, 2016 48

-continued (iv) (v) QR R R Q RQ Q Q 2, ( iii. R Q () ) R. R.

(vi)

(vii) (viii)

US 2016/02877.45 A1 Oct. 6, 2016 49

-continued (ix) (x)

Q QN^g ox^oQ R. R. Q Q f Q- leC R

R. R. Q- leC QR

R R () QR

(xi) (xii) k al

(2) indicates text missing or illegible when filed and any combinations thereof, and wherein: halogen Substituents; and any combinations thereof, and m, n, and X are each independently selected from an integer of 0282 Q is independently selected from the group con O-1OOO. sisting of O, S, Se, NH, CH and any combination thereof; 0284 11. The method of any of paragraphs 4-10, wherein said at least two crosslinking moieties com 0283 R is selected from the group consisting of a hydro prise at least one N-hydroxysuccinimide (NHS) or gen, straight or branched alkyl, cycloalkyl, aryl, olefin or maleimide (MAL) moeity. alkene, alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl or aryl 0285 12. The method of any of paragraphs 4-10, alkyl chain of 1-50 carbons, fluorocarbon, and any combi wherein said at least two crosslinking moieties com nations thereof, wherein each alkyl, cycloalkyl, aryl, olefin, prise at least two N-hydroxysuccinimide (NHS) or alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl, fluorocarbon, or maleimide (MAL) moeities. arylalkyl chain is optionally substituted internally or termi 0286 13. The method of any of paragraphs 1-12, nally by one or more hydroxyl, hydroxyether, carboxyl, wherein the second cross-linkable polymer has a carboxyester, carboxyamide, amino, mono- or di-substituted chemical structure selected from the group consisting amino, thiol, thioester, Sulfate, phosphate, phosphonate, of structure (xiii)-structure (xl) shown us follows:

(xiii) O Q R. R. O N sex Q -*. O NN O R. R. Q s O

US 2016/02877.45 A1 Oct. 6, 2016 51

-continued

(xxi)

(xxii) US 2016/02877.45 A1 Oct. 6, 2016 52

-continued

(xxiii)

(xxiv) US 2016/02877.45 A1 Oct. 6, 2016 53

-continued

(XXv) (xxvi)

(xxvii) US 2016/02877.45 A1 Oct. 6, 2016 54

-continued

(xxviii)

(XXix) US 2016/02877.45 A1 Oct. 6, 2016 55

-continued

(XXX)

(XXXi) US 2016/02877.45 A1 Oct. 6, 2016 56

-continued

(XXXii)

K.y R-fso R > O RR Q R. R. Q R. R. Q RR O xix.6-rret------O Q O

2, i.

(XXXiii) US 2016/02877.45 A1 Oct. 6, 2016 57

-continued

(XXXiv)

(XXXv)

R O N. O Ry Q NY QRYÉ, R o O. N. --O US 2016/02877.45 A1 Oct. 6, 2016 58

-continued

(XXXvi)

(XXXvii) Q

R. R Q ty - XM Q y O less R. R. R. R. O Q O Q Q Q. N/ Q Q x y Vy R. R. R. R. O

US 2016/02877.45 A1 Oct. 6, 2016 60

-continued (xl) O V Rican RY o

sQ Q

O848 R. RRR -tory Q N Q Q Q R N-noQ ohn-Q-roded.R. R. R. R. O O Q AS Q ^k pi Q ik, N t;N. R. R. p Q Qaleq O R2 pi R Q O

y-Q R-1NR R 4N/ REi 5N h O and any combination thereof, and wherein nethiols, Thiophenol, Dimercaptosuccinic acid, 0287 Q is independently selected from the group con- Thioacetic acid, 5-mercapto-4H-1,2,4-triazol-3-ol, sisting of O, S, Se, NH, CH, and any combination thereof; 2-mercaptoacetamide, 2-Mercaptoethanol. 1.2-Ethan 0288 R is selected from the group consisting of a hydro edithiol, Ammonium thioglycolate, Cysteamine, gen, straight or branched alkyl, cycloalkyl, aryl, olefin or Methyl thioglycolate. Thiolactic acid, 1-Mercapto-2- alkyne, alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl or aryl propanol, 2-methoxyethanethiol. 3-Mercapto-1-propa alkyl chain of 1-50 carbons, fluorocarbon, and any combi nol. 2,3-Dimercapto-1-propanol. 1-Thioglycerol, Mer nations thereof, wherein each alkyl, cycloalkyl, aryl, olefin, captosuccinic acid, 4-ethyl-5-mercapto-4H-1,2,4- alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl, fluorocarbon, or triazol-3-ol, N-Carbamoyl-L-cysteine, 2-Methyl-3- arylalkyl chain is optionally substituted internally or termi Sulfanylpropanoic acid, 4-mercaptobutyric acid, nally by one or more hydroxyl, hydroxyether, carboxyl, N-Acctyley'steamine, 3-Methyl-1-butanethiol, 1.5-Pen carboxyester, carboxyamide, amino, mono- or di-substituted tanedithiol, 4-Chlorothiophenol, 4-Aminothiophenol, amino, thiol, thioester, Sulfate, phosphate, phosphonate, Benzyl mercaptan, 2-Furanmethanethiol, 3-Mercapto halogen Substituents; and any combinations thereof, and hexanol. Furfuryl thiol, derivatives thereof, a disulfide 0289 m, n, x, y and Z are each independently selected complex of one or more thereof, and any combinations from an integer of 0-1000. thereof. 0290 14. The method of any of paragraphs 10-13, 0292) 16. The method of any of paragraphs 1-15, wherein R is selected from the group consisting of wherein the dissolvable hydrogel layer is at least par poly(ethylene glycol), poly(ethylene oxide), poly(hy tially flexible. droxyacid), a carbohydrate, a protein, a polypeptide, an 0293. 17. The method of any of paragraphs 1-16, amino acid, a nucleic acid, a nucleotide, a polynucle otide, a DNA segment, a RNA segment, a lipid, a wherein the dissolvable hydrogel layer is at least par polysaccharide, an antibody, a pharmaceutical agent, an tially adhesive. epitope for a biological receptor, and any combinations 0294 18. The method of any of paragraphs 1-17, thereof. wherein the dissolvable hydrogel layer is capable of 0291. 15. The method of any of paragraphs 1-14, withstanding a pressure of at least about 2 mmHg. wherein the thiolate compound is selected from the 0295) 19. The method of any of paragraphs 1-18, group consisting of linear, branched and/or dendritic wherein the dissolvable hydrogel layer is transparent. multi-thiol macromolecule, poly(ethylene glycol)thiol, thiol containing glycerol, thiol containing peptide, cys 0296. 20. The method of any of paragraphs 1-19, teine, cystine, alkyl ester of cysteine, alkyl ester of wherein the dissolvable hydrogel layer is hydrophilic. cystine, MeSCHSH, (R)/(S)-3-methyl-3-sulfanyl 0297 21. The method of any of paragraphs 1-20, hexan-1-ol, Ethanethiol, 1-Propanethiol, 2-Propa wherein the dissolvable hydrogel layer is elastic or nethiol, Butanethiol, tert-Butyl mercaptan, Penta viscoelastic. US 2016/02877.45 A1 Oct. 6, 2016 61

0298 22. The method of any of paragraphs 1-21, crosslinkable polymer comprises at least two crosslink wherein the dissolvable hydrogel layer has about 5 wt ing moieties that are capable of reacting with said at % to about 70 wt % of the crosslinkable polymers. least two thiol moieties of the first crosslinkable poly 0299 23. The method of any of paragraphs 1-22, mer to form the thioester linkages between the first wherein the hydrogel composition further comprises a crosslinkable polymer and the second crosslinkable bioactive agent. polymer, 0300 24. The method of paragraph 23, wherein the 0308 31. The dissolvable hydrogel composition of bioactive agent is selected from the group consisting of paragraph 29, wherein the first crosslinkable polymer pharmaceutical agents, drugs, cells, gases and gaseous comprises at least two thioester linkages and the second precursors, synthetic organic molecules, proteins, crosslinkable polymer comprises at least two crosslink enzymes, growth factors, vitamins, steroid, polyanions, ing moieties that are capable of forming a linkage with nucleosides, nucleotides, polynucleotides, nanopar the first crosslinkable polymer. ticles, diagnostic agents, genetic materials, and any combinations thereof. 0309 32. The dissolvable hydrogel composition of 0301 25. The method of any of paragraphs 1-24, paragraph 29, wherein the first crosslinkable polymer wherein the hydrogel composition is formulated to comprises at least two nucleophilic moieties that are form a bandage, glue, Sealant, dressing, scaffold, coat capable of forming a linkage with at least two cross ing, or covering. linking moieties of the second crosslinkable polymer 0302. 26. The method of any of paragraphs 1-25, that comprises at least two thioester linkages. wherein the hydrogel composition is used with vacuum 0310 33. The dissolvable hydrogel composition of any assisted closure. of paragraphs 28-32, wherein the linear crosslinkable polymer comprises polyesters, polyethers, polyglycer 0303 27. The method of any of paragraphs 1-26, ols, polypeptides, polyether-esters, polyamino acids, wherein the thiolate compound is formulated as a polyester-amines, polyurethanes, polycarbonates, Solution or a spray. polyamino alcohols, thiols, amines, N-hydroxysuccin 0304, 28. A dissolvable hydrogel composition com imide (NHS) moieties, maleimide (MAL) moieties, or prising: an adhesive hydrogel layer comprising a first any combinations thereof. water-soluble linear, branched, and/or dendritic cross 0311. 34. The dissolvable hydrogel composition of any linkable polymer and a second water-soluble linear, of paragraphs 28-33, wherein the branched crosslink branched, and/or dendritic crosslinkable polymer held able polymer comprises polyesters, polyethers, together by thioester linkages formed between the first polyglycerols, polypeptides, polyether-esters, crosslinkable polymer and the second crosslinkable polyamino acids, polyester-amines, polyurethanes, polymer, polycarbonates, polyamino alcohols, thiols, amines, 0305 wherein the first crosslinkable polymer com N-hydroxysuccinimide (NHS) moieties, maleimide prises at least two thiol moieties and the second (MAL) moiety, or any combinations thereof. crosslinkable polymer comprises at least two cross 0312 35. The dissolvable hydrogel composition of any linking moieties that are capable of reacting with of paragraphs 28-34, wherein the dendritic crosslink said at least two thiol moieties of the first crosslink able polymer comprises polyesters, polyethers, able polymer to form the thioester linkages between polyglycerols, polypeptides, polyether-esters, the first crosslinkable polymer and the second cross polyamino acids, polyester-amines, polyurethanes, linkable polymer. polycarbonates, polyamino alcohols, thiols, amines, 0306. 29. A dissolvable hydrogel composition com N-hydroxysuccinimide (NHS) moieties, maleimide prising: an adhesive hydrogel layer comprising a first (MAL) moieties, or any combinations thereof. water-soluble linear, branched and/or dendritic cross 0313 36. The dissolvable hydrogel composition of any linkable polymer and a second water-soluble linear, of paragraphs 28-35, wherein when both the first and branched and/or dendritic crosslinkable polymer held second crosslinkable polymers are branched or den dritic crosslinkable polymers, at least one of the first together by covalent bonds formed between the first and the second dendritic crosslinkable polymers does crosslinkable polymer and the second crosslinkable not comprise poly(ethylene glycol). polymer, wherein the adhesive hydrogel layer com 0314 37. The dissolvable hydrogel composition of any prises thioester linkages. of paragraphs 28-36, wherein the first crosslinkable 0307 30. The dissolvable hydrogel composition of polymer has a chemical structure selected from the paragraph 29, wherein the first crosslinkable polymer group consisting of structure (i) to structure (xii) shown comprises at least two thiol moieties and the second as follows: S-S-N-N, US 2016/02877.45 A1 Oct. 6, 2016 62

-continued ------(ii) > k 3. QR (iii)

(iv) (v)

US 2016/02877.45 A1 Oct. 6, 2016 64

-continued

(xi) (xii) RQ Q

chR a ro Q Q -N1)No Q Q

QR (2) indicates text missing or illegible when filed and any combinations thereof, and wherein: 0317 m, n, X, and y are each independently selected from 0315 Q is independently selected from the group con an integer of 0-1000. sisting of O, S, Se, NH, CH, and any combination thereof; 0318 38. The dissolvable hydrogel composition of any 0316 R is selected from the group consisting of a hydro of paragraphs 28-37, wherein said at least two cross gen, straight or branched alkyl, cycloalkyl, aryl, olefin or linking moieties comprise at least one N-hydroxysuc alkene, alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl or aryl cinimide (NHS) moiety or maleimide (MAL) moiety. alkyl chain of 1-50 carbons, fluorocarbon, and any combi 0319. 39. The dissolvable hydrogel composition of any nations thereof, wherein each alkyl, cycloalkyl, aryl, olefin, of paragraphs 28-38, wherein said at least two cross alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl, fluorocarbon, or linking moieties comprise at least two N-hydroxysuc arylalkyl chain is optionally substituted internally or termi cinimide (NHS) moieties or maleimide (MAL) moi nally by one or more hydroxyl, hydroxyether, carboxyl, eties. carboxyester, carboxyamide, amino, mono- or di-substituted 0320 40. The dissolvable hydrogel composition of any amino, thiol, thioester, Sulfate, phosphate, phosphonate, of paragraphs 28-39, wherein the second crosslinkable halogen Substituents; and any combinations thereof, when at polymer has a chemical structure selected from the least two R groups are in the same structure, R can be group consisting of structure (xiii) to structure (x1) different from each other and shown as follows:

(xiii) O Q R. R. O N S-x Q -*. ONN O R. R. Q s O (xiv) O Q R. R. O Nulls--4.No o 's okn- Qa -Q r-O NN O R R ) s O (xv) O O R. R. Q Q N1 O * Q (-1\o pi o1 N Q Q R. R. O

US 2016/02877.45 A1 Oct. 6, 2016 66

-continued

(xxii)

(xxiii)

O Q Q Co------RQ Q Q US 2016/02877.45 A1 Oct. 6, 2016 67

-continued

(xxiv)

(XXv) (xxvi)

O O Q Q Q Q R. Q N R Q Q O R N^or-o-o-o:R O O O US 2016/02877.45 A1 Oct. 6, 2016 68

-continued

(xxvii)

(xxviii) US 2016/02877.45 A1 Oct. 6, 2016 69

-continued

(XXix)

(XXX) US 2016/02877.45 A1 Oct. 6, 2016 70

-continued

(XXXi)

(XXXii)

R rso > O RR Q R. R. Q R. R. Q RR O

****{-rrer------O Q O 2. l, *f;f; R R25N A O US 2016/02877.45 A1 Oct. 6, 2016 71

-continued

(XXXiii)

(XXXiv) US 2016/02877.45 A1 Oct. 6, 2016 72

-continued

(XXXv)

(XXXvi) US 2016/02877.45 A1 Oct. 6, 2016 73

-continued

(XXXvii) O Q N O R R Q N

O N M.y Q 24- R.WX. R. R. R. O Q O Q Q

(XXXviii) US 2016/02877.45 A1 Oct. 6, 2016 74

-continued (XXXix) SR RQR R x YQ Q O

Q Q Q RR O re----,,

(xl)

O R. RRR Q 848M -tory O N Q Q X N-oQ ohn-Q-roded.R. R. R. R. O O Q -- Q NQ{Q“FR % Q ik,Qaleq O R2 pi Q O -Q R-1N R RJ-4 it.Q O O and any combination thereof, and wherein alkyl chain of 1-50 carbons, fluorocarbon, and any combi 0321 Q is independently selected from the group con nations thereof, wherein each alkyl, cycloalkyl, aryl, olefin, sisting of O, S, Se, NH, CH, and any combination thereof; alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl, fluorocarbon, or 0322 R is selected from the group consisting of a hydro arylalkyl chain is optionally substituted internally or termi gen, straight or branched alkyl, cycloalkyl, aryl, olefin or nally by one or more hydroxyl, hydroxyether, carboxyl, alkene, alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl or aryl carboxyester, carboxyamide, amino, mono- or di-substituted US 2016/02877.45 A1 Oct. 6, 2016 75 amino, thiol, thioester, Sulfate, phosphate, phosphonate, 0330 47. The dissolvable hydrogel composition of any halogen Substituents; and any combinations thereof, when at of paragraphs 28-46, wherein the adhesive hydrogel least two R groups are in the same structure, R can be layer is hydrophilic. different from each other and 0331 48. The dissolvable hydrogel composition of any 0323 m, n, x, y and Z are each independently selected of paragraphs 28–47, wherein the adhesive hydrogel from an integer of 0-1000. layer is elastic or viscoelastic. 0324. 41. The dissolvable hydrogel composition of any 0332 49. The dissolvable hydrogel composition of any of paragraphs 37-40, wherein R is selected from the of paragraphs 28–48, wherein the adhesive hydrogel group consisting of poly(ethylene glycol), poly(ethyl layer has about 5 wt % to about 70 wt % of the ene oxide), poly(hydroxyacid), a carbohydrate, a pro crosslinkable polymers. tein, a polypeptide, an amino acid, a nucleic acid, a 0333 50. The dissolvable hydrogel composition of any nucleotide, a polynucleotide, a DNA segment, a RNA of paragraphs 28-49, further comprising a bioactive segment, a lipid, a polysaccharide, an antibody, a agent. pharmaceutical agent, an epitope for a biological recep 0334 51. The dissolvable hydrogel composition of tor, and any combinations thereof. paragraph. 50, wherein the bioactive agent is selected 0325 42. The dissolvable hydrogel composition of any from the group consisting of pharmaceutical agents, of paragraphs 28-41, wherein the first crosslinkable drugs, cells, gases and gaseous precursors, synthetic polymer has a chemical structure as follows: organic molecules, proteins, enzymes, growth factors,

SH

HN O O NH --> S- H SH O O

--Su-N44 N HN O

HS NH

SH

0326 43. The dissolvable hydrogel composition of any vitamins, steroids, polyanions, nucleosides, nucleo of paragraphs 28-42, wherein the second crosslinkable tides, polynucleotides, nanoparticles, diagnostic polymer is poly(ethylene glycol) disuccinimidyl Valer agents, genetic materials, and any combinations ate. thereof. 0335 52. The dissolvable hydrogel composition of any 0327 44. The dissolvable hydrogel composition of any of paragraphs 28-51, wherein the adhesive layer is of paragraphs 28-43, wherein the adhesive hydrogel hydrolytically stable at pH in a range of about 0 to at layer is at least partially flexible. least about 9. 0336 53. The dissolvable hydrogel composition of any 0328 45. The dissolvable hydrogel composition of any of paragraphs 28-52, wherein the dissolvable hydrogel of paragraphs 28-44, wherein the adhesive hydrogel composition is formulated to form a bandage, glue, layer is capable of withstanding a pressure of at least Sealant, dressing, scaffold, coating, or covering. about 2 mmHg. 0337 54. The dissolvable hydrogel composition of any 0329 46. The dissolvable hydrogel composition of any of paragraphs 28-53, wherein the dissolvable hydrogel of paragraphs 28-45, wherein the adhesive hydrogel composition is adapted for use with vacuum assisted layer is transparent. closure. US 2016/02877.45 A1 Oct. 6, 2016 76

0338 55. A kit comprising: 0353 66. A kit comprising: 0339 a dissolvable hydrogel composition compris 0354 a first water-soluble linear, branched, and/or ing: an adhesive hydrogel layer comprising linear, dendritic crosslinkable polymer comprising at least branched, and/or dendritic crosslinkable polymers two thiol moieties, wherein the first crosslinkable held together by thioester linkages formed between polymer is at least about 200 Da; the linear, branched, and/or dendritic crosslinkable 0355 a second water-soluble linear, branched, and/ polymers; and or dendritic crosslinkable polymer that can react with the first crosslinkable polymer to form a dissolvable 0340 a thiolate compound. and adhesive hydrogel, wherein the second cross 0341 56. A kit comprising: linkable polymer comprises at least two crosslinking 0342 a dissolvable hydrogel composition compris moieties that are capable of reacting with the thiol ing: an adhesive hydrogel layer comprising hum, moieties of the first crosslinkable polymer to form branched and/or dendritic crosslinkable polymers thioester linkages between the first and the second held together by covalent bonds formed between the crosslinkable polymers; and wherein the second first crosslinkable polymer and the second crosslink crosslinkable polymer is at least about 200 Da; and able polymer, wherein the adhesive hydrogel layer 0356 a thiolate compound. comprises thioester linkages; and 0357 67. A kit comprising: 0358 a first water-soluble linear, branched, and/or 0343 a thiolate compound. dendritic crosslinkable polymer comprising at least 0344 57. The kit of paragraph 56, wherein the adhe two thioester linkages, wherein the first crosslinkable sive hydrogel layer is derived from a first water-soluble polymer is at least about 200 Da; linear, branched, and/or dendritic crosslinkable poly 0359 a second water-soluble linear, branched, and/ mer comprising at least two thiol moieties and a second or dendritic crosslinkable polymer that can react with water-soluble linear, branched, and/or dendritic cross the first crosslinkable polymer to form a dissolvable linkable comprising at least two crosslinking moieties and adhesive hydrogel, wherein the second cross that are capable of reacting with said at least two thiol linkable polymer comprises at least two crosslinking moieties of the first crosslinkable polymer to form the moieties that are capable of forming a linkage with thioester linkages between the first and the second the first crosslinkable polymer; and wherein the crosslinkable polymers. second crosslinkable polymer is at least about 200 0345) 58. The kit of paragraph 56, wherein the adhe Da; and sive hydrogel layer is derived from a first water-soluble 0360 a thiolate compound. linear, branched, and/or dendritic crosslinkable poly 0361 68. A kit comprising: mer comprising at least two thioester linkages and a 0362 a first water-soluble linear, branched and/or dendritic crosslinkable polymer that can react with second water-soluble linear, branched, and/or dendritic the second crosslinkable polymer to form a dissolv crosslinkable polymer comprising at least two cross able and adhesive thioester hydrogel, wherein the linking moieties that are capable of forming a linkage first crosslinkable polymer comprises at least two with the first water-soluble linear, branched, and/or nucleophilic moieties that are capable of forming a dendritic polymer. linkage with the second crosslinkable polymer; and 0346 59. The kit of paragraph 56, wherein the adhe wherein the first crosslinkable polymer is at least sive hydrogel layer is derived from a first water-soluble about 200 Da; linear, branched and/or dendritic crosslinkable polymer 0363 a second water-soluble linear, branched and/ comprising at least two nucleophilic moieties that are or dendritic crosslinkable polymer comprising at capable of forming a linkage with the second water least two thioester linkages, wherein the second soluble linear, branched and/or dendritic polymer, crosslinkable polymer is at least about 200 Da; and wherein at least one of the first and second water 0364 a thiolate compound. soluble linear, branched and/or dendritic crosslinkable 0365 69. The kit of any of paragraphs 55-68, wherein polymers comprises at least two thioester linkages. the first crosslinkable polymer, the second crosslink (0347 60. The kit of any of paragraphs 55-59, wherein able polymer, and the thiolate compound are each the adhesive hydrogel layer is hydrolytically stable at independently formulated in a form selected from the pH in a range of about 0 to at least about 9. group consisting of a spray, a foam, a solution, a 0348 61. The kit of any of paragraphs 55-60, wherein powder, and any combinations thereof. the adhesive hydrogel layer has a larger molecular 0366 70. The kit of any of paragraphs 55-69, further weight than the crosslinkable polymers. comprising a bioactive agent. 0367 71. The kit of paragraph 70, wherein the bioac 0349 62. The kit of any of paragraphs 55-61, wherein tive agent is selected from the group consisting of the adhesive hydrogel layer has a molecular weight of pharmaceutical agents, drugs, cells, gases and gaseous at least about 100 kDa. precursors, synthetic organic molecules, proteins, 0350 63. The kit of any of paragraphs 55-62, wherein enzymes, growth factors, vitamins, steroids, polyan the dissolvable hydrogel composition is formulated to ions, nucleosides, nucleotides, polynucleotides, nano form a bandage, Sealant, coating or covering. particles, diagnostic agents, genetic materials, and any 0351) 64. The kit of any of paragraphs 55-63, further combinations thereof. comprising at least one component for performing 0368 72. The kit of any of paragraphs 55-71, wherein vacuum assisted closure. the thiolate compound is provided in an amount Such 0352 65. The kit of any of paragraphs 55-64, wherein that the stoichiometric ratio of the number of thiols in the dissolvable hydrogel composition further comprises the thiolate compound to the number of thioester link a bioactive agent. ages in the dissolvable hydrogel is greater than 1:1. US 2016/02877.45 A1 Oct. 6, 2016 77

0369 73. The kit of any of paragraphs 55-72, wherein the first crosslinkable polymer has a chemical structure Selected from the group consisting of structure (i) to structure (xii) shown as follows:

S-S-N-N,

(ii) 4No-N- --~~~~ N-N-No. Q

(iii) US 2016/02877.45 A1 Oct. 6, 2016 78

-continued (iv) (v) QR R R Q RQ Q Q 2, ( iii. R Q () ) R. R.

(vi)

(vii) (viii)

US 2016/02877.45 A1 Oct. 6, 2016 79

-continued (ix) (x) Q R. R. gyxos RN-4- R. R. Q Q Q N^g ox^o Q Q Q, Q R R R Q f R Rorxso R R QR R. R. Q- leC QR

R R () QR

(xi) (xii) RQ Q

chR to Q Q k Q N-1No Q XQ Q xor Q R\s Q1pi O 3 R R R R QR (2) indicates text missing or illegible when filed and any combinations thereof, and wherein: 0372 m, n, x, and y are each independently selected from an integer of 0-1000. 0370 Q is independently selected from the group con 0373) 74. The kit of any of paragraphs 55-73, wherein sisting of O, S, Se, NH, CH and any combination thereof; said at least two crosslinking moieties of the second crosslinkable polymer comprises at least one N-hy 0371 R is selected from the group consisting of a hydro droxysuccinimide (NHS) moiety or maleimide (MAL) gen, straight or branched alkyl, cycloalkyl, aryl, olefin or moiety. alkene, alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl or aryl 0374 75. The kit of any of paragraphs 55-74, wherein alkyl chain of 1-50 carbons, fluorocarbon, and any combi said at least two crosslinking moieties of the second nations thereof, wherein each alkyl, cycloalkyl, aryl, olefin, crosslinkable polymer comprises at least two N-hy alkyne, silyl, alkylsilyl, arylsilyl, alkylaryl, fluorocarbon, or droxysuccinimide (NHS) moieties or maleimide arylalkyl chain is optionally substituted internally or termi (MAL) moieties. nally by one or more hydroxyl, hydroxyether, carboxyl, 0375 76. The kit of any of paragraphs 55-75, wherein carboxyester, carboxyamide, amino, mono- or di-substituted the second crosslinkable polymer has a chemical struc amino, thiol, thioester, Sulfate, phosphate, phosphonate, ture selected from the group consisting of structure halogen Substituents; and any combinations thereof, and (xiii) to structure (x1) shown as follows:

(xiii) O Q R. R. O N sex Q -*. O NN O R. R. Q s O

US 2016/02877.45 A1 Oct. 6, 2016 81

-continued

(xxi)

(xxii)

Q R R Q R R Q N Me--~~~-2. ---N US 2016/02877.45 A1 Oct. 6, 2016 82

-continued

(xxiii)

(xxiv) US 2016/02877.45 A1 Oct. 6, 2016 83

-continued

(XXv) (xxvi)

(xxvii) US 2016/02877.45 A1 Oct. 6, 2016 84

-continued

(xxviii)

(XXix) US 2016/02877.45 A1 Oct. 6, 2016 85

-continued

(XXX)

(XXXi) US 2016/02877.45 A1 Oct. 6, 2016 86

-continued

(XXXii)

K.y R-fso R > O RR Q R. R. Q R. R. Q RR O xix.6-rret------O Q O

2, i.

(XXXiii) US 2016/02877.45 A1 Oct. 6, 2016 87

-continued

(XXXiv)

(XXXv)

R O N. O Ry Q NY QRYÉ, R o O. N. --O US 2016/02877.45 A1 Oct. 6, 2016 88

-continued

(XXXvi)

(XXXvii)