Sterilized hydrogel compositions and related methods

Abstract

Disclosed herein are sterilized hydrogel compositions, methods of producing the sterilized hydrogel compositions, and the use of the compositions in the treating wounds. In some aspects, the sterilized hydrogels are sterilized by irradiation without losing structural integrity, such as the ability to absorb an aqueous medium, and the ability to swell when contacted with an aqueous medium.

Description

DESCRIPTIONSTERILIZED HYDROGEL COMPOSITIONS AND RELATED METHODSCROSS-REFERENCE WITH RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 611,567, filed December 18, 2023, the contents of which are incorporated into the present application by reference.FIELD

[0002] The present invention generally relates to sterilized hydrogel compositions and uses thereof, such as in the field of wound management.BACKGROUND

[0003] A wound is a disruption of the structure and function of tissue, such as cuts, tears, bums, breaks, or other damage to living tissue. A dermal wound involves the disruption of the skin and associated soft tissue architecture. Dermal wounds can be partial or full thickness wounds. They can also be acute wounds, chronic wounds, or burns (which can be acute or chronic). Wounds may also include, without limitation, internal organ wounds; mucous membrane wounds; vascular tissue wounds; soft tissue wounds including ligaments, tendons, and cartilage; and bone wounds. Wounds can result from various conditions and injuries and may be classified in a variety of ways.

[0004] Promoting rapid and effective wound healing is an essential component of medical care for individuals with wounds. Devices for wound healing, such as wound dressings, can help facilitate the wound healing process. Wound dressings, e.g., hydrogels, can help facilitate the wound healing process if they provide an environment allowing cellular migration, vascular ingrowth, and / or the formation of granulation tissues. For example, wound dressings can contain components that can be helpful for wound healing or tissue regeneration. These components can include extracellular matrix (ECM), growth factors, and cells that are responsible for orchestrating the healing process in different tissue types. ECM is particularly beneficial for healing wounds, as the ECM can provide mechanical support for new tissue development and neovascularization in the wound. However, many commercially available wound dressings lack some or all of these characteristics, and lack effectiveness. Additionally, some commercially available wound dressings are not cost-efficient or manageable for the medical practitioner.

[0005] Hydrogel-based wound dressings represent a broad class of biomaterials with various applications in research and medicine, including wound management. In some aspects, hydrogels are biphasic materials made up of a mixture of porous, permeable solids containing interstitial fluid (e.g., water). In wound management, hydrogels can provide a suitable environment for supporting the wound healing process, and are also ideally free of contaminants that may lead to infection. Hydrogel-based wound dressings may include tissuebased components (e.g., from placental tissues) that can have characteristics that are well-suited for promoting wound healing and / or tissue regeneration. For example, cells, extracellular matrix (ECM), and growth factors in the tissue-based wound dressing can provide mechanical support for healing, and promote neovascularization within the wound. However, hydrogelbased wound dressings including those including tissue-based components are also associated with certain challenges. For example, hydrgel-based wound dressings can be challenging to sterilize. Wound dressings are ideally sterilized to remove contaminants and reduce the chances of infection, while retaining desired characteristics. Sterilization, while effective in removing contaminants and / or reducing the chances of infection, can undermine the structure (e.g., impaired or reduced mechanical, structural, and / or functional properties) of the hydrogel, including the structure of the ECM of tissue-based components comprised therein, thereby negatively affecting the use of the hydrogel to heal wounds. Certain efficient methods of sterilization, such as irradiation, can also negatively impact the desired physical characteristics of the hydrogel, such as elasticity, viscosity, rigidity, ability to absorb an aqueous medium (e.g., water), and ability to swell when contacted with an aqueous medium.

[0006] While certain commercially available wound dressings, including hydrogel-based wound dressings, exist in the art, many of these dressings cannot be sterilized without negatively affecting the structure of the hydrogel present in the dressing. This can result in hydrogel having reduced mechanical, structural, and / or functional properties, which can negatively affect new tissue development and / or neovascularization in the wound and can therefore negatively impact wound healing and / or repair.SUMMARY

[0007] A discovery has been made that provides a solution to at least one or more of the aforementioned problems associated with preparation of sterilized hydrogel compositions for wound management and tissue repair. In one aspect, the solution can include compositions and methods relating to assembly of an ECM material and a hydrogel material into sterilized or sterilizable compositions (e.g., hydrogels) for wound healing, including compositions withmechanical, structural, and / or functional integrity, such as wound dressings, or components thereof. In some aspects, the sterilized or sterilizable compositions (e.g., hydrogels) are capable of absorbing water and swelling when contacted with an aqueous medium. In some aspects, the sterilized or sterilizable compositions (e.g., hydrogels) retain or improve on the elasticity, viscosity, rigidity, ability to absorb an aqueous medium, and / or ability to swell when contacted with an aqueous medium compared to sterilized or sterilizable compositions (e.g., hydrogels) prior to sterilization. In some aspects, the sterilized or sterilizable compositions (e.g., hydrogels) retain or improve on the elasticity, viscosity, rigidity, ability to absorb an aqueous medium, and / or ability to swell when contacted with an aqueous medium compared to sterilized or sterilizable compositions (e.g., hydrogels) that do not include an ECM material or components thereof or a hydrogel material or components thereof. In some aspects, the sterilized or sterilizable compositions for wound healing can include any suitable tissue, such as placental tissue, and / or other components which may be advantageous for wound healing and / or structural properties of the composition.

[0008] In some aspects, the methods and compositions herein provide several advantages. In some aspects, provided herein are sterilized or sterilizable compositions having mechanical, structural, and / or functional integrity, such as sterilized or sterilizable hydrogels, which can serve as wound dressings or components thereof. The resulting compositions have the advantageous absorption profile of hydrogels, while also having mechanical, structural, and / or functional integrity for providing support for wound management and tissue repair. In some aspects, provided herein are hydrogel compositions, such as sterilized or sterilizable hydrogel compositions, which are sterilized or sterilizable without loss of desired physical characteristics. Thus, the hydrogel compositions provided herein can be efficiently sterilized or are sterilizable without loss of desired characteristics, thereby providing an advantage over certain available hydrogel compositions for wound healing, which can lose structural integrity following sterilization (e.g., by irradiation).

[0009] In some aspects, provided herein is a sterilized hydrogel composition. In some embodiments, the sterilized hydrogel composition comprises: a first component comprising an extracellular matrix (ECM) material; and a second component comprising a hydrogel including a plasticizer and a cellulose ether. In some embodiments, the sterilized hydrogel composition is capable of absorbing water and swelling when contacted with an aqueous medium.

[0010] In some aspects, provided herein is a method of manufacturing a sterilized hydrogel composition. In some embodiments, the method comprises: obtaining a first component comprising an ECM material; combining the first component with a second componentcomprising a hydrogel including a plasticizer and a cellulose ether to form the hydrogel composition; and sterilizing the hydrogel composition. In some embodiments, the sterilized hydrogel composition is capable of absorbing water and swelling when contacted with an aqueous medium.

[0011] In some aspects, provided herein is a method of treating a wound in a subject, the method comprising applying to the wound any sterilized hydrogel composition provided herein, or any sterilized hydrogel composition produced by any method provided herein. The wound can be any suitable wound, such as a dermal wound. In some embodiments, the wound comprises any of: a chronic wound, an ulcer, a diabetic ulcer, a foot ulcer, a diabetic foot ulcer, a venous ulcer, a venous leg ulcer, a leg ulcer, a pressure ulcer, a burn, a thermal bum, a chemical bum, a partial thickness burn, a full thickness burn, a laceration, a scrape, an incision, a puncture, a wound caused by a projectile, an epidermal wound, a dermal wound, a surgical wound, an acute wound, a congenital wound, a toxic epidermal necrolysis, an epidermolysis bullosa, or a pyoderma gangrenosum. In some embodiments, the wound is a dermal wound.

[0012] In some embodiments, an aqueous medium is applied to the wound before the sterilized hydrogel composition is applied to the wound. In some embodiments, an aqueous medium is applied to the wound after the sterilized hydrogel composition is applied to the wound.

[0013] The ECM material can be any suitable ECM material, such as an ECM material derived from or consisting of one or more tissues, a tissue (e.g., a processed and / or dehydrated tissue), or an ECM hydrogel. The hydrogel composition can include up to 75% w / w (e.g., at least, at most, exactly, or between any two of 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% w / w) of the ECM material. In some embodiments, the ECM material is an ECM hydrogel. In some embodiments, the first component is formed by contacting an aqueous medium with the ECM material. In some embodiments, the ECM material is lyophilized ECM. In some embodiments, the form of the lyophilized ECM is a sheet or a particulate. In some embodiments, the ECM material is from one or more tissues selected from: dermis, tendon, forestomach, small intestinal submucosa, liver, bone, adipose, brain, colon, cornea, esophagus, heart, liver, lung, small intestine, tooth, urinary bladder, and placenta, optionally wherein the placenta tissue is from amnion, chorion, and / or decidua.

[0014] Any suitable plasticizer can be used. In some embodiments, the plasticizer comprises one or more hydrophilic polyols. In some embodiments, the plasticizer comprises one or more polyethylene glycols (PEGs). In some embodiments, the plasticizer comprises 0% w / w to 30% w / w of the hydrogel (e.g., at least, at most, exactly, or between any two of 0%,1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% w / w of the hydrogel). In some embodiments, the plasticizer comprises 5% w / w to 30% w / w of the hydrogel. In some embodiments, the plasticizer comprises 10% w / w to 25% w / w of the hydrogel. Any suitable cellulose ether can be used. In some embodiments, the cellulose ether comprises hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), or a combination thereof. In some embodiments, the cellulose ether comprises 1% w / w to 80% w / w of the hydrogel (e.g., at least, at most, exactly, or between any two of 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% w / w of the hydrogel). In some embodiments, the cellulose ether comprises 20% w / w to 80% w / w of the hydrogel. In some embodiments, the cellulose ether comprises 30% w / w to 80% w / w of the hydrogel. In some embodiments, the cellulose ether comprises 40% w / w to 80% w / w of the hydrogel. In some embodiments, the second component is formed by contacting an aqueous medium with the plasticizer and the cellulose ether.

[0015] In some embodiments, one or more mechanical properties of the sterilized hydrogel are maintained or increased in comparison to the hydrogel prior to sterilization. In some embodiments, one or more mechanical properties of the sterilized hydrogel are maintained or increased in comparison to a control hydrogel not comprising the plasticizer and / or not comprising the cellulose ether. The mechanical properties can be any desired mechanical property, such as a mechanical property important or essential to the structural integrity of the hydrogel and / or to the wound healing process. In some embodiments, the one or more mechanical properties are selected from the list consisting of: elasticity, viscosity, rigidity, ability to absorb an aqueous medium, and ability to swell when contacted with an aqueous medium.

[0016] The sterilization can be any suitable form of sterilization. In some embodiments, the sterilization comprises irradiation of the hydrogel composition. In some embodiments, the irradiation is ultraviolet (UV) irradiation, gamma irradiation, and / or electron beam irradiation. In some embodiments, the irradiation is UV irradiation. In some embodiments, the irradiation is gamma irradiation. In some embodiments, the irradiation is electron beam irradiation. In some embodiments, the irradiation is irradiation by ionizing radiation. In some embodiments, the amount of irradiation (e.g., as measured in gray (Gy) or kilogray (kGy)) is any suitable amount of irradiation. In some embodiments, the irradiation comprises an amount of irradiation that is suitable and / or medically relevant for sterilization of a wound dressing. In some embodiments, the irradiation comprises at least, at most, exactly, or between any two of 5 kGy,10 kGy, 15 kGy, 20 kGy, 25 kGy, 30 kGy, 35 kGy, or 40 kGy. In some embodiments, the irradiation comprises at least 5 kGy, at least 10 kGy, at least 20 kGy, at least 30 kGy, or at least 40 kGy of irradiation.

[0017] In some embodiments, the first component and / or the second component are provided as dehydrated or lyophilized compositions prior to formation of the sterilized hydrogel composition. The dehydration or lyophilized compositions can be prepared according to any suitable method, such as any of the methods provided herein. In some embodiments, the first component and / or the second component are provided as hydrated compositions prior to formation of the sterilized hydrogel composition. In some embodiments, the sterilized hydrogel composition is formed by contacting an aqueous medium with the first component and / or the second component. In some embodiments, the hydrogel composition is sterilized after hydrating the first component and the second component.

[0018] In some aspects, provided herein is a sterilized hydrogel composition comprising: a first component comprising an extracellular matrix (ECM) material; and a second component comprising a hydrogel including a plasticizer and a cellulose ether, wherein the sterilized hydrogel composition is capable of absorbing water and swelling when contacted with an aqueous medium. In some aspects, provided herein is a method of manufacturing a sterilized hydrogel composition, the method comprising: obtaining a first component comprising an ECM material; combining the first component with a second component comprising a hydrogel including a plasticizer and a cellulose ether to form the hydrogel composition; and sterilizing the hydrogel composition, wherein the sterilized hydrogel composition capable of absorbing water and swelling when contacted with an aqueous medium. In some aspects, provided herein is a method of treating a wound in a subject, the method comprising applying to the wound any sterilized hydrogel composition provided herein, or any sterilized hydrogel composition produced by any method provided herein. In some embodiments, the wound comprises any of: a chronic wound, an ulcer, a diabetic ulcer, a foot ulcer, a diabetic foot ulcer, a venous ulcer, a venous leg ulcer, a leg ulcer, a pressure ulcer, a bum, a thermal burn, a chemical burn, a partial thickness bum, a full thickness burn, a laceration, a scrape, an incision, a puncture, a wound caused by a projectile, an epidermal wound, a dermal wound, a surgical wound, an acute wound, a congenital wound, a toxic epidermal necrolysis, an epidermolysis bullosa, or a pyoderma gangrenosum. In some embodiments, the wound is a dermal wound. In some embodiments, an aqueous medium is applied to the wound before the sterilized hydrogel composition is applied to the wound, or wherein an aqueous medium is applied to the wound after the sterilized hydrogel composition is applied to the wound. In some embodiments, theECM material is an ECM hydrogel. In some embodiments, the first component is formed by contacting an aqueous medium with the ECM material. In some embodiments, the ECM material is lyophilized ECM. In some embodiments, the form of the lyophilized ECM is a sheet or a particulate. In some embodiments, the ECM material is from one or more tissues selected from: dermis, tendon, forestomach, small intestinal submucosa, liver, bone, adipose, brain, colon, cornea, esophagus, heart, liver, lung, small intestine, tooth, urinary bladder, and placenta, optionally wherein the placenta tissue is from amnion, chorion, and / or decidua. In some embodiments, the ECM material comprises up to 75% w / w of the hydrogel. In some embodiments, the plasticizer comprises one or more hydrophilic polyols. In some embodiments, the plasticizer comprises one or more polyethylene glycols (PEGs). In some embodiments, the plasticizer comprises 1% w / w to 30% w / w of the hydrogel. In some embodiments, the cellulose ether comprises hydroxy ethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), or a combination thereof. In some embodiments, the cellulose ether comprises 1% w / w to 80% w / w of the hydrogel. In some embodiments, the second component is formed by contacting an aqueous medium with the plasticizer and the cellulose ether. In some embodiments, one or more mechanical properties of the sterilized hydrogel are maintained or increased in comparison to the hydrogel prior to sterilization. In some embodiments, one or more mechanical properties of the sterilized hydrogel are maintained or increased in comparison to a control hydrogel not comprising the plasticizer and / or not comprising the cellulose ether. In some embodiments, the one or more mechanical properties are selected from the list consisting of: elasticity, viscosity, rigidity, ability to absorb an aqueous medium, and ability to swell when contacted with an aqueous medium. In some embodiments, the sterilization comprises irradiation of the hydrogel composition. In some embodiments, the irradiation is UV irradiation, gamma irradiation, and / or electron beam irradiation. In some embodiments, the irradiation comprises at least 10 kGy, at least 20 kGy, at least 30 kGy, or at least 40 kGy of irradiation. In some embodiments, the first component and / or the second component are provided as dehydrated or lyophilized compositions prior to formation of the sterilized hydrogel composition. In some embodiments, the first component and / or the second component are provided as hydrated compositions prior to formation of the sterilized hydrogel composition. In some embodiments, the sterilized hydrogel composition is formed by contacting an aqueous medium with the first component and / or the second component. In some embodiments, the hydrogel composition is sterilized after hydrating the first component and the second component.

[0019] In another aspect of the present invention, disclosed is a method of treating a wound in a subject, the method comprising applying the compositions of the present invention to the wound (e.g., a sterilized hydrogel composition). In some embodiments, the composition is applied in conjunction with applying another wound dressing. In some embodiments, the composition or dehydrated composition is a powder. In some embodiments, the wound is a dermal wound. In some embodiments, the dermal wound is a partial thickness wound. In other embodiments, the dermal wound is a full thickness wound. In some embodiments, the dermal wound is a bum, a chronic wound, or an acute wound. In some embodiments, the dermal wound is a burn and is selected from a superficial (first degree) bum, a partial thickness (second degree) burn, a full thickness (third degree) bum, or a radiation bum. In other embodiments, the dermal wound is a chronic wound and is selected from a dermal ulcer, a diabetic ulcer, a diabetic foot ulcer, a venous ulcer, a venous leg ulcer, an arterial ulcer, an arterial leg ulcer, a decubitus ulcer, a stasis ulcer, an ischemic ulcer, a vascular ulcer, a pressure ulcer (stage I- IV), a podiatric wound, a draining wound, a tunneling wound, or an undermining wound. In still other embodiments, the dermal wound is an acute wound and is selected from a trauma wound, a laceration, an abrasion, a skin tear, a skin lesion, a blister, a surgical incision, a donor skin site, a skin graft, a laser surgery wound, a Mohs surgery wound, or a dehisced wound.

[0020] Also disclosed herein are the following Aspects 1-28. Aspect 1 is a sterilized hydrogel composition comprising: a first component comprising an extracellular matrix (ECM) material; and a second component comprising a hydrogel including a plasticizer and a cellulose ether, wherein the sterilized hydrogel composition is capable of absorbing water and swelling when contacted with an aqueous medium.

[0021] Aspect 2 is a method of manufacturing a sterilized hydrogel composition, the method comprising: obtaining a first component comprising an ECM material; combining the first component with a second component comprising a hydrogel including a plasticizer and a cellulose ether to form the hydrogel composition; and sterilizing the hydrogel composition, wherein the sterilized hydrogel composition capable of absorbing water and swelling when contacted with an aqueous medium.

[0022] Aspect 3 is a method of treating a wound in a subject, the method comprising applying to the wound the sterilized hydrogel composition of Aspect 1, or the sterilized hydrogel composition produced by the method of Aspect 2. Aspect 4 is the method of Aspect 3, wherein the wound comprises any of: a chronic wound, an ulcer, a diabetic ulcer, a foot ulcer, a diabetic foot ulcer, a venous ulcer, a venous leg ulcer, a leg ulcer, a pressure ulcer, a bum, a thermal bum, a chemical burn, a partial thickness bum, a full thickness burn, alaceration, a scrape, an incision, a puncture, a wound caused by a projectile, an epidermal wound, a dermal wound, a surgical wound, an acute wound, a congenital wound, a toxic epidermal necrolysis, an epidermolysis bullosa, or a pyoderma gangrenosum. Aspect 5 is the method of Aspect 3 or 4, wherein the wound is a dermal wound. Aspect 6 is the method of any one of Aspects 3-5, wherein an aqueous medium is applied to the wound before the sterilized hydrogel composition is applied to the wound, or wherein an aqueous medium is applied to the wound after the sterilized hydrogel composition is applied to the wound.

[0023] Aspect 7 is the composition or method of any one of Aspects 1-6, wherein the ECM material is an ECM hydrogel. Aspect 8 is the composition or method of Aspect 7, wherein the first component is formed by contacting an aqueous medium with the ECM material. Aspect 9 is the composition or method of any one of Aspects 1-6, wherein the ECM material is lyophilized ECM. Aspect 10 is the composition or method of Aspect 9, wherein the form of the lyophilized ECM is a sheet or a particulate. Aspect 11 is the composition or method of any one of Aspects 1-10, wherein the ECM material is from one or more tissues selected from: dermis, tendon, forestomach, small intestinal submucosa, liver, bone, adipose, brain, colon, cornea, esophagus, heart, liver, lung, small intestine, tooth, urinary bladder, and placenta, optionally wherein the placenta tissue is from amnion, chorion, and / or decidua. Aspect 12 is the composition or method of any one of Aspects s 1-11, wherein the ECM material comprises up to 75% w / w of the hydrogel. Aspect 13 is the composition or method of any one of Aspects 1-12, wherein the plasticizer comprises one or more hydrophilic polyols. Aspect 14 is the composition or method of any one of Aspects 1-13, wherein the plasticizer comprises one or more polyethylene glycols (PEGs). Aspect 15 is the composition or method of any one of Aspects 1-14, wherein the plasticizer comprises 1% w / w to 30% w / w of the hydrogel. Aspect 16 is the composition or method of any one of Aspects 1-15, wherein the cellulose ether comprises hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), or a combination thereof. Aspect 17 is the composition or method of any one of Aspects 1-16, wherein the cellulose ether comprises 1% w / w to 80% w / w of the hydrogel. Aspect 18 is the composition or method of any one of Aspects 1-17, wherein the second component is formed by contacting an aqueous medium with the plasticizer and the cellulose ether. Aspect 19 is the composition or method of any one of Aspects 1-18, wherein one or more mechanical properties of the sterilized hydrogel are maintained or increased in comparison to the hydrogel prior to sterilization. Aspect 20 is the composition or method of any one of Aspects 1-19, wherein one or more mechanical properties of the sterilized hydrogel are maintained or increased in comparison to a control hydrogel notcomprising the plasticizer and / or not comprising the cellulose ether. Aspect 21 is the composition or method of Aspect 19 or 20, wherein the one or more mechanical properties are selected from the list consisting of: elasticity, viscosity, rigidity, ability to absorb an aqueous medium, and ability to swell when contacted with an aqueous medium. Aspect 22 is the composition or method of any one of Aspects 1-21, wherein the sterilization comprises irradiation of the hydrogel composition. Aspect 23 is the composition or method of Aspect 22, wherein the irradiation is gamma irradiation, UV irradiation, and / or electron beam irradiation. Aspect 24 is the composition or method of Aspect 22 or 23, wherein the irradiation comprises at least 10 kGy, at least 20 kGy, at least 30 kGy, or at least 40 kGy of irradiation. Aspect 25 is the composition or method of any one of Aspects 1-24, wherein the first component and / or the second component are provided as dehydrated or lyophilized compositions prior to formation of the sterilized hydrogel composition. Aspect 26 is the composition or method of any one of Aspects 1-25, wherein the first component and / or the second component are provided as hydrated compositions prior to formation of the sterilized hydrogel composition. Aspect 27 is the composition or method of any one of Aspects 1-26, wherein the sterilized hydrogel composition is formed by contacting an aqueous medium with the first component and / or the second component. Aspect 28 is the composition or method of any one of Aspects 1-27, wherein the hydrogel composition is sterilized after hydrating the first component and the second component.

[0024] The disclosed materials, compositions, and components may be used for, may be used in conjunction with, may be used in preparation for, or are products of the disclosed method and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that, while specific reference of each various individual and collective combinations and permutation of these materials may not be explicitly disclosed, each is specifically contemplated and described herein. Thus, for example, if a class of components A, B, and C are disclosed as well as a class of components D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, is this example, each of the combinations A-E, A-F, B- D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the examplecombination A-D. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific aspect or combination of aspects of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.

[0025] It is contemplated that any aspect discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.

[0026] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific aspects of the present disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.DETAILED DESCRIPTION

[0027] The present invention relates to sterilized or sterilizable compositions (e.g., hydrogels) and uses of these compositions for the treatment of wounds, such as dermal wounds. The compositions disclosed herein are also useful for the repair of tissue such as soft tissue including, but not limited to tendons, ligaments, cartilage, and other connective tissue. The hydrogel compositions are capable of being sterilized, such as by irradiation, without losing mechanical, structural, and / or functional integrity and other properties which are essential for the function of the hydrogel in wound healing. This is in contrast to certain other similar hydrogel compositions (e.g., those that do not include an ECM material or components thereof or a hydrogel material or components thereof), which can lose structural integrity upon irradiation. Irradiation is an effective method for sterilizing compositions for wound treatment. Sterilization is an important aspect of the medical application of hydrogels, allowing for the removal of unwanted organisms such as bacteria from the compositions, preventing infection, and reducing the need for reapplication. Thus, the hydrogel compositions described in this disclosure can provide superior conditions to support the wound healing process versus existing products.I. Exemplary Definitions

[0028] In various aspects, the subject of the herein disclosed methods is a vertebrate, e.g., a mammal. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. In some aspects, the subject is a human. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects. The term “subject” as used herein means a vertebrate animal and includes mammals which includes human beings. In some preferred aspects, the subject is a human.

[0029] The term “body” as used herein means the body of a subject.

[0030] The term “tissue injury” means an injury of any tissue such as skin or the outer layer of any organ. By injury, it is meant a pathology that involves or results from a mechanical, metabolic, or other insult. Examples of such tissue injuries are bums, wounds, ulcerations, and lacerations, ablations (including laser, freezing, cryo-surgery, heat and electrical ablations), and surgical incisions.

[0031] The term “wound” as used herein means tendon repair, cartilage repair (e.g., femoral condyle, tibial plateau), ACL replacement at the tunnel / bone interface, dental tissue augmentation, fistulas (e.g., Crohn's disease, G-tube, tracheoesophogeal), missing tissue at adhesion barriers (e.g., nasal septum repair, vaginal wall repair, abdominal wall repair, tumor resection), dermal wounds (e.g., partial thickness burns, toxic epidermal necrolysis, epidermolysis bullosa, pyoderma gangrenosum, ulcers e.g., diabetic ulcers (e.g., foot), venous leg ulcers), surgical wounds, hernia repair, tendon repair, bladder repair, periosteum replacement, keloids, organ lacerations, epithelial defects, and repair or replacement of a tympanic membrane. Optionally, the wound is a laceration, scrape, thermal or chemical burn, incision, puncture, or wound caused by a projectile. Optionally, the wound is an epidermal wound, skin wound, chronic wound, acute wound, external wound, internal wounds, congenital wound, ulcer, or pressure ulcer. Such wounds may be accidental or deliberate, e.g., wounds caused during or as an adjunct to a surgical procedure. Optionally, the wound is closed surgically prior to administration. Optionally, the burn is a first-degree burn, second-degree bum (partial thickness burns), third degree burn (full thickness burns), infection of burn wound, infection of excised and unexcised burn wound, loss of epithelium from a previously grafted or healed bum, or burn wound impetigo.

[0032] The compositions disclosed herein are useful in treating wounds. Non-limiting examples of wound sites to which the compositions can be applied include those that are surgically induced or associated with surgery involving the spine, laminectomy, knee, shoulder, or child birth, trauma related wounds or injuries, cardiovascular procedures, angiogenesis stimulation, brain / neurological procedures, burn and wound care, and ophthalmic procedures. Direction for such procedures, including the selection of wound sites and / or methodologies, can be found, for example, in WO 2009 / 132186 and US 2010 / 0098743, which are hereby incorporated by reference.

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed method and compositions belong. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present method and compositions, the particularly useful methods, devices, and materials are as described. Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. No admission is made that any reference constitutes prior art. The discussion of references states what their authors assert, and applicants reserve the right to challenge the accuracy and pertinence of the cited documents. It will be clearly understood that, although a number of publications are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0034] The terms “optional” or “optionally” as used herein mean that the subsequently described event, circumstance, or material may or may not occur or be present, and that the description includes instances where the event, circumstance, or material occurs or is present and instances where it does not occur or is not present.

[0035] The terms “about” or “approximately” as used herein are defined as being close to as understood by one of skill in the art, and in one non-limiting aspect the terms are defined to be within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5% of an associated disclosed value. The terms may be removed from the associated disclosed value and the exact value may be used instead.

[0036] Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, also specifically contemplated and considered disclosed is the range from the one particular value and / or to the other particular value unless the context specifically indicates otherwise. Similarly, whenvalues are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another, specifically contemplated aspect that should be considered disclosed unless the context specifically indicates otherwise. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint unless the context specifically indicates otherwise. Finally, it should be understood that all of the individual values and sub-ranges of values contained within an explicitly disclosed range are also specifically contemplated and should be considered disclosed unless the context specifically indicates otherwise. The foregoing applies regardless of whether in particular cases some or all of these aspects are explicitly disclosed.

[0037] When the lower limit value of a given percentage range does not include the % symbol and / or the percentage type (e.g., w / w, v / v, etc.), then the percentage type for the lower limit value is the same as for the upper limit value of the given percentage range. For example, the percentage range of “0.01 to 0.5% w / w” means “0.01% w / w to 0.5% w / w.”

[0038] The terms “wt.%”, “w / w”, “vol.%”, “'NIN”, “ I / N”, or “mol.%” refers to a weight percentage of a component, a volume percentage of a component, or molar percentage of a component, respectively, based on the total weight, the total volume of material, or total moles, which includes the component. In non-limiting examples, 10 grams of component in 100 grams of a material is 10 wt.% or 10% w / w of component, 10 mL of component in 100 mL of a material is 10 vol.% or 10% v / v of component, and 10 grams of component in 100 mL of a material is 10 w / v of component.

[0039] The use of the word “a” or “an” when used in conjunction with the terms “comprising”, “having”, “including”, or “containing” (or any variations of these words) may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0040] The phrase “and / or” means “and” or “or”. To illustrate, A, B, and / or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.

[0041] For purposes of this application, a number value with one or more decimal places can be rounded to the nearest whole number using standard rounding guidelines, i.e., round up if the number being rounded is 5, 6, 7, 8, or 9; and round down if the number being rounded is 0, 1, 2, 3, or 4. For example, 0.42 can be rounded to 0.4.

[0042] The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (andany form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) as used herein are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0043] The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of’ any of the ingredients or steps disclosed throughout the specification. With respect to the transitional phrases “consist essentially of’ or “consisting essentially of,” in one non-limiting aspect, a basic and novel characteristic of the compositions and methods of the present disclosure are their abilities to treat wounds and / or repair tissue in a subject with composition or dehydrated compositions comprising placental tissue, preferably with compositions comprising dehydrated placental tissue.II. Compositions, Hydrogels, and Components Thereof

[0044] In some aspects, provided herein are sterilized hydrogels comprising an extracellular matrix material, a plasticizer (e.g., a hydrophilic polyol), and a cellulose ether. In some aspects, provided herein is a sterilized hydrogel composition comprising: a first component comprising an extracellular matrix (ECM) material; and a second component comprising a hydrogel including a plasticizer (e.g., a hydrophilic polyol) and a cellulose ether, wherein the sterilized hydrogel composition is capable of absorbing water and swelling when contacted with an aqueous medium. The extracellular matrix material may be or be derived from one or more tissues.

[0045] Assembling a sterilized hydrogel composition can include obtaining a first component comprising an ECM material, and combining the first component with a second component comprising a hydrogel. The hydrogel of the second component can include a plasticizer (e.g., a hydrophilic polyol) and a cellulose ether. The first component and the second component can be combined in any order (e.g., the first component can be added to and combined with the second component, the second component can be added to and combined with the first component, or the first component and the second component simultaneously be mixed together). Combination of the first component and the second component can form a hydrogel composition that can be sterilized. In some aspects, the sterilized hydrogel composition capable of absorbing water and swelling when contacted with an aqueous medium (e.g., water, saline, etc.).

[0046] The hydrogel can be an aqueous-based hydrogel. The hydrogel or components thereof can be prepared by incorporating and / or combining the components of the hydrogel using methods known to those of skill in the art. Such methods can include the use of varioustypes of mixers, blenders, and homogenizers. The compositions may be impregnated in gauzes, bandages, or other wound dressing materials. In some embodiments, the tissue or product thereof is in the form of pieces or powder and is distributed uniformly within a carrier. In some embodiments, the carrier is a pharmaceutically acceptable carrier. In some embodiments, the carrier or the pharmaceutically acceptable carrier is aqueous-based. The compositions can be aqueous-based, anhydrous, or dehydrated. Non-limiting examples of dehydrated compositions comprising tissue and a carrier include films, sheets, or powders. In some aspects of the present invention, an aqueous-based composition, carrier, gel, or hydrogel can include at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% w / w or more of water, preferably at least 50% w / w water.A. Tissue and Extracellular Matrix Materials

[0047] In some aspects, provided herein are sterilized hydrogels comprising an extracellular matrix (ECM) material. Thus, in some aspects, the hydrogels can be referred to as ECM hydrogels (e.g., hydrogels comprising ECM materials). ECM hydrogels are biomaterials with various applications in tissue engineering, regenerative medicine, and wound healing. ECM materials can provide a biological scaffold, giving the resulting hydrogel structural integrity, or certain desired mechanical characteristics, such as elasticity, viscosity, rigidity, ability to absorb an aqueous medium (e.g., water), and ability to swell when contacted with an aqueous medium. In some aspects, the ECM material can be a tissue, or be derived from a tissue.

[0048] ECM materials for use in the hydrogels provided herein can be any suitable ECM materials, and can be derived from any suitable source, e.g., human, bovine, porcine, ovine, fish, etc. ECM materials and hydrogels have been prepared from a variety of tissues, including dermis, tendon, forestomach, small intestinal submucosa, liver, bone, adipose, brain, colon, cornea, esophagus, heart, liver, lung, small intestine, tooth, urinary bladder, and placental tissues (such as amnion, chorion, and / or decidua). Methods for preparing ECM material from such tissues for use in hydrogels have been described, for example in: L.J. White et al., The impact of sterilization upon extracellular matrix hydrogel structure and function, J. Immunol. Regen. Med. 2:11-20 (2018); D.A. Young et al., Injectable hydrogel scaffold from decellularized human lipoaspirate, Acta Biomaterialia 7(3) (2011) 1040-1049; M.J. Sawkins et al., Hydrogels derived from demineralized and decellularized bone extracellular matrix, Acta Biomater 9(8) (2013) 7865-73; P.M. Crapo et al., Biologic scaffolds composed of central nervous system extracellular matrix, Biomaterials 33(13) (2012) 3539-3547; T.J. Keane et al., Preparation and characterization of a biologic scaffold and hydrogel derived from colonicmucosa, J Biomed Mater Res B Appl Biomater (2015); M. Ahearne et al., Early Observation of Extracellular Matrix-Derived Hydrogels for Corneal Stroma Regeneration, Tissue Eng Part C Methods 21(10) (2015) 1059-69; T.J. Keane et al., Preparation and characterization of a biologic scaffold from esophageal mucosa, Biomaterials 34(28) (2013) 6729-37; S.B. Seif- Naraghi et al., Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction, Science translational medicine 5(173) (2013) 173ra25; A.E. Loneker et al., Solubilized liver extracellular matrix maintains primary rat hepatocyte phenotype in-vitro, J Biomed Mater Res A 104(4) (2016) 957-65; J. Cordelia et al., Influence of acellular natural lung matrix on murine embryonic stem cell differentiation and tissue formation, Tissue Eng Part A 16(8) (2010) 2565-80; S.L. Voytik-Harbin et al., Small intestinal submucosa: A tissue derived extracellular matrix that promotes tissue-specific growth and differentiation of cells in vitro, Tissue Eng 4 (1998) 157-174; A. Viswanath et al., Extracellular matrix-derived hydrogels for dental stem cell delivery, J Biomed Mater Res A 105(1) (2017) 319-328; T.W. Gilbert et al., Production and characterization of ECM powder: implications for tissue engineering applications, Biomaterials 26(12) (2005) 1431-1435; each of which is incorporated by reference herein.

[0049] ECM materials can be provided in any suitable form, prepared according to any suitable method, and can be from any suitable tissue. The hydrogel composition can include up to 75% w / w (e.g., at least, at most, exactly, or between any two of 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% w / w) of the ECM material.

[0050] In some aspects, ECM materials can be obtained from placental tissues including decidua, whole placenta, or portion of a placenta. Obtaining a tissue can be performed by those methods known in the art. The method of obtaining a tissue can depend on the type of tissue being obtained. For example, obtaining placental tissues can occur at the time of childbirth.

[0051] In some embodiments, the ECM material is tissue from or derived from decidua. The decidua is a mucosal tissue of the uterus that forms in preparation for pregnancy. The decidua is comprised of three parts: decidua basalis, decidua capsularis, and decidua parietalis. The decidua basalis is the maternal part of the placenta. The decidua is generally discarded even if the remaining placental tissue is to be processed into placental products. The decidua tissue of the compositions disclosed herein can comprise decidua basalis tissue, decidua capsularis tissue, or decidua parietalis tissue, or any combinations thereof. In some embodiments, the decidua tissue comprises decidua basalis tissue. In some embodiments, the decidua tissue comprises decidua basalis tissue. In some embodiments, the decidua tissue comprises decidua capsularis tissue. In some embodiments, the decidua tissue is deciduacapsularis tissue. In some embodiments, the decidua tissue comprises decidua parietalis tissue. In some embodiments, the decidua tissue is decidua parietalis tissue. In some embodiments, the decidua tissue comprises the whole decidua, that is, all three parts of the decidua, i.e., basalis tissue, decidua capsularis tissue and decidua parietalis tissue. In some embodiments, the decidua tissue comprises decidua basalis tissue and decidua capsularis tissue but not decidua parietalis tissue. In some embodiments, the decidua tissue comprises decidua basalis tissue and decidua parietalis tissue but not decidua capsularis tissue. In some embodiments, the decidua tissue comprises decidua capsularis tissue and decidua parietalis tissue but not decidua basalis tissue. In some embodiments, the decidua tissue does not contain amniotic tissue, chorionic tissue, and / or umbilical cord tissue.

[0052] In some embodiments, the ECM material is tissue from or derived from a whole placenta or portion of a placenta. Portions of the placenta may include chorion, amnion, a chorion and amniotic membrane (e.g., amnio-chorion), Wharton’s jelly, umbilical cord, placental cotyledons or combinations thereof. Accordingly, in some aspects, a placenta or placental tissue can be amniotic tissue, chorionic tissue, umbilical cord tissue, or any combination thereof. The placental tissue may be dissected or digested (or combinations thereof) to remove portions, membrane, or structures. In some aspects, placental tissue is used in a purposeful wound dressing product with superior biological properties with respect to supporting the wound healing process by allowing cellular proliferation and migration, vascular ingrowth, and / or the formation of granulation tissues.

[0053] In specific aspects, the tissue is any placental tissue, such as but not limited to amnion, chorion, amnion with chorion, double layered amnion, chorion with trophoblast, umbilical cords, and any mixture composed of birth tissues. In some aspects, the umbilical tissue has a Wharton’s jelly layer side and an amniotic epithelial layer side. The disclosed methods may comprise producing umbilical tissue (e.g., by removing blood vessels from the received umbilical cords) and / or rinsing the umbilical tissue. In some aspects, umbilical tissue is devoid of viable blood cells. In some instances, one or more anticoagulants can be used to help remove blood and blood products, for instance ACD-A (anticoagulant Citrate dextrose solution, solution A, USP), heparin, dalteparin sodium, and bivalirudin. In some aspects, umbilical tissue is devoid of blood vessels. In some instances, the disclosed compositions are devoid of the two arteries and one vein typically found in the umbilical cord. In some aspects, disclosed is placental tissue comprising umbilical tissue, wherein the umbilical tissue is between 1 cm2and 350 cm2. Removing the blood vessels from the umbilical cord may allow for larger pieces of umbilical tissue to be used instead of having to cut around the blood vessels.

[0054] In some aspects, the placental tissue comprises one or more growth factors native to the placental tissue. Growth factors native to the placental tissue refer to growth factors that are present in naturally occurring placental tissue. In some instances, the growth factors may be epidermal growth factor (EGF), human growth factor (HGF), keratinocyte growth factor (KGF), basic fibroblast growth factor (bFGF), TGF-pi, 2, and 3, insulin-like growth factor- 1 (IGF-1), vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, TGF-a, Interleukin 10 (IL-10), Interleukin-1 receptor a (IL-lra), Stromal cell-derived factor-1 (SDF-1), Basic fibroblasts growth factor (bFGF), Neutrophil gelatinase-associated lipocalin (N-Gal), Matrix metalloproteinase 8 (MMP8), Tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP2, Angiopoietin 2 (hAng2), thrombospondin 2 (TSP2), Platelet derived growth factor AA (PDGF- AA), PDGF-AB, Placental growth factor (PIGF), Insulin-like growth factor (IGFBP1), IGFBP2, IGFBP3, a2-macroglobulin, Adiponectin (hACRP30), and / or Fibronectin.

[0055] In some aspects, the placental tissue further comprises one or more cytokines native to the placental tissue. Cytokines native to the placental tissue refers to cytokines that are present in naturally occurring placental tissue. In some instances, the one or more cytokines may be stromal cell derived factor- 1 (SDF-1 or CXCL12), IL- 10, and / or IL-lra.

[0056] In some aspects, the placental tissue is capable of releasing placental factors, such as angiogenic factors, optionally at an increased rate over time compared to native placental tissue. In some instances, the placental tissue releases placental factors, such as angiogenic factors, optionally at an increased rate over time compared to native placental tissue. In some instances, the angiogenic factors may be growth factors. For example, the disclosed compositions may optionally have greater release of growth factors in comparison to growth factor levels released by native placental tissue for the same period of time. In some instances, the growth factors may be EGF, HGF, KGF, bFGF, TGF-pl, 2, and 3, IGF-1, VEGF, VEGF- C, VEGF-D, TGF-a, IL- 10, IL-lra, SDF-1, bFGF, N-Gal, MMP8, TIMP1, TIMP2, hAng2, TSP2, PDGF-AA, PDGF-AB, PIGF, IGFBP1, IGFBP2, IGFBP3, a2-macroglobulin, hACRP30, and / or Fibronectin.

[0057] In specific aspects, the placental tissue is chorionic membrane and / or amniotic membrane. Optionally, a layer of epithelial cells of the amniotic membrane may be retained. Optionally, the chorionic membrane or portion thereof may be removed. Optionally, trophoblasts may be removed from the chorionic membrane while retaining the stromal cell layer, reticular layer, and / or basement membrane of the chorionic membrane. The chorionic membrane and / or amniotic membrane optionally secrete factors that stimulate cell migrationand / or wound healing. Examples include IGFBP1, adiponectin, a2-macroglobulin, and / or bFGF. Other examples include MMP-9 and TIMP1.

[0058] In some aspects, the tissue comprises viable cells native to the tissue. Cells native to the tissue refers to cells that are present in naturally occurring tissue. In some instances, the viable cells may be stromal cells, mesenchymal stem cells, fibroblasts, epithelial cells, or any combination thereof.

[0059] In some aspects, the tissue can be immunocompatible. Immunocompatability can be accomplished by any selective depletion step that removes immunogenic cells or factors or immunogenicity from the tissue. In one aspect, the tissue is made immunocompatible by selectively depleting it of functional immunogenic cells. A tissue can be made immunocompatible by selectively removing immunogenic cells from the tissue relative to therapeutic cells. For example, immunogenic cells can be removed by killing the immunogenic cells or by purification of the tissue therefrom. In some aspects, the tissue is made immunocompatible by selectively depleting trophoblasts, for example, by removal of the trophoblast layer. In one aspect, the tissue is made immunocompatible by selective depletion of functional CD 14+ macrophages, optionally as demonstrated by a substantial decrease in EPS stimulation of TNFa release or by MLR assay. In some aspects, the tissue is made immunocompatible by selective depletion of vascularized tissue-derived cells. In some aspects, vascularized tissue is removed, for example, by lysing red blood cells, by removing blood clots, or a combination thereof. In some aspects, the tissue is made immunocompatible by selective depletion of functional CD 14+ macrophages, trophoblasts, and vascularized tissue-derived cells. In some aspects, the tissue is selectively depleted of immunogenicity as demonstrated by a reduction in LPS stimulated TNF-a release. In some aspects, the tissue is selectively depleted of macrophages. In some aspects, TNF-a is depleted by killing or removal of macrophages. In some aspects, TNF-a is functionally depleted by treatment with IL- 10, which suppresses TNF- a secretion.

[0060] In some aspects, disclosed are compositions comprising tissue, wherein the tissue comprises one or more engineered channels or no engineered channels. In some aspects, a tissue can be cut to a desired size. In some aspects, a tissue can be minced. In some aspects, a tissue can be decellularized and / or disinfected (e.g., viral inactivation) tissue (e.g., decidua, amnion, chorion, amnion with chorion, double layered amnion, chorion with trophoblast, umbilical cords, and any mixture composed of birth tissues). In some aspects, a tissue can be treated with an antibiotic. In some aspects, the disclosed methods may comprise obtaining or receiving tissue (e.g., decidua, amnion, chorion, amnion with chorion, double layered amnion,chorion with trophoblast, umbilical cords, and any mixture composed of birth tissues). In some aspects, the tissue may be fresh or previously cryopreserved or lyopreserved. In some aspects, impacts to the tissue’s natural tissue characteristics, such as extracellular matrix and mechanical properties, may be minimized such that one or more of the tissue’s natural tissue characteristics, such as extracellular matrix and mechanical properties, are preserved. In some aspects, cellular components, microorganisms, and / or viral particles may be removed, washed away, or inactivated, thus promoting additional safety features to tissue-based (e.g., decidua, amnion, chorion, amnion with chorion, double layered amnion, chorion with trophoblast, umbilical cords, and any mixture composed of birth tissues) devices.

[0061] In some embodiments, the ECM material comprises amnion, chorion, and / or decidua tissue, a component thereof, or a combination of any of the foregoing.

[0062] A tissue can be processed according to any suitable means to produce the ECM material. In some embodiments, the tissue can be dehydrated and / or that have previously been dehydrated. For example, the tissue can be dehydrated and / or subjected to one or more additional processing steps prior to be used to form the hydrogel. The dehydration of the tissue can be conducted by any suitable means known to one of skill in the art, including, but not limited to lyophilizing (freeze-drying), evaporative air drying (e.g., thermal drying with heated air under gravity convection or forced air convection conditions; or drying under ambient or room temperature conditions under gravity convection or forced air convection conditions), indirect drying (e.g., vacuum drying), contact drying (e.g., drying through contact with a heated material or source), dielectric drying (e.g., use of radiofrequency or microwaves), infrared drying, and / or supercritical drying. The dehydrated tissue is considered “dehydrated” or “dry” when it has a water content (moisture content) of less than 15% w / w, or less than 14% w / w, or less than 13% w / w, or less than 12% w / w, or less than 10% w / w, or less than 9% w / w, or less than 8% w / w, or less than 7% w / w, or less than 6% w / w, or less than 5% w / w, or less than 4% w / w, or less than 3% w / w, or less than 2% w / w, less than 1% w / w, or less than 0.5% w / w. In some embodiments the water content is less than 5% w / w, or less than 4% w / w, or less than 3% w / w. The dehydrated tissue can, for example, have a water content of 0, 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14% w / w, or any percentage derivable therein. The water content (moisture content) of the dehydrated tissue can be determined by methods known to one of skill in the art such as by Karl Fischer titration or by oven drying. In a preferred embodiment, the dehydrated tissue is lyophilized tissue. The tissue can be non-viable, meaning that no viable cells are present in or on the tissue. The tissue can be rendered non-viable by any suitable means known to one of skill in the art, including, but not limited to cell lysis, sterilization,irradiation, or cell removal by enzymatic or physical means. In some embodiments, the tissue is non- viable. In some embodiments the compositions of the present invention and / or the tissue of the present invention are sterilized. In some embodiments, the tissue is viable meaning that the tissue comprises viable cells. The viable cells can be native cells or exogenous cells, or mixtures thereof. The tissue or dehydrated tissue, e.g., evaporative air-dried or lyophilized tissue, can be in the form of pieces or powder. In some embodiments, the tissue is dehydrated by lyophilization resulting in lyophilized tissue. In some embodiments, the tissue is rendered non-viable by cell lysis. In some embodiments, the tissue is in powder form. In some embodiments, the tissue is dehydrated, non-viable, and in powder form. In some embodiments, the tissue is lyophilized, non-viable, and in powder form. In some embodiments, the tissue or dehydrated tissue powder is non-immunogenic and / or immunoprivileged.

[0063] The dehydrated, e.g., evaporative air-dried or lyophilized, tissue powder can have a particle size of 90% less than 250 microns. The dehydrated tissue powder can have a particle size or particle size distribution (mean particle size) of from about 425 to about 1000 microns, or from about 216 to about 425 microns, or less than about 216 microns. The dehydrated tissue powder can have a particle size of from about 1 to about 1000 microns, or from about 1 to about 500 microns, or from about 1 to about 250 microns, or from about 50 to about 1000 microns, or from about 50 to about 500 microns, or from about 50 to about 250 microns, or from about 100 to about 1000 microns, or from about 100 to about 500 microns, or from about 100 to about 250 microns, or from about 200 to about 1000 microns, or from about 200 to about 500 microns, or from about 200 to about 250 microns, or from about 400 to about 1000 microns, or from about 400 to about 500 microns. The particle size can be determined by particle sizing methods known to one of skill in the art such as, but not limited to microscopic analysis, stacked sieving methods, and particle size analyzers. Particle size analyzers can employ light obscuration methods or laser diffraction methods. Suitable particle size analyzers include but are not limited to analyzers made by Malvern such as the Malvern Mastersizer™, AccuSizer, Shimadzu Corporation, and Beckman Coulter. A particle size distribution can be expressed as a mean particle size based on number distribution or volume distribution.

[0064] The concentration of tissue, dehydrated tissue, lyophilized tissue, or evaporative air-dried tissue in the composition can be at an amount effective to provide an environment to supporting the wound healing process by allowing cellular migration, vascular ingrowth, and the formation of granulation tissues when the composition is applied to a wound or damaged tissue as demonstrated in vitro by the cellular attachment and proliferation of mesenchymal cells in culture with the composition.

[0065] The concentrations of ECM material, such as tissue, dehydrated tissue, lyophilized tissue, or evaporative air-dried tissue in the compositions in the hydrous state (e.g., in the sterilized hydrogel) disclosed herein can be from about 0.05% to about 50% w / w, or from about 0.05% to about 40% w / w, or from about 0.05% to about 30% w / w, or from about 0.05% to about 25% w / w, or from about 0.05% to about 20% w / w, or from about 0.05% to about 15% w / w, or from about 0.05% to about 10% w / w, or from about 0.05% to about 5% w / w, or from about 0.05% to about 4% w / w, or from about 0.05% to about 3% w / w, or from about 0.05% to about 2% w / w, or from about 0.05% to about 1% w / w, or from about 0.1% to about 50% w / w, or from about 0.1% to about 40% w / w, or from about 0.1% to about 30% w / w, or from about 0.1% to about 25% w / w, or from about 0.1% to about 20% w / w, or from about 0.1% to about 15% w / w, or from about 0.1% to about 10% w / w, or from about 0.1% to about 5% w / w, or from about 0.1% to about 4% w / w, or from about 0.1% to about 3% w / w, or from about 0.1% to about 2% w / w, or from about 0.1% to about 1% w / w, or from about 0.5% to about 50% w / w, or from about 0.5% to about 40% w / w, or from about 0.5% to about 30% w / w, or from about 0.5% to about 25% w / w, or from about 0.5% to about 20% w / w, or from about 0.5% to about 15% w / w, or from about 0.5% to about 10% w / w, or from about 0.5% to about 5% w / w, or from about 0.5% to about 4% w / w, or from about 0.5% to about 3% w / w, or from about 0.5% to about 2% w / w, or from about 0.5% to about 1% w / w, or from about 1% to about 50% w / w, or from about 1% to about 40% w / w, or from about 1% to about 30% w / w, or from about 1% to about 25% w / w, or from about 1% to about 20% w / w, or from about 1% to about 15% w / w, or from about 1% to about 10% w / w, or from about 1% to about 5% w / w, or from about 1% to about 4% w / w, or from about 1% to about 3% w / w, or from about 1% to about 2% w / w, of the total composition for compositions in the hydrous state.

[0066] The concentrations of ECM material, such as tissue, dehydrated tissue, lyophilized tissue, or evaporative air-dried tissue in the compositions in the dehydrated state disclosed herein can be from about 1% to about 75% w / w, or from about 1% to about 60% w / w, or from about 1% to about 50% w / w, or from about 2% to about 50% w / w, or from about 3% to about 50% w / w, or from about 4% to about 50% w / w, or from about 5% to about 50% w / w, or from about 6% to about 50% w / w, or from about 7% to about 50% w / w, or from about 8% to about 50% w / w, or from about 9% to about 50% w / w, or from about 10% to about 50% w / w, or from about 15% to about 50% w / w, or from about 20% to about 50% w / w, or from about 1% to about 40% w / w, or from about 2% to about 40% w / w, or from about 3% to about 40% w / w, or from about 4% to about 40% w / w, or from about 5% to about 40% w / w, or from about 6% to about 40% w / w, or from about 7% to about 40% w / w, or from about 8% to about 40% w / w, orfrom about 9% to about 40% w / w, or from about 10% to about 40% w / w, or from about 15% to about 40% w / w, or from about 20% to about 40% w / w, or from about 1% to about 30% w / w, or from about 2% to about 30% w / w, or from about 3% to about 30% w / w, or from about 4% to about 30% w / w, or from about 5% to about 30% w / w, or from about 6% to about 30% w / w, or from about 7% to about 30% w / w, or from about 8% to about 30% w / w, or from about 9% to about 30% w / w, or from about 10% to about 30% w / w, or from about 15% to about 30% w / w, or from about 20% to about 30% w / w, of the total composition for compositions in the dehydrated state.

[0067] The tissue can be processed as described in the following non-limiting exemplified embodiment. The unprocessed tissue (e.g., decidua or placenta tissue) is added to water or buffer solution, such as phosphate buffered saline (PBS), then added to a suitable homogenizer, such as a blender or other type of homogenizer, and homogenized to form pieces. The homogenized tissue pieces are collected by centrifugation techniques. A suitable lysing buffer, such as ACK RBC Lysing Buffer, is added to the tissue and allowed to contact the tissue for a time sufficient to lyse the cells. The lysed treated tissue is then washed with water or a buffer solution and collected by centrifugation techniques. The tissue is then lyophilized (freeze- dried) using a lyophilizer or other suitable freeze-drying technique. The lyophilized tissue is then processed into a powder form using a suitable mill, grinder, or dissociator. In some embodiments, the tissue or dehydrated tissue powder is non-immunogenic and / or immunoprivileged. In some embodiments, the compositions or dehydrated compositions disclosed herein comprising tissue or dehydrated tissue are non-immunogenic and / or immunoprivileged .B. Plasticizers and Hydrophilic Polyols

[0068] In some aspects, provided herein are compositions such as hydrogels comprising plasticizers, such as hydrophilic polyols. In some embodiments, the plasticizer is a hydrophilic polyol. In some embodiments, the hydrophilic polyol is polyethylene glycol.

[0069] Plasticizers can serve to enhance the desired physical properties of compositions such as hydrogels, or dehydrated films or sheets, including brittleness, flexibility, elasticity, viscosity, rigidity, ability to absorb an aqueous medium, and ability to swell when contacted with an aqueous medium. Non-limiting examples of plasticizers include hydrophilic polyols, hydrophilic polymeric polyols, propylene glycol, glycerol, polyethylene glycol (PEG), polypropylene glycol, poloxamers, and povidone. The concentration of the plasticizer in the composition can be from about 0% to about 30% w / w, or from about 5% to about 30% w / w,or from about 10% to about 25% w / w for the composition in the dehydrated or hydrated state (e.g., in the hydrogel). In some embodiments, the plasticizer is a hydrophilic polyol. Suitable hydrophilic polyols are water-soluble, polar aliphatic alcohols with at least two hydroxyl groups, and can include polymeric polyols, e.g., polyethylene glycols and poloxamers. In some embodiments, the hydrophilic polyol is a hydrophilic polymeric polyol. In some embodiments, the hydrophilic polymeric polyol is one or more polyethylene glycols. In some embodiments, the polyethylene glycol is polyethylene glycol 600.

[0070] Hydrophilic polyols are water-soluble, polar aliphatic alcohols with at least two hydroxyl groups, and include polymeric polyols, e.g., polyethylene glycols and poloxamers. In some embodiments, the liquid hydrophilic polyol is a liquid polyethylene glycol. Other examples of liquid hydrophilic polyols include but are not limited to propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, glycerin, hexylene glycol, methoxy polyethylene glycol, propylene carbonate, and ethoxy diglycol.

[0071] Polyethylene glycols are homo-polymers of ethylene glycol and water represented by the formula:H(OCH2CH2)WOH, in which n represents the average number of oxyethylene groups. Polyethylene glycols can be either liquid or solid at 25 °C depending on their molecular weights.

[0072] The following suitable non-limiting examples of liquid polyethylene glycols are described using USP nomenclature: polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 500, and polyethylene glycol 600.

[0073] The following suitable non-limiting examples of solid polyethylene glycols are described using USP nomenclature: polyethylene glycol 700, polyethylene glycol 800, polyethylene glycol 900, polyethylene glycol 1000, polyethylene glycol 1100, polyethylene glycol 1200, polyethylene glycol 1300, polyethylene glycol 1400, polyethylene glycol 1450, polyethylene glycol 1500, polyethylene glycol 1600, polyethylene glycol 1700, polyethylene glycol 1800, polyethylene glycol 1900, polyethylene glycol 2000, polyethylene glycol 2100, polyethylene glycol 2200, polyethylene glycol 2300, polyethylene glycol 2400, polyethylene glycol 2500, polyethylene glycol 2600, polyethylene glycol 2700, polyethylene glycol 2800, polyethylene glycol 2900, polyethylene glycol 3000, polyethylene glycol 3250, polyethylene glycol 3350, polyethylene glycol 3750, polyethylene glycol 4000, polyethylene glycol 4250, polyethylene glycol 4500, polyethylene glycol 4750, polyethylene glycol 5000, polyethyleneglycol 5500, polyethylene glycol 6000, polyethylene glycol 6500, polyethylene glycol 7000, polyethylene glycol 7500, and polyethylene glycol 8000.

[0074] Liquid and solid polyethylene glycols are available commercially from the DOW Chemical Company under the CARBOWAX™ and SENTRY™ names and from the BASF Corporation under the LUTROL® E, PLURACARE® E, and PLURIOL® names. Polyethylene glycols are available in cosmetic grades and pharmaceutical grades (USP / NF) and are suitable for use in the disclosed compositions. The concentration of the plasticizer (e.g., hydrophilic polyol) (e.g., polyethylene glycol) in the composition (cumulative concentration if more than one polyethylene glycol is present) can be from about 0% to about 30% w / w, or from about 5% to about 30% w / w, or from about 10% to about 25% w / w for the composition in the dehydrated or hydrated state (e.g., in the hydrogel). In some embodiments, the carrier comprises polyethylene glycol (PEG) 600. PEG 600 is available under the name PLURACARE® E 600 from BASF and under the name CARBOWAX™ SENTRY™ Polyethylene Glycol 600 NF from Dow.C. Cellulose Ethers

[0075] In some aspects, provided herein are compositions such as hydrogels comprising one or more cellulose ethers. Any suitable cellulose ether(s) can be included in the compositions such as hydrogels provided herein. In some embodiments, the cellulose ethers comprise hydroxy ethyl cellulose (HEC) and hydroxypropylmethyl cellulose (HPMC).

[0076] Cellulose ethers include non-ionic and anionic cellulose ethers and are available in a variety of viscosity grades. Nonionic cellulose ethers are high-molecular- weight compounds that can be made by replacing the hydrogen atoms of hydroxyl groups in the glucose units of cellulose with alkyl or hydroxylalkyl groups. Non-limiting examples of non-ionic alkyl cellulose ethers include methyl cellulose (MC), ethyl cellulose (EC), and ethyl methyl cellulose (EMC). Non-limiting examples of non-ionic hydroxyalkyl cellulose ethers include hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxymethyl cellulose (HMC), hydroxypropylmethyl cellulose (HPMC), ethylhydroxyethyl cellulose (EHEC), hydroxyethylmethy cellulose (HEMC), methylhydroxyethyl cellulose (MHEC), methylhydroxypropylcellulose (MHPC), and hydroxyethylcarboxymethyl cellulose (HECMC). There are a wide range of commercial sources for each of these cellulose ethers (e.g., Dow Chemical Company, Ashland, Spectrum Chemical). HEC is available under the name Natrosol™ from Ashland. HPC is available under the name KLUCEL™ from Ashland. HPMC (also known as hypromellose) is available under the name BENECEL™ from Ashland.An example of an anionic cellulose ether is sodium carboxymethyl cellulose (CMC) available commercially under the name Aquaion™ from Ashland. The cellulose ethers are available in cosmetic grades and pharmaceutical grades (USP / NF) and are suitable for use in the disclosed compositions. The concentration of the cellulose ether in the composition can vary as needed to achieve a particular characteristic of the dehydrated film or sheet. The concentration of the cellulose ether in the composition (cumulative concentration if more than one cellulose ether is present) can be from at least, at most, exactly, or between any two of 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% w / w. The concentration of the cellulose ether in the composition (cumulative concentration if more than one cellulose ether is present) can be from about 20% to about 80% w / w, or from about 30% to about 80% w / w, or from about 40% to about 80% w / w for a composition in the dehydrated state. The carrier can comprise one or more cellulose ethers. In some embodiments, the carrier comprises one or more cellulose ethers. In some embodiments, the cellulose ether is a nonionic cellulose ether. In some embodiments, the non-ionic cellulose ether is hydroxyethyl cellulose (HEC) or hydroxypropyl cellulose (HPC), or mixtures thereof.III. Dehydrated Compositions and Methods of Preparation

[0077] In some aspects, provided herein are dehydrated (dry) compositions. For example, the ECM material, hydrophilic polyol, cellulose ether, or any combination thereof, can be dehydrated. The dehydrated composition can be any individual component prior to use in the formation of the hydrogel. Alternatively, the dehydrated composition comprise combinations of the components of the hydrogel, including the ECM material, hydrophilic polyol, and cellulose ether. The hydrogel can itself also be dehydrated, and can be reconstituted or rehydrated by contact with an aqueous medium (e.g., water or a composition comprising water). Any of the dehydrated compositions can be provided in any suitable form, and may or may not have an overall structure or structural integrity. For example, a dehydrated composition can be in the form of a particulate (e.g., a lyophilized particulate), or may be in the form of a composition such as a sheet-, film-, foam-, or sponge-like structure. In some embodiments, the dehydrated composition is a sheet or film.

[0078] The films or sheets can comprise dehydrated tissue, evaporative air-dried tissue, or lyophilized tissue in pieces or in powder form, and a carrier. The terms “films” and “sheets” as used herein can be used interchangeably, but generally a film is thinner than a sheet. The carrier or pharmaceutically acceptable carrier of the compositions can be a dehydrated film or sheet. Exemplary methods for preparing compositions of dehydrated films or sheets comprisedehydrating compositions of aqueous gels or hydrogels comprising tissue or dehydrated tissue. The aqueous gel or hydrogel comprising tissue or dehydrated tissue can be poured into a suitable mold such as a petri dish prior to dehydration. The aqueous-based gel or hydrogel comprising the tissue or dehydrated tissue can be dehydrated by any suitable means including but not limited to lyophilizing (freeze-drying), evaporative air drying (e.g., thermal drying with heated air under gravity convection or forced air convection conditions; or drying under ambient or room temperature conditions under gravity convection or forced air convection conditions), indirect drying (e.g., vacuum drying), contact drying (e.g., drying through contact with a heated material or source), dielectric drying (e.g., use of radiofrequency or microwaves), infrared drying, and / or supercritical drying. The resultant film or sheet from evaporative airdrying can be referred to as a xerogel. Evaporative air drying can be accomplished under gravity convection or forced air convention conditions at ambient or room temperature or higher temperatures. Drying using heated air can be accomplished in a heating chamber at temperatures above room temperature with gravity convection or with forced air convection conditions. Drying under gravity convection at ambient or room temperature can be accomplished in a chamber or in an open air space such as on a table or bench. In some embodiments, the evaporative air-drying is thermal evaporative air-drying with heated air under gravity convection or forced air convection conditions. In other embodiments, the evaporative air-drying is ambient or room temperature evaporative air-drying under gravity convection or forced air convection conditions. In still other embodiments, the evaporative airdrying is room temperature evaporative air-drying under gravity convection conditions. Lyophilizing, aka freeze-drying, can be accomplished by first freezing the aqueous gel or hydrogel in a freezer, e.g., at -80°C, then drying in a lyophilizer; or by freezing and drying in a lyophilizer. In some embodiments the gel or hydrogel comprising tissue or dehydrated tissue is dehydrated by evaporative air-drying or lyophilization. The film or sheet is considered “dehydrated” or “dry” when it has a water content (moisture content) of less than 15% w / w, or less than 14% w / w, or less than 13% w / w, or less than 12% w / w, or less than 10% w / w, or less than 9% w / w, or less than 8% w / w, or less than 7% w / w, or less than 6% w / w, or less than 5% w / w, or less than 4% w / w, or less than 3% w / w, or less than 2% w / w, less than 1% w / w, or less than 0.5% w / w. In some embodiments the water content is less than 5% w / w, or less than 4% w / w, or less than 3% w / w. The dehydrated film or sheet can, for example, have a water content of 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, or 14% w / w, or any percentage derivable therein. The water content (moisture content) of the dehydrated film or sheet can be determined by methods known to one of skill in the art such as by Karl Fischertitration or by oven drying. For example, the dehydrated film or sheet can be placed in a 65 °C oven for 3 minutes at atmospheric pressure and measuring the weight loss after incubation to determine moisture content.

[0079] The tissue pieces or powder, dehydrated tissue pieces or powder, evaporative airdried tissue pieces or powder, or lyophilized tissue pieces or powder can be uniformly dispersed within the aqueous gel or hydrogel carrier prior to the dehydration step to form the dehydrated film or sheet. A rheology modifier, such as a gellant, can be used to form the aqueous gel or hydrogel prior to dehydration by the addition of the rheology modifier to water or an aqueous medium. The tissue pieces or powder can be added prior to or after the addition of the rheology modifier. The tissue pieces or powder can first be suspended in water or a buffer solution, such as PBS, prior to its addition to wet the tissue to form a slurry then the slurry can further be homogenized with a homogenizer such as a Tissue Tearor™ to facilitate incorporation of the tissue into the aqueous gel or hydrogel carrier. Mixing of the tissue pieces or powder and rheology modifier in the water or aqueous medium can be conducted using methods known to one of skill in the art using suitable mixing equipment known to one of skill in the art, such as propeller mixers, dissolvers, homogenizers, and the like. Suitable rheology modifiers include, but are not limited to cellulose ethers, microcrystalline cellulose, acrylic polymers, alginates, gums, and organoclays, examples of which can be found in “Rheology Modifiers Handbook, Practical Use and Application,” William Andrew Publishing, 2000, herein incorporated by reference. In some embodiments, the carrier comprises one or more rheology modifiers. In some embodiments, the rheology modifier is a cellulose ether. In some embodiments, the carrier comprises one or more cellulose ethers.

[0080] In some embodiments, a feature of the dehydrated film and sheet compositions disclosed herein is that they have the capability of forming a hydrogel when they come in contact with water or other aqueous medium, such as a buffer or saline solution, or moisture from a wound. Thus, when the dehydrated film or sheet composition is applied to a wound, the moisture from the wound or external source can reconstitute the composition back into a hydrogel. The resultant hydrogel can have a sufficient viscosity that it remains on the wound and does not drain off. The dehydrated film or sheet can be capable of not disintegrating as is the case with other film wound dressings, but rather forms a hydrogel that remains on the wound creating an environment and a physical matrix or scaffold that provides conditions to support the wound healing process by allowing cellular migration, vascular ingrowth, and the formation of granulation tissues. The amount of the cellulose ether and / or plasticizer within the dehydrated film or sheet composition can vary as needed to achieve a desired viscosity inthe resultant hydrogel that is formed when the dehydrated film or sheet comes in contact with water or other aqueous medium. In some embodiments, the resultant hydrogel has a sufficient viscosity so that it will remain in a wound bed and not drain off the wound. The viscosity of the resultant hydrogel can be measured using a viscometer, such as a Brookfield viscometer. A preferred method of measuring the viscosity of the resultant hydrogel is using a Brookfield viscometer Model RV-DV2T cone & plate viscometer using cone spindle CP-52 at 0.5 RPM at RT and running for 1 minute. The sample for the viscosity measurement is prepared by contacting about 1 part by weight of the dehydrated film or sheet with about 20 parts of water or other aqueous medium such as normal saline solution. Viscosity values are reported in centipoise (cps). Viscosity values using the preferred method can be from about 100 cps to about 100,000 cps, or from about 100 cps to about 75,000 cps, or from about 100 cps to about 50,000 cps, or from about 100 cps to about 40,000 cps, of from about 100 cps to about 30,000 cps, or from about 100 cps to about 25,000 cps, or from about 100 cps to about 20,000 cps, or from about 100 cps to about 19,000 cps, or from about 100 cps to about 18,000 cps, or from about 100 cps to about 17,000 cps, or from about 100 cps to about 16,000 cps, or from about 100 cps to about 15,000 cps, or from about 100 cps to about 14,000 cps, or from about 100 cps, to about 13,000 cps, or from about 100 cps to about 12,000 cps, or from about 500 cps to about 100,000 cps, or from about 500 cps to about 75,000 cps, or from about 500 cps to about 50,000 cps, or from about 500 cps to about 40,000 cps, of from about 500 cps to about 30,000 cps, or from about 500 cps to about 25,000 cps, or from about 500 cps to about 20,000 cps, or from about 500 cps to about 19,000 cps, or from about 500 cps to about 18,000 cps, or from about 500 cps to about 17,000 cps, or from about 500 cps to about 16,000 cps, or from about 500 cps to about 15,000 cps, or from about 500 cps to about 14,000 cps, or from about 500 cps, to about 13,000 cps, or from about 500 cps to about 12,000 cps, or from about 1000 cps to about 100,000 cps, or from about 1000 cps to about 75,000 cps, or from about 1000 cps to about 50,000 cps, or from about 1000 cps to about 40,000 cps, of from about 1000 cps to about 30,000 cps, or from about 1000 cps to about 25,000 cps, or from about 1000 cps to about 20,000 cps, or from about 1000 cps to about 19,000 cps, or from about 1000 cps to about 18,000 cps, or from about 1000 cps to about 17,000 cps, or from about 1000 cps to about 16,000 cps, or from about 1000 cps to about 15,000 cps, or from about 1000 cps to about 14,000 cps, or from about 1000 cps, to about 13,000 cps, or from about 1000 cps to about 12,000 cps, or from about 5000 cps to about 100,000 cps, or from about 5000 cps to about 75,000 cps, or from about 5000 cps to about 50,000 cps, or from about 5000 cps to about 40,000 cps, of from about 5000 cps to about 30,000 cps, or from about 5000 cps to about 25,000 cps, or from about 5000 cps to about 20,000cps, or from about 5000 cps to about 19,000 cps, or from about 5000 cps to about 18,000 cps, or from about 5000 cps to about 17,000 cps, or from about 5000 cps to about 16,000 cps, or from about 5000 cps to about 15,000 cps, or from about 5000 cps to about 14,000 cps, or from about 5000 cps, to about 13,000 cps, or from about 5000 cps to about 12,000 cps, or from about 10,000 cps to about 100,000 cps, or from about 10,000 cps to about 75,000 cps, or from about 10,000 cps to about 50,000 cps, or from about 10,000 cps to about 40,000 cps, of from about10,000 cps to about 30,000 cps, or from about 10,000 cps to about 25,000 cps, or from about10,000 cps to about 20,000 cps, or from about 10,000 cps to about 19,000 cps, or from about10,000 cps to about 18,000 cps, or from about 10,000 cps to about 17,000 cps, or from about10,000 cps to about 16,000 cps, or from about 10,000 cps to about 15,000 cps, or from about10,000 cps to about 14,000 cps, or from about 10,000 cps, to about 13,000 cps, or from about10,000 cps to about 12,000 cps, or from about 12,000 cps to about 100,000 cps, or from about 12,000 cps to about 75,000 cps, or from about 12,000 cps to about 50,000 cps, or from about12,000 cps to about 40,000 cps, of from about 12,000 cps to about 30,000 cps, or from about12,000 cps to about 25,000 cps, or from about 12,000 cps to about 20,000 cps, or from about12,000 cps to about 19,000 cps, or from about 12,000 cps to about 18,000 cps, or from about12,000 cps to about 17,000 cps, or from about 12,000 cps to about 16,000 cps, or from about12,000 cps to about 15,000 cps, or from about 12,000 cps to about 14,000 cps, or from about12,000 cps, to about 13,000 cps or from about 15,000 cps to about 100,000 cps, or from about 15,000 cps to about 75,000 cps, or from about 15,000 cps to about 50,000 cps, or from about15,000 cps to about 40,000 cps, of from about 15,000 cps to about 30,000 cps, or from about15,000 cps to about 25,000 cps, or from about 15,000 cps to about 20,000 cps, or from about20,000 cps to about 100,000 cps, or from about 20,000 cps to about 75,000 cps, or from about 20,000 cps to about 50,000 cps, or from about 20,000 cps to about 40,000 cps, of from about 20,000 cps to about 30,000 cps, or from about 20,000 cps to about 25,000 cps.

[0081] The terms “films” and “sheets” as used herein can be used interchangeably, but generally a film is thinner than a sheet. The thickness of the films or sheets is a function of the amount of the hydrogel placed into a mold prior to dehydration, i.e., the more hydrogel in a given mold, will result in a thicker film or sheet after dehydrating. The thickness of the dehydrated film or sheet can be from about 0.1 mm to about 25 mm, or from about 0.1 to about 20 mm, or from about 0.1 to about 15 mm, or from about 0.1 to about 10 mm, or from about 0.1 to about 9 mm, or from about 0.1 to about 8 mm, or from about 0.1 to about 7 mm, or from about 0.1 to about 6 mm, or from about 0.1 to about 5 mm, or from about 0.1 to about 4 mm, or from about 0.1 to about 3 mm, or from about 0.1 to about 2 mm, or from about 0.1 to about1.5 mm, or from about 0.1 to about 1 mm, or from about 0.2 mm to about 25 mm, or from about 0.2 to about 20 mm, or from about 0.2 to about 15 mm, or from about 0.2 to about 10 mm, or from about 0.2 to about 9 mm, or from about 0.2 to about 8 mm, or from about 0.2 to about 7 mm, or from about 0.2 to about 6 mm, or from about 0.2 to about 5 mm, or from about 0.2 to about 4 mm, or from about 0.2 to about 3 mm, or from about 0.2 to about 2 mm, or from about 0.2 to about 1.5 mm, or from about 0.2 to about 1 mm, or from about 0.3 mm to about 25 mm, or from about 0.3 to about 20 mm, or from about 0.3 to about 15 mm, or from about 0.3 to about 10 mm, or from about 0.3 to about 9 mm, or from about 0.3 to about 8 mm, or from about 0.3 to about 7 mm, or from about 0.3 to about 6 mm, or from about 0.3 to about 5 mm, or from about 0.3 to about 4 mm, or from about 0.3 to about 3 mm, or from about 0.3 to about 2 mm, or from about 0.3 to about 1.5 mm, or from about 0.3 to about 1 mm, or from about 0.4 mm to about 25 mm, or from about 0.4 to about 20 mm, or from about 0.4 to about 15 mm, or from about 0.4 to about 10 mm, or from about 0.4 to about 9 mm, or from about 0.4 to about 8 mm, or from about 0.4 to about 7 mm, or from about 0.4 to about 6 mm, or from about 0.4 to about 5 mm, or from about 0.4 to about 4 mm, or from about 0.4 to about 3 mm, or from about 0.4 to about 2 mm, or from about 0.4 to about 1.5 mm, or from about 0.4 to about 1 mm, or from about 0.5 mm to about 25 mm, or from about 0.5 to about 20 mm, or from about 0.5 to about 15 mm, or from about 0.5 to about 10 mm, or from about 0.5 to about 9 mm, or from about 0.5 to about 8 mm, or from about 0.5 to about 7 mm, or from about 0.5 to about 6 mm, or from about 0.5 to about 5 mm, or from about 0.5 to about 4 mm, or from about 0.5 to about 3 mm, or from about 0.5 to about 2 mm, or from about 0.5 to about 1.5 mm, or from about 0.5 to about 1 mm, or from about 1 to about 25 mm, or from about 1 to about 20 mm, or from about 1 to about 15 mm, or from about 1 to about 10 mm, or from about 1 to about 9 mm, or from about 1 to about 8 mm, or from about 1 to about 7 mm, or from about 1 to about 6 mm, or from about 1 to about 5 mm, or from about 1 to about 4 mm, or from about 1 to about 3 mm, or from about 1 to about 2 mm, or from about 1 to about 1.5 mm. The film or sheet can be cut or pre-cut in any size suitable for application to a wound or tissue. The film or sheet can be transparent or opaque. Generally, dehydrated compositions which are dehydrated by lyophilization (freeze-dried) are thicker and opaquer than dehydrated compositions which are dehydrated by evaporative air-drying. Although non-limiting, evaporative air-dried compositions could be considered films whereas lyophilized compositions could be considered sheets.

[0082] In some embodiments, the dehydrated composition is opaque. In other embodiments, the dehydrated composition is transparent. In some embodiments, thedehydrated composition is translucent. In some embodiments, the dehydrated composition comprises markings, symbols, letters, or numbers, which can be helpful in identifying the source of the composition and / or can be helpful in orienting the composition during use or application to a wound (e.g., top side opposite the wound and bottom side in contact with the wound).IV. Compositions, Carriers, and Other Ingredients

[0083] The compositions of the present disclosure can include additional components such as carriers or diluents, which can be non-active components. In some aspects, the additional components do not substantially interfere with or inhibit the intended purpose of the composition.

[0084] The compositions disclosed herein can further comprise excipients, functional ingredients, and additional ingredients. Non-limiting examples of such ingredients include active pharmaceutical ingredients (APIs), absorbents, antimicrobial agents, antioxidants, antibiofilm agents, binders, buffering agents (e.g., Tris buffer solutions and PBS), bulking agents, chelating agents, colorants, debriding agents, dyes, biocides, deodorant agents, emulsion stabilizers, film formers, fragrance ingredients, humectants, gellants (e.g., cellulose ethers, microcrystalline cellulose, acrylic polymers, alginates, gums, organoclays), lytic agents, enzymes, proteolytic enzymes, opacifying agents, oxidizing agents, pH adjusters, plasticizers, preservatives (e.g., methylparaben, propylparaben, benzyl alcohol), reducing agents, emollients, humectants, hydrophilic polyols, hydrophilic polymeric polyols, polyethylene glycols, moisturizers, surfactants, emulsifying agents, cleansing agents, foaming agents, hydrotopes, solvents, suspending agents, rheology modifiers, viscosity control agents, viscosity increasing agents (e.g., thickeners), vulnerary agents, and propellants. In some embodiments, the composition does not include or contain an enzyme, a proteolytic enzyme, an antibiofilm agent, and / or a debriding agent. In some embodiments, the composition does not include or contain an active pharmaceutical ingredient.

[0085] The compositions may, for example, take the form of solutions, suspensions, instillations, sprays, salves, creams, gels, foams, ointments, emulsions, lotions, paints, sustained release formulations, dissolvable gel-forming films, or powders, and can contain any suitable concentration of active ingredient. For example, the compositions can contain about 0.01% to about 1% of active ingredient(s), about l%-50% or active ingredient(s), about 2%- 60% of active ingredient(s), about 2%-70% of active ingredient(s), or up to about 90%) of active ingredient(s). Other suitable formulations include poloxamer gel-based formulations,carboxymethylcellulose (CMC)-based formulations, hydroxylethylcellulose (HEC)-based formulations, hydroxypropycellulose (HPC)-based formulations, and hyroxypropylmethylcellulose (HPMC)-based formulations. Other useful formulations include slow or delayed release preparations. In some specific embodiments, the composition is formulated as an ointment.

[0086] Gels or jellies may be produced using a suitable gelling agent including, but not limited to, gelatin, tragacanth, or a cellulose derivative and may include glycerol as a humectant, emollient, and preservative. Ointments are semi-solid preparations that consist of the active ingredient incorporated into a fatty, waxy, or synthetic base. Examples of suitable creams include, but are not limited to, water-in-oil and oil-in-water emulsions. Water-in-oil creams may be formulated by using a suitable emulsifying agent with properties similar, but not limited, to those of the fatty alcohols such as cetyl alcohol or cetostearyl alcohol and to emulsifying wax. Oil-in-water creams may be formulated using an emulsifying agent such as cetomacrogol emulsifying wax. Suitable properties include the ability to modify the viscosity of the emulsion and both physical and chemical stability over a wide range of pH. The water soluble or miscible cream base may contain a preservative system and may also be buffered to maintain an acceptable physiological pH. In some embodiments, the compositions comprise petrolatum. In some embodiments, the compositions comprise white petrolatum.

[0087] Foam preparations may be formulated to be delivered from a pressurized aerosol canister, via a suitable applicator, using inert propellants. Suitable excipients for the formulation of the foam base include, but are not limited to, propylene glycol, emulsifying wax, cetyl alcohol, and glyceryl stearate. Potential preservatives include methylparaben and propylparaben.

[0088] Suitable carriers and diluents include isotonic saline solutions, for example phosphate-buffered saline. Suitable diluents and excipients also include, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof. In addition, if desired, substances such as wetting or emulsifying agents, stabilizing or pH buffering agents may also be present.

[0089] The term “pharmaceutically acceptable carrier” can refer to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, and amino acid copolymers.

[0090] Pharmaceutically acceptable salts can also be present, e.g., mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.

[0091] Suitable carrier materials include any carrier or vehicle commonly used as a base for creams, lotions, sprays, foams, gels, emulsions, lotions or paints for topical administration. Examples include emulsifying agents, inert carriers including hydrocarbon bases, emulsifying bases, non-toxic solvents or water-soluble bases. Examples include poloxamers, petrolatum, white petrolatum, HPMC, CMC and other cellulose-based ingredients, lanolin, hard paraffin, liquid paraffin, soft yellow paraffin or soft white paraffin, white beeswax, yellow beeswax, cetostearyl alcohol, cetyl alcohol, dimethicones, emulsifying waxes, isopropyl myristate, microcrystalline wax, oleyl alcohol and stearyl alcohol. In some embodiments, the composition comprises petrolatum. In some embodiments, the composition comprises white petrolatum.

[0092] Auxiliary agents such as casein, gelatin, albumin, glue, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose or polyvinyl alcohol may also be included in the compositions described herein.

[0093] The compositions provided herein may include hydrophobic bases. Hydrophobic bases can comprise, but are not limited to, plant, animal, paraffinic, and synthetic derived fats, butters, greases, waxes, solvents, and oils; mineral oils, vegetable oils, petrolatum, water insoluble organic esters and triglycerides, silicones, or fluorinated compounds; or mixtures thereof. In some embodiments, the hydrophobic phase comprises petrolatum.

[0094] Plant derived materials include, but are not limited to, arachis (peanut) oil, balsam Peru oil, carnauba wax, candelilla wax, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, corn oil, cotton seed oil, jojoba oil, macadamia seed oil, olive oil, orange oil, orange wax, palm kernel oil, rapeseed oil, safflower oil, sesame seed oil, shea butter, soybean oil, sunflower seed oil, tea tree oil, vegetable oil, and hydrogenated vegetable oil.

[0095] Non-limiting examples of animal derived materials include beeswax, cod liver oil, emu oil, lard, mink oil, shark liver oil, squalane, squalene, and tallow.

[0096] Non-limiting examples of paraffinic materials include isoparaffin, microcrystalline wax, heavy mineral oil, light mineral oil, ozokerite, petrolatum, and paraffin.

[0097] Suitable non-limiting examples of organic esters and triglycerides include C12-15 alkyl benzoate, isopropyl myristate, isopropyl palmitate, medium chain triglycerides, trilaurin, and trihydroxystearin.

[0098] Non-limiting examples of silicones are dimethicone and cyclomethicone. A nonlimiting example of a fluorinated compound is polytetrafluoroethylene (PTFE).

[0099] In some embodiments, the composition comprises petrolatum. In some aspects, petrolatum is a purified mixture of semisolid hydrocarbons obtained from petroleum and varies from dark amber to light yellow in color. White petrolatum is wholly or nearly decolorized petrolatum and varies from cream to snow white in color. Petrolatum and White Petrolatum can also vary in melting point, viscosity, and consistency.

[0100] Various grades are available commercially from the PENRECO Corporation under the tradenames: PENRECO®ULTIMA, PENRECO®SUPER, PENRECO®SNOW, PENRECO®REGENT, PENRECO®LILY, PENRECO®CREAM, PENRECO® ROY AL, PENRECO® BLOND, and PENRECO® AMBER. Various grades are also available commercially from the SONNEBORN Corporation under the tradenames: ALBA®, SUPER WHITE PROTOPET®, SUPER WHITE FONOLINE®, WHITE PROTOPET IS®, WHITE PROTOPET 2L®, WHITE PROTOPET 3C®, WHITE FONOLINE®, PERFECT A®, YELLOW PROTOPET 2A®, YELLOW FONOLINE®, PROTOLINE®, SONOJELL #4®, SONOJELL #9®, MINERAL JELLY #10®, MINERAL JELLY #14®, MINERAL JELLY #17®, AND CARNATION TROUGH GREASE®.

[0101] Petrolatum and White Petrolatum are available in cosmetic grade and pharmaceutical (USP / NF) grade and both are suitable for the compositions of the present disclosure.

[0102] The compositions can be anhydrous as defined herein. The compositions can be semisolid or liquid. The composition can be impregnated on a pad, gauze, or sponge. The compositions can also be sterile.

[0103] The compositions can be topical. The compositions can include additional materials known in the art that are suitable for topical compositions, e.g., absorbents, deodorizers, surfactants, solvents, rheology modifiers, film formers, stabilizers, emollients, moisturizers, preservatives, antimicrobials, antioxidants, chelating agents, fragrances, and colorants.

[0104] The compositions can also include additional pharmaceutical active ingredients known in the art that are suitable for topical compositions of this nature, e.g., antimicrobial agents, wound healing agents, anesthetic agents, vulnerary agents, and haemostatic agents. A non-limiting example of a vulnerary agent is balsam Peru.

[0105] The compositions can be packaged in any sutiable package. The compositions can be packaged in multi-use, single-dose, or metered dose packages. Non-limiting examplesinclude a tube, bottle, jar, pump container, pressurized container, bladder container, aerosol container, aerosol spray container, non-aerosol spray container, syringe, pouch, or sachet.

[0106] In some aspects, the compositions described herein can be provided in the form of a wound dressing. The wound dressing may contain one or more agents specific to a desired biomarker. The term “wound dressing” used herein is taken to include any medically or pharmaceutically acceptable wound covering or support matrix. Examples of suitable wound dressing materials include, but are not limited to, a) films, including those of a semipermeable or a semi-occlusive nature such as polyurethane copolymers, polyurethane film, acrylamides, acrylates, paraffin, polysaccharides, cellophane and lanolin; b) hydrocolloids including carboxymethylcellulose protein constituents of gelatin, pectin, and complex polysaccharides including Acacia gum, guar gum and karaya, which may be utilized in the form of a flexible foam, formulated in polyurethane, or formulated as an adhesive mass such as polyisobutylene; c) polymers such as agar, starch or propylene glycol, which typically contain about 80% to about 90% water and are conventionally formulated as sheets, powders, pastes and gels in conjunction with cross-linked polymers such as polyethylene oxide, polyvinyl pyrrolidone, acrylamide, propylene glycol; d) foams such as polysaccharide which consist of a hydrophilic open-celled contact surface and hydrophobic closed-cell polyurethane; e) impregnates including pine mesh gauze, paraffin and lanolin-coated gauze, polyethylene glycol-coated gauze, knitted viscose, rayon, and polyester; and f) cellulose-like polysaccharide such as alginates, including calcium alginate, which may be formulated as non-woven composites of fibers or spun into woven composites.

[0107] The compositions described herein may also include additional therapeutic components that are known to treat skin conditions and / or wounds. Such therapeutic components include antimicrobials such as, for example, antiseptics and antibiotics.

[0108] Antiseptics are disinfectants that can be used on intact skin and some open wounds to kill or inhibit microorganisms. They often have multiple microbial targets, a broad antimicrobial spectrum, and residual anti-infective activity but are often toxic to host tissues (e.g., fibroblasts, keratinocytes, and possibly leukocytes). Commonly used antiseptics include hydrogen peroxide, which has limited bactericidal and debriding activity; and chlorhexidine, which has long-acting activity against a wide range of both gram-negative and gram-positive bacteria.

[0109] Antibiotics are chemicals produced either naturally (by a microorganism) or synthetically that in dilute solution inhibit or kill other microorganisms. They usually act on one specific cell target, have a narrower spectrum of activity, are relatively nontoxic, and aremore susceptible to losing their effectiveness to bacterial resistance. The first topical antibiotics were derived from agents developed for systemic use (i.e., sulfonamides in the mid- 19308), followed in the next decade by topical penicillins, bacitracin, gramicidin, aminoglycosides (including neomycin), polymixin, tetracyclines, and chloramphenicol. Agents introduced later include fusidic acid, clindamycin, mupirocin and retapamulin. Antibiotics that may be used in the compositions described in the disclosure include bacitracin, fisidic acid, gentamicin, mafenide acetate, mupirocin and mupirocin calcium, neomycin sulfate, nitrofurazone, polymixin B, retapumulin, and sulfacetamide.

[0110] The compositions described herein may also comprise additional agents that reduce skin inflammation such as, for example, antihistamines, corticosteroids (e.g., hydrocortisone or clobetasol propionate), and immunosuppressants e.g., pimecrolimus and tacrolimus).

[0111] The compositions described herein may also be combined with other treatments known in the art to promote wound repair.

[0112] The compositions provided herein may also comprise any suitable agents for reducing pain, such as topical analgesics. A variety of topical analgesics may be used in connection with the compositions of the present disclosure. The most common topical analgesics are local anesthetics and anti-inflammatories such as salicylates or NSAIDS, and counter-irritants including capsaicin and aromatic compounds. Anesthetics such as lidocaine, that act on local sensory afferents, are intended to totally block pain receptors and numb the area of application. Salicylates and NSAIDS such as ibuprofen, are anti-inflammatory compounds that inhibit pain and inflammation and are generally taken internally. Counter- irritants and aromatics, especially terpenes, are substances such as menthol, oil of wintergreen, camphor, eucalyptus, mustard plasters and turpentine oil, that mask sensations of pain by stimulating local pain afferents and thereby creating a feeling of cold or heat over the affected area. Capsaicin is a natural ingredient found in cayenne peppers. Capsaicin is believed to operate in an anesthetic fashion by depleting Substance-P from sensory afferents and thereby suppressing transmission of pain to the brain. Menthol is a compound obtained from peppermint oils, or other mint oils, or made synthetically. Menthol has local anesthetic and counterirritant qualities. Topical analgesics can include menthol / menthyl derivatives, such as 1-menthol or menthyl lactate. Capsaicin, or other capsaicinoids, vanilloids, or vanillyl butyl ether, may also be used.V. Methods of Use

[0113] Disclosed are methods of treating a wound, such as with any of the sterilized hydrogel compositions provided herein.

[0114] In some aspects, provided herein is a method of manufacturing a sterilized hydrogel composition. In some embodiments, the method comprises contacting an extracellular matrix material, a hydrophilic polyol, and a cellulose ether with an aqueous medium to form a hydrogel. In some embodiments, the method comprises sterilizing the hydrogel to form a sterilized hydrogel. In some aspects, provided herein is a method of treating a wound in a subject, the method comprising applying to the wound any of the hydrogel compositions provided herein.

[0115] In some embodiments, the wound comprises any of: a chronic wound, an ulcer, a diabetic ulcer, a foot ulcer, a diabetic foot ulcer, a venous ulcer, a venous leg ulcer, a leg ulcer, a pressure ulcer, a bum, a thermal bum, a chemical bum, a partial thickness burn, a full thickness burn, a laceration, a scrape, an incision, a puncture, a wound caused by a projectile, an epidermal wound, a dermal wound, a surgical wound, an acute wound, a congenital wound, a toxic epidermal necrolysis, an epidermolysis bullosa, or a pyoderma gangrenosum. In some embodiments, the wound is a dermal wound.

[0116] The compositions and methods disclosed herein can, in some aspects, be useful for the treatment of wounds of a subject by applying the compositions to or on the wound. A wound can include a disruption of the stmcture and function of tissue. In addition to the other nonlimiting examples disclosed elsewhere herein, wounds can include: internal organ wounds; mucous membrane wounds; vascular tissue wounds; soft tissue wounds including ligaments, tendons, and cartilage; bone wounds; and dermal wounds. In some aspects, the wound is a dermal wound. In some aspects, the compositions can be applied topically to a dermal wound. In some aspects, the compositions can be applied so as to be in direct contact with at least a portion of the wound surface.

[0117] A dermal wound may involve the disruption of the skin and associated soft tissue architecture. Dermal wounds may be partial or full thickness wounds. They may also be acute wounds, chronic wounds, or bums, which may be acute or chronic. Non-limiting examples of a bum wound include a superficial (first degree) bum, a partial thickness (second degree) bum, a full thickness (third degree) burn, or a radiation bum. Non-limiting examples of a chronic wound include a dermal ulcer, a diabetic ulcer, a diabetic foot ulcer, a venous ulcer, a venous leg ulcer, an arterial ulcer, an arterial leg ulcer, a decubitus ulcer, a stasis ulcer, an ischemic ulcer, a vascular ulcer, a pressure ulcer (stage I-IV), a podiatric wound, a draining wound, atunneling wound, or an undermining wound. Non-limiting examples of an acute wound include a trauma wound, a laceration, an abrasion, a skin tear, a skin lesion, a blister, a surgical incision, a donor skin site, a skin graft, a laser surgery wound, a Mohs surgery wound, or a dehisced wound. In some aspects, the dermal wound includes necrotic tissue. In some aspects, removal of the necrotic tissue is facilitated by a method of debridement.

[0118] In some aspects, compositions disclosed herein may provide a topical wound covering which functions as a protective barrier for the wound.

[0119] In some aspects, compositions disclosed herein may be used as a dressing to provide a physical barrier for the management of chronic wounds (such as diabetic foot ulcers, venous leg ulcers, pressure ulcers), acute wounds, and in the post-operative care of surgical incisions. In some aspects, compositions disclosed herein may be sutured onto the wound bed, which either independently or in combination with its physical barrier function, may protect the innate wound healing response. In some aspects, the subject device may also act as a biodegradable scaffold that supports the body’s own wound healing processes.

[0120] In some aspects, the compositions disclosed herein may be used, optionally as a wound dressing, for management of chronic, acute and post-surgical exuding wounds including partial- and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled, surgical wounds (e.g., donor sites / grafts, post-Mohs surgery, postlaser surgery, podiatric, wound dehiscence), trauma wounds (e.g., abrasions, lacerations, second-degree bums and skin tears), and draining wounds. In some aspects, the compositions disclosed herein may be used as a dressing to provide a protective cover to chronic wounds, acute wounds, and in post-operative care of surgical incisions. In some aspects, the dressing may promote an environment that helps with wound management by serving as protective barrier. In some aspects, the dressing’s thickness and tensile strength may enable the dressing to be sutured on the wound.

[0121] In some aspects, the compositions disclosed herein may provide benefits, including barrier that protects the wound environment, ability to suture the subject device on the wound, terminal sterilization and viral inactivation reducing the risk of microbial and viral contamination of the device, ability of biodegrading within 10-21 days (e.g., at least, at most, exactly, or between any two of 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days), elasticity properties of subject device which may allow it to conform to complex wound anatomy, and / or availability in multiple sizes.

[0122] In another aspect, the compositions or methods disclosed herein may be applied to the wound periodically, for example, daily. A therapeutic regimen could be followed to includeperiodic dressing changes with wound cleansing and application of fresh composition between changes until the wound is healed. The compositions and methods may be applied in conjunction with the application of other wound dressings including but not limited to gauze bandages, sponge wound dressings, foam wound dressings (e.g., ALLEVYN™ foam dressing), antimicrobial wound dressings, ECM based wound dressings, placental tissue wound dressings, wound debriding dressings, calcium alginate dressings, hydrogels, and wound dressings with vulnerary agents. For example, after application of the composition, the wound may be covered with another wound dressing. The composition can be applied before or after the application of another wound dressing. The method may be performed before or after the application of another wound dressing.

[0123] In some aspects, the sterilized hydrogels disclosed herein may be applied to a wound after an aqueous medium is applied to the wound. In some aspects, the sterilized hydrogels disclosed herein may be applied to a wound before an aqueous medium is applied to the wound.

[0124] In some aspects, the sterilized hydrogels disclosed herein may support and promote subsequent wound healing processes, such as cellular migration, vascular ingrowth, and / or the formation of granulation tissues.VI. Kits and Packaging

[0125] The compositions of the present disclosure may be packaged in any package configuration suitable, for example, for use in storing, shipping, and / or using the compositions of the present disclosure. Non-limiting examples of packaging configurations may include containers, such as plastic packages, foil packages, pouches, packets, and / or boxes. In certain aspects where the composition is flowable (e.g., in liquid or hydrogel form), the compositions bottles, jars, bottles with pumps, toddles, tubes (e.g., aluminum, plastic, or laminated), jars, non-aerosol pump sprayers, and / or aerosol containers could be used. The packages may be configured for single-dose or multiple-dose administration.

[0126] Containers such as kits that have multiple compartments may also be used. For instance, the different components of the sterilized hydrogel (e.g., the first component, second component, ECM material, hydrophilic polyol, and / or cellulose ether) can be provided in different compartments. Kits may also include 3, 4, 5, or more additional compartments or containers.

[0127] In various aspects, the compositions described herein can be provided in a kit, such as a kit comprising the sterilized hydrogel or one or more components of the sterilized hydrogel.

[0128] Packaging may also include informational material relating to the compositions of the present disclosure. In various aspects, the informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and / or to the use of the sterilized hydrogel compositions, such as for the methods described herein. Instructions may include an explanation of how to apply, use, and maintain the products or compositions, for example in accordance with the methods provided herein.EXAMPLES

[0129] The following examples are included to demonstrate aspects of the present disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the present disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.I. Example 1 - Hydrogel Sterilization by Irradiation with Maintenance of Mechanical Properties

[0130] A hydrogel composition is prepared and the effects of irradiation on the mechanical properties of the hydrogel is assessed.

[0131] A hydrogel is prepared by combining in an aqueous medium: an ECM material (such as from placenta or decidua), polyethylene glyocol (PEG; an exemplary hydrophilic polyol), and cellulose ethers including hydroxyethyl cellulose (HEC) and hydroxypropylmethyl cellulose (HPMC).

[0132] The hydrogel is sterilized by irradiation with 20 kGy, 30 kGy, or 40 kGy of UV irradiation, gamma irradiation, or electron beam irradiation. A control hydrogel is not irradiated.

[0133] The control and irradiated hydrogels are assessed for one or more mechanical properties, including elasticity, viscosity, rigidity, ability to absorb an aqueous medium, and ability to swell when contacted with an aqueous medium. On or more of the mechanical properties are maintained or increased in the irradiated hydrogels in comparison to the controlhydrogels. The maintained or increased mechanical properties support the utility of the sterilized hydrogels for therapeutic use, such as in the treatment of wounds as described herein.***

[0134] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred aspects, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.

Claims

CLAIMS1. A sterilized hydrogel composition comprising: a first component comprising an extracellular matrix (ECM) material; and a second component comprising a hydrogel including a plasticizer and a cellulose ether, wherein the sterilized hydrogel composition is capable of absorbing water and swelling when contacted with an aqueous medium.

2. A method of manufacturing a sterilized hydrogel composition, the method comprising: obtaining a first component comprising an ECM material; combining the first component with a second component comprising a hydrogel including a plasticizer and a cellulose ether to form the hydrogel composition; and sterilizing the hydrogel composition, wherein the sterilized hydrogel composition capable of absorbing water and swelling when contacted with an aqueous medium.

3. A method of treating a wound in a subject, the method comprising applying to the wound the sterilized hydrogel composition of claim 1, or the sterilized hydrogel composition produced by the method of claim 2.

4. The method of claim 3, wherein the wound comprises any of: a chronic wound, an ulcer, a diabetic ulcer, a foot ulcer, a diabetic foot ulcer, a venous ulcer, a venous leg ulcer, a leg ulcer, a pressure ulcer, a burn, a thermal bum, a chemical burn, a partial thickness burn, a full thickness burn, a laceration, a scrape, an incision, a puncture, a wound caused by a projectile, an epidermal wound, a dermal wound, a surgical wound, an acute wound, a congenital wound, a toxic epidermal necrolysis, an epidermolysis bullosa, or a pyoderma gangrenosum.

5. The method of any one of claims 3-4, wherein an aqueous medium is applied to the wound before the sterilized hydrogel composition is applied to the wound, or wherein anaqueous medium is applied to the wound after the sterilized hydrogel composition is applied to the wound.

6. The composition or method of any one of claims 1-5, wherein the ECM material is an ECM hydrogel.

7. The composition or method of any one of claims 1-5, wherein the ECM material is lyophilized ECM.

8. The composition or method of any one of claims 1-7, wherein the ECM material is from one or more tissues selected from: dermis, tendon, forestomach, small intestinal submucosa, liver, bone, adipose, brain, colon, cornea, esophagus, heart, liver, lung, small intestine, tooth, urinary bladder, and placenta, optionally wherein the placenta tissue is from amnion, chorion, and / or decidua.

9. The composition or method of any one of claims 1-8, wherein the ECM material comprises up to 75% w / w of the hydrogel.

10. The composition or method of any one of claims 1-9, wherein the plasticizer comprises one or more hydrophilic polyols or one or more polyethylene glycols (PEGs).

11. The composition or method of any one of claims 1-10, wherein the plasticizer comprises 1% w / w to 30% w / w of the hydrogel.

12. The composition or method of any one of claims 1-11, wherein the cellulose ether comprises hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), or a combination thereof.

13. The composition or method of any one of claims 1-12, wherein the cellulose ether comprises 1% w / w to 80% w / w of the hydrogel.

14. The composition or method of any one of claims 1-13, wherein the second component is formed by contacting an aqueous medium with the plasticizer and the cellulose ether.

15. The composition or method of any of one claims 1-14, wherein one or more mechanical properties of the sterilized hydrogel are maintained or increased in comparison to the hydrogel prior to sterilization or a control hydrogel not comprising the plasticizer and / or not comprising the cellulose ether, and wherein the one or more mechanical properties areselected from the list consisting of: elasticity, viscosity, rigidity, ability to absorb an aqueous medium, and ability to swell when contacted with an aqueous medium.

16. The composition or method of any one of claims 1-15, wherein the sterilization comprises at least 10 kGy, at least 20 kGy, at least 30 kGy, or at least 40 kGy irradiation of the hydrogel composition.

17. The composition or method of any of one claims 1-16, wherein the first component and / or the second component are provided as dehydrated or lyophilized compositions prior to formation of the sterilized hydrogel composition.

18. The composition or method of any one of claims 1-17, wherein the first component and / or the second component are provided as hydrated compositions prior to formation of the sterilized hydrogel composition.

19. The composition or method of any one of claims 1-18, wherein the sterilized hydrogel composition is formed by contacting an aqueous medium with the first component and / or the second component.

20. The composition or method of any one of claims 1-19, wherein the hydrogel composition is sterilized after hydrating the first component and the second component.