WO2021014357A1

WO2021014357A1 - Collagen-based biomaterials for wound management

Info

Publication number: WO2021014357A1
Application number: PCT/IB2020/056853
Authority: WO
Inventors: Diwi ALLEN; Prathamesh Madhav KHARKAR
Original assignee: Kci Licensing, Inc.
Priority date: 2019-07-23
Filing date: 2020-07-21
Publication date: 2021-01-28

Abstract

of the Disclosure A bioresorbable sterile composition that may be delivered to a wound, such as a wound with complex architecture, systems for delivering such sterile compositions, and methods of use are described. The bioresorbable sterile composition can include about 0.001 wt.% to about 50 wt.% of solid collagen, about 0.001 wt.% to about 80 wt.% of a bioresorbable polymer, about 20 wt.% to about 99.998 wt.% of saline solution that optionally further comprises a biocompatible dye, and optionally about 0.05 wt.% to about 10 wt.% of an antimicrobial agent. The bioresorbable material delivery system contains at least two compartments and contains components for creating a slurry of collagen and a bioresorbable polymer. The method of use applies the slurry created in the bioresorbable material delivery system to a wound.

Description

COLLAGEN-BASED BIOMATERIALS FOR WOUND MANAGEMENT

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62/877,572, filed on July 23, 2019, which is incorporated herein by reference in its entirety.

FIELD

[0002] The claimed subject matter relates generally therapy of a tissue site and, more particularly, but without limitation, to sterile compositions, bioresorbable material delivery systems, and methods for facilitating wound healing.

BACKGROUND

[0003] A wide variety of materials and devices are generally known in the art for use in treating an injury or other disruption of tissue. Such wounds may be the result of trauma, surgery, or disease, and may affect skin or other tissues. In general, these devices and materials may control bleeding, absorb wound exudate, ease pain, assist in debriding the wound, protect wound tissue from infection, or otherwise promote healing and protect the wound from further damage. Some materials may protect tissue from, or even assist in the treatment of, infections associated with wounds. Infections can retard wound healing and, if untreated, can result in tissue loss, systemic infections, septic shock, and death.

[0004] Some wounds have complex wound geometries that may be difficult to navigate through the opening in the skin. Tunneling wounds, diabetic ulcers, and underminings are several examples of complex wound geometries. These wounds can benefit from delivery of actives and biomaterials inside the wound bed.

SUMMARY

[0005] The present disclosure provides a sterile composition, a bioresorbable material delivery system, and a method of use for the composition and bioresorbable material delivery system. The sterile slurry composition may include about 0.001 wt.% to about 50 wt.% of solid collagen, about 0.001 wt.% to about 80 wt.% of a bioresorbable polymer, about 20 wt.% to about 99.998 wt.% of saline solution further comprising a biocompatible dye, and about 0.05 wt.% to about 10 wt.% of an antimicrobial agent. In certain embodiments, the bioresorbable polymer may be oxidized regenerated cellulose (ORC), hyaluronic acid, alginate, gelatin, or chitosan. In some embodiments, the bioresorbable polymer may be ORC. The ORC, optionally, may be powdered. In certain

embodiments, the antimicrobial agent comprises one or more of copper, polyhexamethylene biguanide (PHMB), silver, ionic silver, zinc, zinc oxide, chlorhexidine, and iodine. In some embodiments, the biocompatible dye fluoresces and/or is visible through tissue of a subject. The composition may be stable when stored from -80°C to 35°C. In some embodiments, the composition may be stored at room temperature.

[0006] In some embodiments, the raw materials for the composition may be obtained from milled collagen ORC sheets post-freeze drying. In other embodiments, the raw materials may be obtained from discarded pieces of collagen-ORC. In certain embodiments, discarded collagen-ORC may be skimmed off a freeze-dried collagen-ORC composition when forming a sheet. The discarded collagen-ORC also may be from a rejected sheet of collagen-ORC. In some embodiments, the collagen and the oxidized regenerated cellulose are byproducts from sheets of a sterile, freeze-dried composite of 44% ORC, 55% collagen, and 1% silver-ORC, wherein the silver-ORC contains 25% w/w ionically bound silver. The collagen also may be in the form of a gelatin.

[0007] In certain embodiments, the composition may be stored between about 15°C to about 35°C. In certain embodiments, the composition may be stored between about 20°C to about 27°C.

[0008] In accordance with yet another aspect of the present disclosure, a bioresorbable material delivery system is described. The bioresorbable material delivery system may include a flexible housing with at least two compartments. The flexible housing may be transparent, translucent, opaque, or some combination of the two. In some embodiments, the flexible housing may include one or more windows to visualize mixing of the contents therein. A first compartment may contain saline solution and optionally a biocompatible dye. A second compartment may contain oxidized regenerated cellulose (ORC) and solid collagen. There may be a releasable internal boundary situated between the first compartment and the second compartment, and an outlet valve in fluid

communication with one of the compartments. In certain embodiments, the outlet valve is in fluid communication with the second compartment. At least one of the compartments further may contain an antimicrobial agent. The antimicrobial agent may be one or more of, but is not limited to, silver, ionic silver, zinc, PHMB, chlorhexidine, and iodine. In some embodiments, at least one of the compartments may further contain zinc or zinc oxide. In certain embodiments, at least one of the compartments also may contain hyaluronic acid, alginate, gelatin or chitosan.

[0009] In some embodiments, the bioresorbable material delivery system may be stable at any temperature between about -80°C to about 35°C for 18 months or more. In certain embodiments, the bioresorbable material delivery system may be stored between about 15°C to about 35°C. In certain embodiments, the bioresorbable delivery system may be stored between about 20°C to about 27°C. In other embodiments, the bioresorbable delivery system may be stored between 4°C to about -80°C.

[0010] The releasable internal boundary may be a breakable seal. The seal can be manufactured using heat sealing or RF welding, among other modes of manufacture. The releasable internal boundary may be a removable tag. The outlet valve of the delivery system may be a lumen with a port at a distal end or proximal end, and the port may open when the internal pressure of the housing exceeds a minimum threshold. The distal end of the outlet valve may be configured to couple to a catheter, syringe, and/or a needle. The catheter, syringe, and/or needle may be configured to enter complex wound geometries. Examples of complex wound geometries include, but are not limited to, diabetic ulcers, tunneling wounds, and underminings. The catheter tip also may be flexible. The catheter may also be a tube made of medical grade materials.

[0011] In some embodiments, the releasable internal boundary may be configured to allow fluid to only pass from the first compartment to the second compartment, and not for solids to pass from the second compartment to the first compartment.

[0012] In an alternative embodiment, the bioresorbable material delivery system may include a third compartment with one or more releasable internal boundary situated on one or more side of the third compartment adjoined to the second compartment and/or the first compartment. In certain embodiments, a third compartment with a releasable internal boundary may be the common boundary for all three compartments of the housing. The third compartment, in some embodiments, may contain a hydrogel or precursors that can form a hydrogel when contacted with an aqueous solution.

[0013] In one embodiment of the disclosure, the bioresorbable material delivery system may include two or more compartments where at least one compartment can be saved for later use. The housing of the bioresorbable material delivery system also may maintain a barrier from external elements for aseptic delivery of the contents in the housing. The releasable internal boundary may be situated on a top side, a bottom side, a front side, a back side, a left side or a right side of a compartment, with the front side referring to the side with a releasable internal boundary that is closest to the outlet valve.

[0014] In accordance with yet another aspect of the present disclosure, a method of use for wound treatment using the sterile composition and bioresorbable material delivery system is described. In some embodiments, the method may include release of a releasable internal boundary. In certain embodiments, the releasable internal boundary may be released by removal of a tag. In other embodiments, the releasable internal boundary may be released by applying a pressure. The releasable internal boundary may be released by applying pressure to the housing by using a user’s hand. The releasable internal boundary may be released by applying mechanical pressure to the housing. In certain methods, the releasable internal boundary is released by applying pressure to the housing mechanically using an instrument, apparatus, or machine. The releasable internal boundary may also be released by applying pressure to certain parts of the housing. In certain embodiments, the method may include the pressure required to release the releasable internal boundary is applied to the first compartment. In other embodiments, the pressure required to release the releasable internal boundary is applied to any compartment.

[0015] In one embodiment, the method may include: (i) releasing the releasable internal boundary;

(ii) moving a saline solution optionally containing a biocompatible dye from the first compartment to the second compartment containing solid collagen, powdered ORC and optionally an antimicrobial such as silver; (iii) mixing the saline solution with the solid collagen, powdered ORC, and optional antimicrobial agent to create a homogenous slurry; (iv) moving the slurry through an outlet valve. In some embodiments, optionally, drawing the slurry into a syringe in fluid communication with one compartment, or optionally moving the slurry into a catheter, syringe, and/or a needle; and (v) applying the slurry to a wound optionally through the catheter, syringe, and/or needle. In certain embodiments, gravity may move the saline solution from the first compartment to the second compartment in step (ii) and/or the slurry through the valve in step (iv).

[0016] In certain versions of the method, pressure may be applied to the housing to release the releasable internal boundary. In certain versions of the method, pressure may be applied to the housing manually, such as by squeezing, pressing, or pinching with a hand. In other versions of the method, the pressure may be applied mechanically. The pressure applied to break the releasable internal boundary may be applied to the first compartment. The pressure applied to break the releasable internal boundary also may be applied to any compartment.

[0017] The slurry may be applied to a complex wound geometry. In some embodiments of the method, the slurry may be applied directly in a wound. The biocompatible dye or pigment in the saline solution also may be used to visualize homogenous mixing of the slurry during and after step

(iii). The biocompatible dye optionally may include antimicrobial agents, including, but not limited to, one or more of copper, PHMB, silver, ionic silver, zinc, chlorhexidine, and iodine. The biocompatible dye or pigment also may be used to visualize the location of the slurry upon entering and dispersing within a three-dimensional wound geometry. In some embodiments, gelatin may be added to at least one compartment to give matrix metalloproteases (MMPs) instant access to a sacrificial substrate.

BRIEF DESCRIPTION OF THE DRAWINGS [0018] FIG. 1 shows a top perspective of an exemplary bioresorbable material delivery system containing a sterile composition for wound therapy.

[0019] FIG. 2 illustrates a top perspective of a bioresorbable material delivery system containing a sterile composition with two compartments and a flexible catheter attached to an outlet valve.

[0020] FIG. 3A depicts a top perspective of a bioresorbable material delivery system containing a sterile composition with three compartments.

[0021] FIG. 3B depicts atop perspective of a bioresorbable material delivery system containing a sterile composition with three compartments where a compartment shares at least one common releasable internal boundary.

[0022] FIG. 4 is a top perspective of a bioresorbable material delivery system containing a sterile composition with more than two compartments where the contents of at least one compartment may be saved for later use.

[0023] FIG. 5 illustrates a method of wound treatment using a bioresorbable material delivery system containing a sterile composition.

DETAILED DESCRIPTION

[0024] The following terms are used throughout as defined below.

[0025] As used herein and in the appended claims, singular articles such as“a” and“an” and“the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non- claimed element as essential.

[0026] As used herein,“about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used,“about” will mean up to plus or minus 10% of the particular term.

[0027] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as“up to,”“at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. All language such as“greater than,”“less than,” refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

[0028] As used herein and in the appended claims, a“minimum” is an amount sufficient to produce a desired result. For example, a minimum pressure threshold sufficient to induce breakage of an internal releasable boundary as used herein may be any amount of psi that will break the internal releasable boundary.

[0029] A bioresorbable sterile composition that may be delivered to a wound, systems for delivering such sterile compositions, and methods of use are described herein. The bioresorbable sterile composition includes about 0.001 wt.% to about 50 wt.% of solid collagen, about 0.001 wt.% to about 80 wt.% of a bioresorbable polymer, such as oxidized regenerated cellulose (ORC), about 20 wt.% to about 99.998 wt.% of saline solution optionally further comprising a biocompatible dye, and optionally about 0.05 wt.% to about 10 wt.% of an antimicrobial agent. The collagen and/or ORC may be from a freeze-dried collagen-ORC matrix. The bioresorbable material delivery system may contain at least two compartments and further may contain components for creating a slurry. The method of use applies a slurry created in the bioresorbable material delivery system to a wound, including those that have complex geometries. As used herein,“complex wound geometries” include, but are not limited to, tunneling wounds, diabetic ulcers, and underminings.

[0030] As used herein, wt.% is compared to the combined weight of the components that make up the sterile slurry composition. Referring to FIG. 1, an exemplary bioresorbable material delivery system containing components for creating a sterile composition for wound therapy in accordance with the principles of the present disclosure is described. The sterile composition may have about 0.001 wt.% to about 50 wt.% of solid collagen 100 as compared to the total weight of the components for creating the sterile slurry composition; about 0.001 wt.% to about 80 wt.% of oxidized regenerated cellulose (ORC) 102; about 20 wt.% to about 99.998 wt.% of saline solution 104 and biocompatible dye 106; and about 0.001 wt.% to about 10 wt.% of an antimicrobial agent 108. In some embodiments, the weight ratio of collagen 100 to ORC 102 is about 60:40 to about 40:60. In some embodiments, a micronized collagen-ORC powder may include particles sized from about 100 microns to about 500 microns.

[0031] The amount of collagen 100 in the composition may be about 0.001 wt.%, about 0.01 wt.%, about 0.1 wt.%, about 1 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 22 wt.%, about 24 wt.%, about 26 wt.%, about 28 wt.%, about 30 wt.%, about 32 wt.%, about 34 wt.%, about 36 wt.%, about 38 wt.%, about 40 wt.%, about 42 wt.%, about 44 wt.%, about 46 wt.%, about 48 wt.%, about 50 wt.%, or any range including and/or in between any two of these values.

[0032] The amount of ORC 102 in the composition may be about 0.001 wt.%, about 0.01 wt.%, about 0.01 wt.%, about 0.1 wt.%, about 1 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 22 wt.%, about 24 wt.%, about 26 wt.%, about 28 wt.%, about 30 wt.%, about 32 wt.%, about 34 wt.%, about 36 wt.%, about 38 wt.%, about 40 wt.%, about 42 wt.%, about 44 wt.%, about 46 wt.%, about 48 wt.%, about 50 wt.%, about 52 wt.%, about 54 wt.%, about 56 wt.%, about 58 wt.%, about 60 wt.%, about 62 wt.%, about 64 wt.%, about 66 wt.%, about 68 wt.%, about 70 wt.5, about 72 wt.%, about 74 wt.%, about 76 wt.%, about 78 wt.%, about 80 wt.%, or any range including and/or in between any two of these values.

[0033] The amount of saline in the composition may be about 20 wt.%, about 22 wt.%, about 24 wt.%, about 26 wt.%, about 28 wt.%, about 30 wt.%, about 32 wt.%, about 34 wt.%, about 36 wt.%, about 38 wt.%, about 40 wt.%, about 42 wt.%, about 44 wt.%, about 46 wt.%, about 48 wt.%, about 50 wt.%, about 52 wt.%, about 54 wt.%, about 56 wt.%, about 58 wt.%, about 60 wt.%, about 62 wt.%, about 64 wt.%, about 66 wt.%, about 68 wt.%, about 70 wt.5, about 72 wt.%, about 74 wt.%, about 76 wt.%, about 78 wt.%, about 80 wt.%, about 82 wt.%, about 84 wt.%, about 86 wt.%, about 88 wt.%, about 90 wt.%, about 92 wt.%, about 94 wt.%, about 96 wt.%, about 98 wt.%, about 99 wt.%, about

99.998 wt.%, or any range including and/or in between any two of these values. [0034] In certain embodiments, collagen may be powdered. In certain embodiments, ORC 102 may be powdered. Antimicrobial agent 108 may be one or more of copper, PHMB, silver, ionic silver, zinc, chlorhexidine, and iodine. Biocompatible dye 106 may also fluoresce.

[0035] The pre-mix composition may be stable when stored at about -80°C to about 35°C for at least 18 months. In some embodiments, composition 10 may be stored at room temperature. In some embodiments, composition 10 may be stored between about 15° C to about 35°C. In some embodiments, composition 10 may be stored between about 20° C to about 27° C.

[0036] In some embodiments, the raw materials for the collagen and ORC in composition 10 may be obtained from newly synthesized collagen-ORC 110 milled powder. In other embodiments, the raw materials for the collagen and ORC in composition 10 may be obtained from discarded pieces of collagen-ORC 110. The raw materials may also be a mix of newly synthesized collagen-ORC 110 milled powder and discarded pieces of collagen-ORC 110. This use of discarded materials lowers the cost of production significantly compared to other complex wound geometry biomaterials. In some embodiments, discarded collagen-ORC 110 is skimmed off a freeze-dried collagen-ORC composition when forming a sheet. In some embodiments, discarded collagen-ORC 110 is from a rejected sheet.

[0037] Collagen 100 and ORC 102 may be byproducts from sheets of a sterile, freeze-dried composite of 44% ORC, 55% collagen, and optionally 1% silver-ORC, where in some embodiments, the silver contains 25% w/w ionically bound silver. In some embodiments, the composition from which the byproducts are derived is known as PROMOGRAN™ and/or PROMOGRAN PRISMA™. Collagen 100 may be from a gelatin.

[0038] Composition 10 further may include hyaluronic acid, alginate, gelatin, or chitosan.

Composition 10 further may include hyaluronic acid, alginate, gelatin, or chitosan in lieu of ORC 102.

[0039] In a further related aspect, an exemplary bioresorbable material delivery system in accordance with the principles of the present disclosure is described. FIGS. 1-4 depict certain exemplary embodiments of the bioresorbable material delivery system containing sterile composition.

[0040] Referring to FIG. 1, bioresorbable material delivery system 200 may include flexible housing 202 having at least two compartments within housing 202. In certain embodiments, flexible housing 202 may be transparent. In certain embodiments, flexible housing 202 may be opaque. In some embodiments, flexible housing 202 further may have windows to visualize mixing. First compartment 206 may contain saline solution 104 and further may include biocompatible dye 106. Second compartment 208 may contain ORC 102 and solid collagen 100 and/or collagen-ORC 110. Releasable internal boundary 210 may be situated between first compartment 206 and second compartment 208. In some embodiments, outlet valve 212 can be attached in fluid communication with either first compartment 206 or second compartment 208. In certain embodiments, outlet valve 212 may be a one-way valve. In certain embodiments, outlet valve 212 is attached in fluid communication with second compartment 208.

[0041] In certain embodiments of bioresorbable delivery system 200, at least one of the compartments further contains antimicrobial agent 108. In some embodiments, antimicrobial agent 108 may be, but is not limited to, one or more of silver, ionic silver, zinc, PHMB, chlorhexidine, and iodine. In some embodiments, at least one compartment further may contain zinc or zinc oxide. In some embodiments, at least one compartment further may contain hyaluronic acid, alginate, gelatin, or chitosan, or a combination thereof.

[0042] Delivery system 200 may be stored stably at about -80°C to about 35°C for at least 18 months. In certain embodiments, delivery system 200 may be stored at room temperature. In some embodiments, delivery system 200 may be stored between about 15 °C to about 35 ° C. In some embodiments, delivery system 200 may be stored between about 20 °C to about 27 °C.

[0043] Releasable internal boundary 210 further may be a breakable seal 216. Breakable seal 216 can be manufactured using a variety of methods, including, but not limited to, heat sealing or RF welding.

[0044] Referring again to FIG. 1, delivery system 200 further may have outlet valve 212. Outlet valve 212 may include port 220 at a distal end 222, or proximal end, or therebetween, of lumen 218. Port 220 may be configured to open when the internal pressure of housing 202 exceeds a minimum threshold.

[0045] Referring to FIG. 2, distal end 222 of outlet valve 212 may be further configured to couple to catheter 224. Catheter 224 may be configured to enter complex wound geometries (CWG).

Examples of complex wound geometries include, but are not limited to, diabetic ulcers, tunneling wounds, and underminings. In some embodiments, a tip 225 on a distal end 228 of catheter 224 is flexible. In some embodiments, tip 225 may range from about 18G to about 24G and can be attached for dispensing.

[0046] Releasable internal boundary 210 may be configured to allow fluid to only pass into second compartment 208, and not for solids from second compartment 208 to pass into first compartment 206.

[0047] Referring now to FIG. 3A, in an alternative embodiment, delivery system 200 further may have third compartment 230 with releasable internal boundary 232 situated on side 234 of third compartment 230 adjoined to second compartment 208. Referring now to FIG. 3B, in yet another alternative embodiment, the delivery system may have third compartment 230’ with releasable internal boundary 232’ which acts as a common boundary for all three compartments. In some embodiments, either or both of third compartment 230 or third compartment 230’ may contain a hydrogel or components that will produce a hydrogen when combined with the components in first and second compartments.

[0048] Referring now to FIG. 4, in some embodiments of delivery system 200, there may be more than two compartments and at least one compartment 237 may be saved for later use. In other embodiments, a compartment other than compartment 237 may be saved for later use.

[0049] Housing 202 is designed to maintain a barrier from external elements for aseptic delivery of the sterile composition. Moreover, releasable internal boundary 232 may be situated on any of top side 238 (referring to the side with a releasable internal boundary that is closest to the outlet valve), bottom side 240 (referring to the side with a releasable internal boundary that is closest to the outlet valve), left side (referring as if facing the top side and shown in FIG. 4 regarding the top left compartment) 242, or right side 244 (referring as if facing the top side) of a compartment.

[0050] In a further related aspect, an exemplary method of using bioresorbable material delivery system 200 to deliver a sterile composition to a wound in accordance with the principles of the present disclosure is also described. Referring now to FIG. 5, the method may include (i) releasing releasable internal boundary 210, (ii) moving saline solution 104, which may include biocompatible dye 106, from first compartment 206 to second compartment 208, which may include solid collagen 100, powdered ORC 102 and optionally antimicrobial agent 108 (not shown); (iii) mixing saline solution 104, optional biocompatible dye 106, solid collagen 100, powdered ORC 102, and optional antimicrobial agent 108 (not shown) to create homogenous slurry 300, (iv) pushing slurry 300 through outlet valve 212 in fluid communication with a compartment into catheter 224, and (iv) applying slurry 300 to a wound through catheter 224.

[0051] In certain embodiments of the method, the pressure applied to housing 202 may be applied manually. The pressure applied to housing 202 further may be applied mechanically, for example, within a machine used for antiseptic application and treatment. In certain embodiments of the method, the pressure may be applied through bending or squeezing. The pressure required to break releasable internal boundary 210 also may be applied to first compartment 206. Moreover, in certain embodiments of the method, the pressure applied to break releasable internal boundary 210 can also be applied to any compartment within the housing. Housing 202 may be clear and squeezable to enable visualization of collagen 100 turning from a white powder into a cream or other color when fully hydrated. [0052] Slurry 300 also may be applied to a complex wound geometry (CWG), as illustrated in FIG. 5 In certain instances, slurry 300 may be applied through catheter tip 225 directly into the CWG. Biocompatible dye 106 in saline solution 104 may be used to visualize homogenous mixing of slurry 300 Biocompatible dye 106 also may be used to visualize the location of slurry 300 upon entering and dispersing within a three-dimensional CWG. In some instances, the biocompatible dye is a florescent dye or is capable of being visualized through biological tissue.

[0053] In the disclosed methods, gelatin also may be added to give matrix metalloproteases instant access to sacrificial substrate. Further, antimicrobial agent 108 in the disclosed methods may be, but is not limited to, one or more of copper, PHMB, silver, ionic silver, zinc, chlorhexidine, and iodine.

[0054] While various illustrative embodiments of the invention are described above, it will be apparent to one of skill in the art that various changes and modifications may be made therein without departing from the invention. The appended claims are intended to cover all such changes and modifications that fall within the true scope of the invention.

Claims

WHAT IS CLAIMED IS:

1. A bioresorbable sterile slurry composition comprising:

about 0.001 wt.% to about 50 wt.% of a solid collagen;

about 0.001 wt.% to about 80 wt.% of a bioresorbable polymer;

about 20 to about 99.998 wt.% of a saline solution; and

a biocompatible dye.

2. The composition of claim 1, further comprising about 0.05 wt.% to about 10 wt.% of an antimicrobial agent.

3. The composition of any one of claims 1 to 2, wherein the bioresorbable polymer comprises oxidized regenerated cellulose (ORC), hyaluronic acid, alginate, gelatin, or chitosan.

4. The composition of any one of claims 1 to 3, wherein the bioresorbable polymer comprises ORC.

5. The composition of any one of claims 1 to 4, wherein the bioresorbable polymer and/or collagen is powdered.

6. The composition of any one of claims 1 to 5, wherein the antimicrobial agent comprises one or more of copper, PHMB, silver, ionic silver, zinc, chlorhexidine, and iodine.

7. The composition of claim 6, wherein the antimicrobial agent further comprises zinc oxide.

8. The composition of any one of claims 1 to 7, wherein the biocompatible dye is a fluorescent dye.

9. The composition of any one of claims 1 to 8, wherein the composition is stable at -80°C to 35°C for at least 540 days.

10. The composition of any one of claims 1 to 9, wherein the bioresorbable polymer comprises ORC, and the solid collagen and ORC are synthesized collagen-ORC milled powder.

11. The composition of any one of claims 1 to 10, wherein the bioresorbable polymer comprises ORC, and the solid collagen and ORC are milled from a freeze-dried collagen-ORC matrix.

12. The composition of claim 11, wherein the collagen-ORC is from a rejected freeze-dried collagen-ORC matrix sheet.

13. The composition of any one of claims 11 to 12, wherein the collagen and the ORC are byproducts from and/or are milled sheets of a sterile, freeze-dried composite of 44% ORC, 55% collagen,

14. The composition of any one of claims 11 to 13, further wherein the milled sheets comprise 1% silver-ORC, wherein the silver-ORC contains 25% w/w ionically bound silver.

15. The composition of any one of claims 1 to 14, wherein the composition further comprises a gelatin.

16. A bioresorbable material delivery system comprising:

a flexible housing comprising at least two compartments within the housing, wherein a first compartment contains saline solution;

wherein a second compartment contains a bioresorbable polymer and solid collagen;

one or more releasable internal boundary situated between the first compartment and the second compartment; and

an outlet valve in fluid communication with at least one of the at least two compartments.

17. The delivery system of claim 16, wherein the outlet valve is in fluid communication with the second compartment.

18. The delivery system of any one of claims 16 to 16, wherein the bioresorbable polymer

comprises oxidized regenerated cellulose (ORC), hyaluronic acid, alginate, gelatin, or chitosan.

19. The delivery system of claim 16, wherein the bioresorbable polymer comprises ORC.

20. The delivery system of any one of claims 16 to 19, wherein the bioresorbable polymer and/or collagen is powdered.

21. The delivery system of any one of claims 16 to 20, further comprising a biocompatible dye.

22. The delivery system of any one of claims 16 to 21, wherein at least a portion of the flexible housing is transparent.

23. The delivery system any one of claims 16 to 21, wherein at least a portion of the flexible housing is translucent and/or opaque.

24. The delivery system of any one of claims 16 to 23, wherein at least one of the compartments further contains an antimicrobial agent.

25. The delivery system of claim 24, wherein the antimicrobial agent comprises one or more of copper, PHMB, silver, ionic silver, zinc, chlorhexidine, and iodine.

26. The delivery system of any one of claims 16 to 25, wherein at least one of the compartments further contains zinc or zinc oxide.

27. The delivery system of any one of claims 16 to 26, wherein at least one of the compartments further contains hyaluronic acid, alginate, gelatin, or chitosan.

28. The delivery system of any one of claim 16 to 27, wherein the delivery system is stable when stored at about -80°C to about 35°C for at least 540 days.

29. The delivery system of claim 28, wherein the delivery system is stable when stored at

between about 20°C to about 27°C for at least 540 days.

30. The delivery system of any one of claim 16 to 29, wherein at least one releasable internal boundary comprises a breakable seal.

31. The breakable seal of claim 30, wherein the breakable seal is manufactured using heat sealing or RF welding.

32. The delivery system of any one of claim 16 to 31, wherein the outlet valve comprises a lumen with a port at a distal or proximal end of the lumen, wherein the port is configured to open when the internal pressure of the housing exceeds a pressure threshold.

33. The delivery system of any one of claims 16 to 32, wherein the outlet valve is configured to be a one-way valve.

34. The delivery system of any one of claims 16 to 32, wherein a distal end of the outlet valve is configured to couple to a catheter, syringe, and/or a needle.

35. The delivery system of any one of claims 16 to 34, wherein the outlet valve is coupled to a catheter, syringe, and/or needle, and the catheter, syringe, and/or needle is at least 5 cm in length.

36. The delivery system of any one of claims 16 to 35, wherein complex wound geometries comprise diabetic ulcers, tunneling wounds, and underminings.

37. The delivery system of any one of claims 16 to 36, wherein the outlet valve is coupled to a catheter and a tip on a distal end of the catheter is flexible.

38. The delivery system of any one of claims 16 to 37, wherein at least one releasable internal boundary situated between the first compartment and the second compartment is configured to allow fluids to only pass into the second compartment, and to prevent solids from the second compartment passing into the first compartment.

39. The delivery system of any one of claims 16 to 38, wherein the saline solution comprises about 20 to about 99.998 wt.% of the combined weight of the mixed contents of the compartments.

40. The delivery system of any one of claims 16 to 39, further comprising a third compartment with:

i) a releasable internal boundary situated between the third compartment and second compartment,

ii) a releasable internal boundary situated between the third compartment and first compartment, or

iii) a releasable internal boundary situated between the third compartment and the second compartment and a releasable internal boundary situated between the third compartment and the second compartment.

41. The delivery system of any one of claims 16 to 40, further comprising a third compartment with a releasable internal boundary that is a common boundary for the first, second, and third compartments.

42. The delivery system of any one of claims 40 to 41, wherein the third compartment contains a composition that can form a hydrogel when hydrated with saline.

43. The delivery system of any one of claims 16 to 42, comprising more than two compartments separated by releasable internal boundaries and wherein the delivery system is configured to be capable of having at least one releasable internal boundary released without releasing all of the releasable internal boundaries.

44. The delivery system of any one of claims 16 to 43, wherein the housing maintains a barrier for the at least two compartments from external elements for aseptic delivery of the bioresorbable material.

45. The delivery system of any one of claims 16 to 44, wherein the releasable internal boundary between the first compartment and the second compartment is situated on a top side, a bottom side, a left side, or a right side of a compartment when referring to the front side as being the side with a releasable internal boundary that is closest to the outlet valve.

46. A method of wound treatment using the delivery system of any one of claims 16 to 45

comprising:

(i) releasing the releasable internal boundary;

(ii) moving at least a portion of the saline solution from the first compartment to the second compartment;

(iii) mixing the at least a portion of the saline solution, solid collagen, and

powdered ORC to create a slurry;

(iv) moving the at least a portion of the slurry through the outlet valve; and

(v) applying at least a portion of the slurry to a wound.

47. The method of claim 46, wherein the slurry further comprises an antimicrobial agent.

48. The method of any one of claims 46 to 47, wherein the slurry is homogenous.

49. The method of any one of claims 46 to 48, wherein the releasable internal boundary is

released by applying pressure to the housing.

50. The method of any one of claims 46 to 49, wherein the releasable internal boundary is

released by applying pressure to the housing by using a user’s hand.

51. The method of any one of claims 46 to 50, wherein at least a portion of the slurry is moved through the outlet valve and out of the flexible housing into a catheter, needle, and/or syringe.

52. The method of any one of claims 46 to 51, wherein at least a portion of the slurry is applied to a wound through a catheter, needle, and/or syringe.

53. The method of any one of claims 46 to 52, wherein the releasable internal boundary is

released by applying pressure to the housing mechanically using an instrument, apparatus, or machine.

54. The method of any one of claims 46 to 53, wherein the pressure required to release the

releasable internal boundary is applied to the first compartment.

55. The method of any one of claims 46 to 54, wherein the pressure required to release the

releasable internal boundary is applied to any compartment.

56. The method of any one of claims 46 to 55, wherein applying at least a portion of the slurry to a wound comprises applying to a wound with a complex geometry.

57. The method of any one of claims 46 to 56, wherein the slurry is applied directly in the wound.

58. The method of any one of claims 46 to 57, wherein the saline solution further comprises a biocompatible dye, and the biocompatible dye is used to visualize mixing sufficient to form a homogenous slurry.

59. The method of any one of claims 46 to 58, wherein the biocompatible dye is capable of being used to visualize the location of the slurry within a wound.

60. The method of claim 59, wherein the biocompatible dye comprises a dye capable of being visualized through biological tissue.

61. The method of any one of claims 46 to 60, wherein the slurry further comprises gelatin.

62. The method of any one of claims 46 to 61, wherein the slurry further comprises an

antimicrobial.

63. The method of claim 62, wherein the antimicrobial agent comprises one or more of copper, PHMB, silver, zinc, ionic silver, chlorhexidine, and iodine.