A swelling hemostatic agent composed of oxidized cellulose

Abstract

It is made of oxidized cellulose and has a density of about 0.8 to about 1.2 gr / cm 3 Disclosed herein is an expandable biodegradable hemostatic matrix having a density in the range of 1000 sq. m / s. The matrix may be capable of expanding to at least three times its original volume within four seconds upon contact with an aqueous solution at room temperature. Additionally, methods for making the hemostatic matrix, as well as methods for treating wounds, are disclosed.

Description

[Technical field]

[0001] The present invention relates inter alia to an expandable biodegradable hemostatic matrix of oxidized cellulose (OC) and uses thereof, such as for treating wounds. [Background technology]

[0002] In a wide variety of situations, animals, including humans, may experience bleeding due to a wound or during a surgical procedure. In some situations, the bleeding is relatively minor and normal blood clotting functions, so that only simple first aid needs to be applied. In other situations, substantial bleeding may occur. These situations usually require specialized equipment and supplies, as well as personnel trained to administer appropriate rescue.

[0003] Traditional methods for achieving hemostasis include the use of surgical techniques, sutures, ligatures or clips, and energy-based coagulation or cauterization. When these traditional measures are ineffective or impractical, adjunctive hemostatic techniques and products are needed.

[0004] Selection of an appropriate method or product for controlling bleeding depends on many factors, including, but not limited to, the severity of the bleeding, the anatomical location of the bleeding source and the proximity of adjacent vital structures, whether the bleeding is from a discrete source or from a larger surface area, visibility and precise identification of the bleeding source, and access to the bleeding source.

[0005] In an effort to address the above-mentioned problems, materials have been developed to control excessive bleeding. Topical absorbable hemostats (TAHs) are widely used in surgical applications. TAHs include products based on oxidized cellulose (OC), gelatin, collagen, chitin, chitosan, etc. To improve hemostatic performance, scaffolds based on the above-mentioned materials can be combined with biologically derived clotting factors such as thrombin and fibrinogen.

[0006] Due to its biodegradability, as well as its bactericidal and hemostatic properties, oxidized cellulose (OC)-based materials, such as oxidized regenerated cellulose (ORC), have long been used as topical hemostatic agents in various surgical procedures, including neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery, and skin and subcutaneous tissue procedures. Several methods are known for forming various types of hemostatic agents based on OC materials, whether made as powders, woven fabrics, nonwoven fabrics, knitted fabrics, and other forms. Currently utilized hemostatic agents include powders or fabrics containing ORC.

[0007] Rapid response to rapid bleeding is important in surgical procedures. Hemostasis can be achieved by various methods. A common practice is the use of manual compression, which applies pressure to the wound via a bandage or hemostatic patch to promote the formation of a clot. Manual compression has some notable drawbacks and is rather tedious and relatively time-consuming for the surgical staff. In terms of its application, manual compression is not effective when blood is lost from narrow and hard-to-reach spaces, gaps, or cavities. In such cases, a flowable sealant is usually applied via a conductive applicator that is used to achieve hemostasis. A range of flowable sealant products are available on the market, most of which are based on biologically active ingredients.

[0008] Biological hemostatic agents carry a potential risk of contamination, their cost is high, and some hemostatic agents on the market require laborious preparation before application, some expertise from the surgical staff, and lack the necessary effectiveness in cases of rapid blood loss.

[0009] U.S. Patent Application having Publication Number 2012 / 0101520 relates to an apparatus and method used to seal a vascular puncture site, particularly a puncture site that is the result of a catheterization or other interventional procedure. The sealing device includes a sealing member and a tether. The sealing member occupies a space in an incision, puncture, or other wound and seals the space it occupies to prevent further blood flow. The tether is attached to the sealing member and provides the user with the ability to withdraw the sealing member when desired.

[0010] U.S. Patent No. 8,518,064 generally relates to a method for anchoring an expandable biocompatible plug material to a blood vessel wall to form a fixed occlusive plug that blocks or reduces blood flow to a desired vascular target, such as tumor tissue or an artery that supplies blood to a tumor.

[0011] U.S. patent application having Publication No. 2005 / 0287215 discloses a plurality of filled particles comprising interstitial pores, the interstitial pores having a pore volume and median pore size effective to provide improved absorption of physiological fluids or aqueous media when placed in contact with the physiological fluids or aqueous media compared to a plurality of unfilled particles of the same material, the particles being made of a biocompatible material and having an average diameter suitable for use in providing hemostasis to a site of a mammalian body in need of hemostasis, hemostatic compositions comprising such a plurality of filled particles, methods of making such particles and compositions, and devices suitable for delivering and containing the hemostatic particles and / or compositions to a site of the body.

[0012] U.S. patent application having Publication No. 2014 / 0142523 discloses, inter alia, a self-expanding wound dressing including a first outer layer, a second outer layer, and a liquid expandable layer disposed between the first outer layer and the second outer layer, the liquid expandable layer including a plurality of liquid expandable articles carried by a substrate, the plurality of liquid expandable articles forming an expanded article upon contact with a liquid.

[0013] US Patent No. 8,828,050 relates to a hemostatic composition comprising a plurality of liquid expandable articles that can expand upon contact with a liquid. A suitable composition comprises a plurality of liquid expandable articles that may not be mechanically connected to each other and thus can move independently of each other. The plurality of liquid expandable articles may comprise a compressible material that allows a high degree of expansion upon contact with a liquid.

[0014] U.S. Patent Application having Publication Number 2007 / 0014862 discloses, inter alia, a hemostatic agent comprising oxidized cellulose in the form of a compressible and moldable mass that can remain in a substantially compressed or molded form for placement on a bleeding site or within a wound gap. The oxidized cellulose may be pellets of non-woven oxidized cellulose fiber strands or may be strands of non-woven cellulose fibers arranged in a woven or otherwise gauze or mesh. The pellets may be compressed prior to application to the wound, thereby allowing the pellets to expand and conform to the shape of the wound. The pellets may remain within the wound during wound healing, thus allowing the pellets to be absorbed by the body's biological processes.

[0015] U.S. Patent Application Publication No. 2006 / 0078589 discloses a device for treating oral wounds that form gapes and are therefore too large for suturing. The device is intended to fill the resulting wound and, upon contact with bleeding tissue, causes localized hemostasis. The device remains in the wound and protects it during the healing process. Summary of the Invention [Problem to be solved by the invention]

[0016] However, because control of bleeding is essential and important in surgical procedures to minimize blood loss, reduce post-operative complications, and shorten operative time in the operating room, there is a need for improved hemostatic forms and materials that facilitate ease of application, especially at hard-to-reach bleeding sites. [Means for solving the problem]

[0017] The present invention relates, inter alia, to an expandable hemostatic matrix constructed from compressed oxidized cellulose (OC), such as oxidized regenerated cellulose (ORC), which may be used to achieve hemostasis in the case of, for example, puncture wounds or tissue gaps. The hemostatic oxidized cellulose material expands rapidly when exposed to bodily fluids, and after absorbing blood, the matrix of the present disclosure can reduce bleeding without further application of external pressure and can take the shape of the wound site to enable hemostasis. The matrix can remain at the wound site while dissolving over time. The matrix can be produced from compression of different processed OC or ORC materials (e.g., nonwoven and knit).

[0018] The common practice of manual compression is quite cumbersome for the surgical staff (common practice), is relatively time consuming, and is ineffective when blood is lost from tight, hard-to-reach spaces.

[0019] In clear distinction, the expandable matrix of the present disclosure may be effective as an immediate solution for treating blood loss injuries where manual compression is not feasible or effective, thus allowing the matrix to apply pressure to the wound via a bandage or hemostatic patch, overcoming the shortcomings of the common practice of manual compression, which promotes the formation of a blood clot.

[0020] The matrix has further significant advantages over existing solutions, requiring no preparation time, being stable at room temperature (RT), and being more cost-effective and safer than biological hemostatic agents.

[0021] In the Examples section below, it is further demonstrated that matrices of the present disclosure comprising ORC nonwoven materials exhibit superior swelling properties and hemostatic effects compared to tablets comprised of ORC knitted source materials and powders.

[0022] Thus, the expandable matrix is ​​also effective as an immediate solution for treating hemostatic injuries (e.g., for dental procedures involving heavy bleeding).Furthermore, in order to function as an efficient hemostatic agent, ORC is a bactericidal compound, which is advantageous following interventions in body cavities such as the oral cavity that harbor high concentrations of bacteria.

[0023] According to one aspect of the present invention, there is provided a biodegradable hemostatic matrix comprising oxidized cellulose (OC), the matrix having (i) about 0.8 to about 1.2 gr / cm 3 and (ii) is capable of expanding to at least 3 times, at least 4 times, or at least 5 times its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 40° C. In some embodiments, the matrix has a density in the range of about 1.2 gr / cm 3 has a density of

[0024] In some embodiments, the OC in the matrix comprises or is in the form of one or more sheets (eg, fibrous and / or filled layered sheets).

[0025] In some embodiments, the matrix is ​​5 mm 3 Ultra (e.g., 0.3-0.9 cm 3 )

[0026] In some embodiments, the matrix is ​​in a compressed form, hi some embodiments, the matrix is ​​in a pre-expanded state or form.

[0027] The term "compressed" can refer to being compressed by a compressive force in one or more directions (eg, horizontal, vertical, and / or radial).

[0028] In some embodiments, the matrix is ​​substantially cylindrical, rectangular, and / or polygonal in shape.

[0029] In some embodiments, the matrix is ​​capable of expanding to at least 90% of its maximum expansion capacity within 30 seconds after immersion in an aqueous solution, and is capable of expanding to 3 to 30 times, or 15 to 30 times, its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 30° C.

[0030] In some embodiments, the matrix is ​​in the form of an article selected from a tablet and a wound dressing.

[0031] In some embodiments, the matrix OC comprises oxidized regenerated cellulose (ORC).

[0032] In some embodiments, the OC matrix is ​​derived from an OC (or ORC) based material having a morphology selected from knitted fabric, nonwoven fabric, woven fabric, shredded material, and any combination thereof.

[0033] In some embodiments, the ORC-based material is in the form of a nonwoven fabric.

[0034] In some embodiments, the matrix further comprises one or more additives selected from calcium salts, anti-infective agents, and hemostatic promoting agents.

[0035] In some embodiments, the matrix further comprises one or more excipients selected from sodium chloride, mannitol, albumin, and sodium acetate.

[0036] In some embodiments, the carboxyl content of the OC is about 12% to about 21% by weight according to United States Pharmacopeia (USP) 23-NF18.

[0037] In some embodiments, the matrix in its pre-expanded form has a length of about 3 to about 5 cm. 2 The total surface area is in the range of

[0038] In some embodiments, the matrix is ​​about 0.4 to about 0.8 cm 3 The pre-expansion volume ranges from 0.01 to 0.1.

[0039] In some embodiments, the matrices are used in controlling bleeding in soft tissue.

[0040] In some embodiments, the matrix finds use in inhibiting or reducing the formation of a microbial load.

[0041] In some embodiments, the matrix has at least one surface thereof having a surface roughness of 0.3 to 7 ton / cm. 2 (For example, 0.3 to 2.5 ton / cm 2 ) by compressing the OC-based material.

[0042] According to one aspect of the present invention, there is provided a method of making a hemostatic matrix, in any of its embodiments, comprising applying from about 0.3 to about 7 ton / cm to at least one surface of the matrix. 2 The method includes compressing the OC-based material by applying a pressure in the range of

[0043] In some embodiments of the methods of making a hemostatic matrix, the OC material comprises ORC.

[0044] In some embodiments of the methods of making a hemostatic matrix, the ORC is in a non-woven form.

[0045] In some embodiments of the method of making a hemostatic matrix, the method further comprises mixing the OC material with one or more additives selected from calcium salts, anti-infective agents, and hemostatic promoting agents.

[0046] According to one aspect of the present invention, a method of treating a wound is provided, comprising applying a biodegradable hemostatic matrix of the present disclosure of any embodiment thereof onto and / or into a wound of a subject in need thereof.

[0047] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice or test embodiments of the present invention, representative methods and / or materials are described below. In case of conflict, the present patent specification, including definitions, will govern. It should be noted that the materials, methods, and examples are merely illustrative and are not necessarily intended to be limiting. [Brief description of the drawings]

[0048] Certain embodiments of the present invention will now be described herein, by way of example only, with reference to the accompanying drawings, in which: Referring now specifically to the drawings in detail, it is stressed that the details shown are exemplary and are for the purpose of illustrating embodiments of the invention; in this regard, the description with the drawings will make apparent to those skilled in the art how embodiments of the invention may be practiced. [Figure 1A] Photographs are presented showing matrices in the form of pellets of the present disclosure with different sizes: large (FIG. 1A) and small (FIG. 1B). The numbers on the ruler are in centimeters. [Figure 1B] Photographs are presented showing matrices in the form of pellets of the present disclosure with different sizes: large (FIG. 1A) and small (FIG. 1B). The numbers on the ruler are in centimeters. [Diagram 2] Photographs are presented demonstrating the application of a matrix in the form of pellets of the present disclosure during a surgical procedure: A white pellet is inserted at the bleeding site (left panel), after which it absorbs blood and rapidly expands from its original volume to promote efficient hemostasis (right panel, follow the arrow). [Figure 3A]A bar graph (FIG. 3A) showing the maximum swelling volume (cm3) in saline of various oxidized regenerated cellulose (ORC) matrix samples (Table 2A) compressed at compressive strengths (T) of 0.5, 2, and 5 tons as described in the Examples section, and a bar graph (FIG. 3B) showing the respective time (sec) it took each sample to reach maximum swelling are presented. In each triplet of bars, the left refers to 0.5 tons (T), the middle refers to 1T, and the right refers to 5T. [Figure 3B] A bar graph (FIG. 3A) showing the maximum swelling volume (cm3) in saline of various oxidized regenerated cellulose (ORC) matrix samples (Table 2A) compressed at compressive strengths (T) of 0.5, 2, and 5 tons as described in the Examples section, and a bar graph (FIG. 3B) showing the respective time (sec) it took each sample to reach maximum swelling are presented. In each triplet of bars, the left refers to 0.5 tons (T), the middle refers to 1T, and the right refers to 5T. [Figure 4A] Based on the data presented in Table 2B showing the swelling volumes in saline of various ORC matrix samples and gauze pads (non-oxidized cellulose) compressed under different forces (compressive strengths; T) ranging from 0.25 to 5 tons, bar graphs are presented as the swelling percentage after 4 s (Figure 4A), the maximum swelling percentage (Figure 4B), and a bar combining the maximum swelling percentage and the swelling percentage after 4 s for the tested ORC materials (Figure 4C). [Figure 4B] Based on the data presented in Table 2B showing the swelling volumes in saline of various ORC matrix samples and gauze pads (non-oxidized cellulose) compressed under different forces (compressive strengths; T) ranging from 0.25 to 5 tons, bar graphs are presented as the swelling percentage after 4 s (Figure 4A), the maximum swelling percentage (Figure 4B), and a bar combining the maximum swelling percentage and the swelling percentage after 4 s for the tested ORC materials (Figure 4C). [Figure 4C]Based on the data presented in Table 2B showing the swelling volumes in saline of various ORC matrix samples and gauze pads (non-oxidized cellulose) compressed under different forces (compressive strengths; T) ranging from 0.25 to 5 tons, bar graphs are presented as the swelling percentage after 4 s (Figure 4A), the maximum swelling percentage (Figure 4B), and a bar combining the maximum swelling percentage and the swelling percentage after 4 s for the tested ORC materials (Figure 4C). [Diagram 5] A graph showing the expansion rate after 4 seconds in saline versus density of ORC material is presented. [Figure 6] A graph showing the maximum swelling rate in saline versus density of ORC materials is presented. [Figure 7] An image is presented showing a schematic of the grades of bleeding levels used in the spleen biopsy punch model. The white circle represents the punch, the grey circle represents the background, and the black circle represents blood flowing from the biopsy punch site (from left to right panel: no bleeding "0", exudation "1", very mild "2", mild "3", moderate "4", severe "5"). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] The object of the present invention is to provide a hemostatic matrix composition comprising oxidized cellulose (OC), e.g., oxidized regenerated cellulose (ORC) having a particular range of densities, which upon contact with bodily fluids can be highly expanded and easily applied to the required site to achieve hemostasis, e.g., in the case of a puncture wound or tissue gap. An advantage of the expandable compositions described herein is their ability to expand rapidly into an expanded form, which allows the expanded composition to rapidly fill the wound cavity and provide a nearly immediate hemostatic effect without the need to apply any external pressure or compression. Additional advantages associated with the present invention include, among others, improved positioning within the wound, improved tissue apposition, and better conformity to complex wound contours.

[0050] As described in more detail below, the compositions of the present disclosure can be applied to bleeding tissue and then, upon exposure to bodily fluids, can rapidly expand while taking the shape of the wound to assist in hemostasis. The composition can remain at the wound site while degrading over time.

[0051] "Hemostasis" (or "haemostasis") refers to the first stage of wound healing. It is the process of stopping bleeding. "Aiding in hemostasis" means reducing or helping to stop bleeding. "Applied to bleeding tissue" means referring to topical application of the composition at the site of bleeding, e.g., at a surgical site to control bleeding. Control of bleeding is necessary in a variety of situations, including during wound treatment or surgical procedures (e.g., laparoscopic surgery, neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery, skin and subcutaneous tissue procedures, etc.). For at least one of these situations, the composition of the present invention may function as a suitable sealant.

[0052] In some embodiments, the composition comprises a compressed OC, hi some embodiments, the OC is compressible.

[0053] The term "compressed" or "compressed state" refers to the state of a material after compression, e.g., by the application of pressure to it. Conversely, the term "uncompressed" refers to the state of a material before compression or upon expansion, e.g., after its breakdown or rupture. The term "compressibility" refers to the ability of a material to undergo compression.

[0054] In some embodiments, the composition in a dry state remains in substantially compressed or molded form prior to contacting or placing in / on an aqueous medium, such as a bleeding site or wound.

[0055] The term "compressed state" is also referred to herein as "original volume."

[0056] In some embodiments, the compressible material may rapidly expand as described herein upon exposure to a liquid (e.g., an aqueous solution) without the use of an exogenous gas or pressure. By "aqueous solution" it is meant to encompass both water and solutions in which the solvent is or contains water (e.g., bodily fluids such as saline and blood). Water may refer to pure water.

[0057] The compressed matrix thus formed exhibits improved expansion and / or liquid (e.g., water) swelling properties when compared to particles (e.g., milled ORC particles). The compositions of the present invention may be applied as is to the bleeding site, or in some embodiments, may be applied simultaneously or sequentially with saline. In some embodiments, the matrix may be applied manually, or in some embodiments, using a device such as a medical device (e.g., trocars of various sizes (e.g., 5, 10, 12, 15 mm diameter)) or other known applicators. Depending on the desired shape, form, and size for the intended use, different molds or other compression techniques may be used to achieve the desired body of the matrix or composition of the present disclosure.

[0058] Embodiments of the present invention further relate, inter alia, to rapidly swellable, superabsorbent, biodegradable hemostatic compositions. Rapid swelling properties can be provided upon contact with plasma, allowing the composition to absorb at least a portion, or even most, of the plasma components.

[0059] The term "absorption," or any verbal variation thereof, refers to the physical state in which fluid (eg, an aqueous medium such as bodily fluids) is distributed throughout the inner body of an OC matrix.

[0060] The composition of the present disclosure, when contacted, swells, for example, up to 2, 3, 4, 5, 6, 7, 8, 9, 10, or even up to 20 times the dry composition, for example, filling a limited wound space, simulating a tamponade effect and enhancing the natural clotting process. In some embodiments, the composition of the present disclosure is flexible, thereby ensuring its access to narrow spaces and its application to uneven surfaces, making it a useful material for dealing with bleeding or exudation during surgery. The matrix is ​​particularly suitable for wounds that are difficult to access, such as tissue tears or bleeding cavities.

[0061] "Dry" is meant to refer to an OC or ORC that contains less than 8% by weight, less than 5% by weight, or less than 1% by weight water.

[0062] The term "flexible" in the context of the matrices of the present disclosure (eg, in the form of tablets or pellets) relates to a material that can be bent or rolled without breaking.

[0063] According to one aspect of the present disclosure, a biodegradable hemostatic matrix is ​​provided that includes oxidized cellulose (OC), the matrix having (i) about 0.8 to about 1.2 gr / cm 3 and (ii) is capable of expanding to at least three times its original volume within four seconds upon contact with an aqueous solution at at least one temperature between 10 and 40°C.

[0064] In some embodiments, the matrix is ​​in the form of an article selected from, but not limited to, a tablet and a pellet.

[0065] As used herein, the term "fabric" typically refers to a flexible material that includes a network of fibers produced by, for example, but not limited to, weaving, knitting, crocheting, knotting, felting, or knotting. Typically, but not exclusively, "gauze" refers to a thin, typically loosely woven cloth used in bandages and swabs, or any material made with an open mesh-like weave.

[0066] In some embodiments, the OC comprises or is in the form of one or more sheets. The term "sheet" refers to a material that is thin compared to its length and width. In some embodiments, the sheet forms a substantially flat configuration. In some embodiments, the sheet has a non-planar configuration. In some embodiments, the sheet is configured in a compressed position. In some embodiments, the OC is not in the form of a powder or particles. In some embodiments, the OC is not milled. The term "the OC is not in the form of a powder or particles" refers to less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 10% by weight, or even essentially none of the OC in the matrix of the present disclosure is in or comprises a powder form and milled particles, or at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, or even essentially all of the OC in the matrix of the present disclosure is in or comprises a powder form and milled particles.

[0067] In some embodiments, "expandable" refers to a structure that can reach a volume greater than its initial volume when exposed to, contacted with, or immersed in an aqueous solution such as water. The term "expandable" may refer to one or more directions in which the matrix may expand, e.g., radially expandable. As used herein, the term "radially expandable" includes segments that can expand radially from a small configuration, typically in a cylindrical configuration. The term "expandable" may further refer to horizontally expandable (i.e., increasing in width) or vertically expandable (i.e., increasing in height). A "small configuration" may refer to at least one dimension, e.g., diameter.

[0068] Additionally or alternatively, the term "expandable" may further refer to either or both of horizontally and vertically expandable. Additionally or alternatively, the term "expandable" may further refer to horizontally expandable, vertically expandable, and / or radially expandable.

[0069] In some embodiments, the composition is capable of expanding at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, or at least 7 times its original volume upon contact with an aqueous solution. In some embodiments, the composition is capable of expanding about 2, about 3, about 4, about 5, about 6, or about 7 times its original volume (including any values ​​and ranges therebetween) upon contact with an aqueous solution. In some embodiments, the composition is capable of expanding 2-5, 3-6, or 4-7 times its original volume (including any values ​​and ranges therebetween).

[0070] In some embodiments, the matrix is ​​capable of expanding at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, or at least 7 times its original volume within 2-6 seconds or 3-5 seconds (e.g., 4 seconds) upon contact with an aqueous solution at about room temperature.

[0071] In some embodiments, the matrix can expand 3 to 40 or 10 to 40 times its original volume within 2 to 6 or 3 to 5 seconds (e.g., 4 seconds) upon contact with an aqueous solution at about room temperature. In some embodiments, the matrix can expand 15 to 30 times its original volume within 2 to 6 or 3 to 5 seconds (e.g., 4 seconds) upon contact with an aqueous solution at about room temperature.

[0072] In some embodiments, the matrix is ​​capable of expanding to 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 times its original volume (including any value and range therebetween) within 2-6 seconds or 3-5 seconds (e.g., 4 seconds) upon contact with an aqueous solution at about room temperature.

[0073] With reference to the results presented in Table 2B (and further shown in Figures 4A to 6), the concentration of 0.95 to 1.2 gr / cm 3 The ORC density of "FIBRILLAR" and "SNoW" provide optimal expansion after 4 seconds, with "FIBRILLAR" and "SNoW" exhibiting the greatest expansion rates.

[0074] In some embodiments, the matrix comprises a nonwoven OC that is capable of expanding to at least 5 times its original volume within 4 seconds upon contact with an aqueous solution at about room temperature.

[0075] In some embodiments, the matrix comprises OC and has a density of about 0.9 to about 1.25 gr / cm 3 and is capable of expanding to at least 5 times its original volume within 4 seconds upon contact with an aqueous solution at about room temperature. In some embodiments, the matrix comprises OC and has a density of about 0.9 to about 1.25 gr / cm 3 and upon contact with an aqueous solution at about room temperature, can expand to about 5 to about 6 of its original volume within 4 seconds.

[0076] In some embodiments, the matrix comprises a non-woven OC and has a density of about 0.9 to about 1.25 gr / cm 3 and is capable of expanding to at least 5 times its original volume within 4 seconds upon contact with an aqueous solution at about room temperature. In some embodiments, the matrix comprises a nonwoven OC and has a density of about 0.9 to about 1.25 gr / cm 3 It has a density of 100 nm and is capable of expanding to approximately 5-6 of its original volume within 4 seconds upon contact with an aqueous solution at near room temperature.

[0077] In some embodiments, the matrix comprises OC and has a density of about 1 to about 1.25 gr / cm 3 and is capable of expanding to at least six times its original volume within four seconds upon contact with an aqueous solution at about room temperature. In some embodiments, the matrix comprises a nonwoven OC and has a density of about 0.9 to about 1.25 gr / cm 3 and upon contact with an aqueous solution at about room temperature, can expand to about 6 to about 8 of its original volume within 4 seconds.

[0078] In some embodiments, the matrix comprises a non-woven OC and has a density of about 1 to about 1.25 gr / cm 3 and is capable of expanding to at least six times its original volume within four seconds upon contact with an aqueous solution at about room temperature. In some embodiments, the matrix comprises a nonwoven OC and has a density of about 0.9 to about 1.25 gr / cm 3 and upon contact with an aqueous solution at about room temperature, can expand to about 6 to about 8 of its original volume within 4 seconds.

[0079] In some embodiments, the matrix comprises a non-woven OC and has a density of about 0.9 to about 1.25 gr / cm 3 and is capable of expanding to at least 5 times its original volume within 4 seconds upon contact with an aqueous solution at about room temperature. In some embodiments, the matrix comprises a nonwoven OC and has a density of about 0.9 to about 1.25 gr / cm 3 and upon contact with an aqueous solution at about room temperature, can expand to about 5 to about 6 of its original volume within 4 seconds.

[0080] In some embodiments, the matrix comprises OC and has a density of about 1 to about 1.25 gr / cm 3 and is capable of expanding to at least four times its original volume within 4 seconds upon contact with an aqueous solution at about room temperature. In some embodiments, the matrix comprises woven OC and has a density of about 1 to about 1.25 gr / cm. 3 and is capable of expanding to at least four times its original volume within four seconds upon contact with an aqueous solution at about room temperature. In some embodiments, the matrix comprises woven OC and has a density of about 0.9 to about 1.25 gr / cm 3 and upon contact with an aqueous solution at about room temperature, can expand to about 4 to about 5 times its original volume within 4 seconds.

[0081] "At or near room temperature" is meant to refer to at least one temperature within the range of 10 to 40° C., e.g., 15 to 37° C., or, for example, 10, 15, 20, 25, 30, 35, 37, or 40° C. (including any values ​​and ranges therebetween).

[0082] In some embodiments, the matrix can expand to at least 70%, at least 80%, or at least 90% of its maximum expansion volume within 20-40 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to at least 70%, at least 80%, or at least 90% of its maximum expansion volume within 20-40 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to at least 70% of its maximum expansion volume within 20-40 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to at least 80% of its maximum expansion volume within 20-40 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to at least 90% of its maximum expansion volume within 20-40 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to 70-95% of its maximum expansion volume within 20-40 seconds after immersion in the aqueous solution.

[0083] In some embodiments, the matrix can expand to at least 70%, at least 80%, or at least 90% of its maximum expansion volume within about 30 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to at least 70% of its maximum expansion volume within about 30 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to at least 80% of its maximum expansion volume within about 30 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to at least 90% of its maximum expansion volume within about 30 seconds after immersion in the aqueous solution. In some embodiments, the matrix can expand to 70-95% of its maximum expansion volume within about 30 seconds after immersion in the aqueous solution.

[0084] The term "swelling" refers to an increase in volume. The terms "swelling capacity", "maximum swelling", or "maximum swelling capacity" may be used interchangeably and refer to the maximum volume that a matrix can reach after contacting an aqueous medium.

[0085] In some embodiments, the matrix is ​​about 0.4 to about 1.5 cm 3 Or about 0.4 to about 1.5 cm 3 In some embodiments, the matrix has a pre-expanded volume in the range of about 0.5 to about 0.75 cm. 3 In some embodiments, the matrix has a pre-expanded volume in the range of about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 cm 3 (including any value and range therebetween).

[0086] Thus, in some embodiments, the matrix is ​​about 3 to about 5 cm 2 In some embodiments, the matrix has a total pre-expanded surface area in the range of about 3 to about 5 cm. 2 In some embodiments, the matrix has a total pre-expanded surface area ranging from about 3.5 to about 4.5 cm. 2 In some embodiments, the matrix has a total pre-expanded surface area in the range of about 3 cm 2 , about 3.1cm 2 , 3.2cm 2 , about 3.3cm 2 , about 3.4cm 2 , about 3.5cm 2 , 3.6cm 2 , about 3.7cm 2 , 3.8cm 2 , approx. 3.9cm 2 , about 4cm 2 , about 4.1cm 2 , 4.2cm 2 , about 4.3cm 2 , 4.4cm 2 , about 4.5cm 2 , approx. 4.6cm 2 , about 4.7cm 2 , 4.8cm 2 , approx. 4.9cm 2, or about 5 cm 2 (including any value and range therebetween).

[0087] The term "matrix" is used interchangeably with the terms "composition" and "composition-of-matter" to define, for example, a three-dimensional structure formed from OC materials. The matrices described herein can differ in their secondary, tertiary, and quaternary structures from the OC used to form them.

[0088] The term "biodegradable" as used in the context of this disclosure describes a material that can be broken down under physiological and / or environmental conditions into degradation products. Such physiological and / or environmental conditions include, for example, hydrolysis (degradation by hydrolytic cleavage), enzyme catalysis (enzymatic degradation), and mechanical interaction. The term typically refers to a material that degrades under these conditions (e.g., at least 30 weight percent of the material degrades within a period of less than one year). The term "biodegradable" as used in the context of this disclosure also encompasses the term "bioresorbable," which describes a material that breaks down under physiological conditions into products that undergo bioabsorption into the host organism (i.e., metabolic products of the host organism's biochemical systems).

[0089] The matrix may be of any shape or form, for example, having a substantially polygonal or rectangular (including substantially square) cross section, a substantially circular cross section, and / or a substantially elliptical cross section along at least one axis. For example, the matrix may have a substantially box-like shape (having a substantially rectangular (optionally rounded) cross section along three axes), a substantially cylindrical shape (having a substantially circular and / or substantially elliptical cross section along one axis and a substantially rectangular (optionally rounded) cross section along two axes), or a substantially circular or elliptical shape (having a substantially circular and / or substantially elliptical cross section along three axes). Other shapes, forms, and sizes of the compositions of the present disclosure may be selected from, but are not limited to, plugs, disks, rods, tubes, cones, cylinders, spheres, hemispheres, cubes, rectangles, triangles, or disks.

[0090] As used herein, the term "contact" or "exposure" in the context of an aqueous solution refers to any manner in which the composition of the present disclosure is brought to a location where it can at least partially absorb the aqueous solution. The term "aqueous solution" refers to a solution in which water is the dissolving medium or solvent. In some embodiments, the aqueous solution comprises a bodily fluid such as blood. For example, "contacting" can include immersing the composition in the bleeding site.

[0091] In some embodiments, the composition is in the form of a pellet or tablet (optionally as shown in FIG. 1A and FIG. 1B). In some embodiments, the composition is in the form of a wound dressing. The term "wound dressing" as used in the context of this disclosure refers to a dressing for topical application on / in a wound and / or bleeding site. Terms such as "wound plaster", "wound dressing" or "wound covering" can also be used interchangeably.

[0092] In some embodiments, the matrix has a density of 0.7 to 1.4 gr / cm 3 , 0.7~1.3gr / cm 3 , 0.8~1.2gr / cm 3, 0.9~1.2gr / cm 3 , 1.1~1.2gr / cm 3 , 0.8~1.3gr / cm 3 , 0.7~1.1gr / cm 3 , 0.7~1gr / cm 3 , 0.7~0.9gr / cm 3 , 0.7~0.8gr / cm 3 In some embodiments, the matrix has a density of 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, or 1.4 gr / cm 3 (including any value and range therebetween). In some embodiments, the matrix has a density of about 1.2 gr / cm 3 As used herein, "density" is meant to refer to the unswollen state (i.e., prior to exposure to an aqueous solution).

[0093] In some embodiments, the volume of the matrix is ​​less than 1 mm 3 In some embodiments, the volume of the matrix is ​​at least 5 mm 3 In some embodiments, the volume of the matrix may be less than 10 mm 3 In some embodiments, the volume of the matrix can be greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mm 3 (including any value and range therebetween). In some embodiments, the volume of the matrix is ​​100 mm 3 In some embodiments, the volume of the matrix is ​​about 1 to 100 mm 3 , 1~10mm 3 (For example, about 5 mm 3 ). As used herein, by "volume of the matrix" is meant to refer to the unswollen state (i.e., the state prior to exposure to an aqueous solution).

[0094] The term "oxidized cellulose" (or "OC") refers to a cellulose derivative in which at least a portion of the primary alcohol groups, e.g., the 6-carbon of the anhydroglucose unit, have been oxidized to a carboxylic acid, and optionally functionalized. OC can include materials, products, articles, or compositions (e.g., bandages, fibrin glues, synthetic adhesives, pads, matrices, powders, tabs, pills, sutures, fibers, stents, implants, scaffolds, solutions, gels, waxes, gelatins, etc.) that comprise or consist essentially of OC.

[0095] OC can be produced by applying an oxidizing agent to cellulose. The oxidizing agent can be selected from, but is not limited to, chlorine, hydrogen peroxide, peracetic acid, chlorine dioxide, nitrogen dioxide, persulfates, permanganates, dichromate-sulfuric acid, hypochlorous acid, hypohalous acids, periodates, or any combination thereof, and / or various metal catalysts. Depending on the nature of the oxidizing agent and the reaction conditions, the oxidized cellulose may contain carboxylic acid, aldehyde, and / or ketone groups in place of or in addition to the original hydroxyl groups of the starting cellulose.

[0096] The OC in the compositions of the present invention is typically, but not exclusively, in the form of a pellet, capsule, or tablet.

[0097] The term "tablet" is used in its general context to refer to a solid composition made by compressing and / or molding a mixture of the composition in a form convenient for application to any body cavity. The term includes matrices (e.g., pharmaceutical compositions) of all shapes and sizes. The term "pellets" is intended herein to include granules and tablets that may be understood as pellets of various sizes and shapes.

[0098] In an exemplary embodiment, the OC is oxidized to contain carboxyl moieties in an amount effective to provide biodegradability. For example, U.S. Patent No. 3,364,200 discloses the preparation of carboxylated cellulose using an oxidizing agent such as dinitrogen tetroxide in a Freon medium. U.S. Patent No. 5,180,398 discloses the preparation of carboxylated cellulose using an oxidizing agent such as nitrogen dioxide in a perfluorocarbon solvent. After oxidation by either method, the fabric may be thoroughly washed with a solvent such as carbon tetrachloride, followed by a 50 percent aqueous solution of isopropyl alcohol (IPA), and finally 99% IPA. Prior to oxidation, the fabric may be constructed of any desired woven or nonwoven structure.

[0099] Typically, a hemostat compatible with acid-sensitive species includes, for example, a fabric substrate prepared from a biocompatible aldehyde-oxidized polysaccharide. In such exemplary hemostat, the polysaccharide contains an effective amount of aldehyde moieties to render the modified polysaccharide biodegradable, meaning that the polysaccharide is capable of breaking down into components that can be absorbed by the body or easily passed through the body. More specifically, the biodegraded components do not induce a permanent chronic foreign body reaction when absorbed into the body, such that no permanent minor amount or component residues are substantially left at the implantation site.

[0100] In certain embodiments of the present invention, the OC comprises a layer prepared from biocompatible, biodegradable aldehyde-oxidized regenerated cellulose. In some embodiments, the OC comprises or consists essentially of oxidized regenerated cellulose (ORC), e.g., aldehyde-oxidized regenerated cellulose. In some embodiments, the aldehyde-oxidized regenerated cellulose comprises repeating units of Structure II of U.S. Pat. No. 8,709,463. In some embodiments, ORC is used to prepare the hemostatic agent. Typically, regenerated cellulose is preferred because it has a higher degree of uniformity relative to unregenerated cellulose. Detailed descriptions of exemplary regenerated cellulose and methods for making ORC are described in U.S. Pat. Nos. 3,364,200 and 5,180,398.

[0101] As noted above, in some embodiments, the degree of oxidation of the OC can be important to its functional properties, such as biocompatibility and bioresorbability. Products exist that contain various degrees of oxidation of the OC, such as a surgical hemostat in which carboxylic acid groups are present at concentrations of 18-21% by weight of the oxidized cellulose.

[0102] As used herein with reference to OC, the terms "oxidation level," "degree of oxidation," "carboxyl content," and "carboxylation level" are interchangeable and may be determined in accordance with United States Pharmacopeia (USP) 23-NF18.

[0103] Thus, in some embodiments, the carboxyl content of the OC is 12-24% by weight. In some embodiments, the carboxyl content of the OC is 12-23% by weight. In some embodiments, the carboxyl content of the OC is 12-22%. In some embodiments, the carboxyl content of the OC is 12-21%.

[0104] In some embodiments, the OC has a carboxyl content of 16-24% by weight, and the composition may function as a hemostatic agent. In some embodiments, the OC has a carboxyl content of 17-23% by weight. In some embodiments, the OC has a carboxyl content of 18-22% by weight. In some embodiments, the OC has a carboxyl content of 18-21% by weight.

[0105] In some embodiments, the carboxyl content of the OC is 12-18% by weight. In some embodiments, the carboxyl content of the OC is 12-17% by weight. In some embodiments, the carboxyl content of the OC is 12-16% by weight.

[0106] In some embodiments, the carboxyl content of the OC is about 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, or 24% by weight (including any values ​​and ranges therebetween).

[0107] The usual source of OC is plant material, but it is understood that the OC may also be derived from bacterial sources, hi some embodiments, the OC is derived from a plant source.

[0108] In some embodiments, the cellulose for use in the present invention does not include CMC.

[0109] According to some embodiments, the matrix comprises fibers prepared from a biocompatible polymer and comprises a surface having properties (e.g., strength, flexibility, and porosity) suitable for use as a hemostat.

[0110] In certain embodiments of the invention, the OC (e.g., ORC) can be further combined with hemostatic agents, including drugs and pharmaceuticals, or other biological or therapeutic compounds. In some embodiments, to improve hemostatic performance, scaffolds based on the above materials can be combined with biologically derived clotting factors, such as thrombin and fibrinogen. In yet other embodiments, the ORC-based composition can be combined with additives, such as carboxymethyl cellulose (CMC), calcium salts, anti-infective agents, hemostatic promoters, gelatin, collagen, saline, or combinations thereof.

[0111] In further embodiments of the present invention, the ORC-based compositions of the present disclosure can be combined with various additives to further improve hemostatic, wound healing, and handling properties. Use of additives known to those skilled in the art include, for example, hemostatic additives (gelatin, collagen, cellulose, chitosan, polysaccharides, starch, etc.), biologic hemostatic agents (exemplified by thrombin, fibrinogen, and fibrin). Additional biologic hemostatic agents include, but are not limited to, procoagulant enzymes, proteins, and peptides. Such agents may each be natural, recombinant, or synthetic, and may further be selected from fibronectin, heparinase, Factor X / Xa, Factor VII / VIIa, Factor IX / IXa, Factor XI / XIa, Factor XII / XIIa, tissue factor, batroxobin, ancrod, ecarin, von Willebrand factor, albumin, platelet surface glycoproteins, vasopressin and vasopressin analogs, epinephrine, selectins, protocoagulant toxins, plasminogen activator inhibitors, platelet activators, synthetic peptides having hemostatic activity, derivatives of the above, and any combinations thereof, anti-infective agents (e.g., chlorhexidine gluconate (CHG), triclosan, silver, and similar antibacterial / antimicrobial agents known in the art), additives that increase the adhesion of the hemostatic agent, and other additives known in the art.

[0112] In some embodiments, OCs such as ORCs are provided in the form of pellets (compressed or uncompressed), beads, granules, aggregates, fibers, sheets (including woven, nonwoven, knit, ground or fine fibers, and combinations thereof), all used independently or dispersed in a pharma- ceutically acceptable vehicle or other form.

[0113] Non-limiting examples of OC-based materials that may be in pellet form or initially milled to obtain multiple sheets and utilized include different engineered OC or ORC materials, such as, but not limited to, INTERCEED® absorbent adhesive barrier, SURGICEL® Original Absorbent Hemostat (loose-knit ORC), SURGICEL® NU-KNIT® Absorbent Hemostat (tightly knit ORC), SURGICEL® FIBRILLAR™ Absorbent Hemostat (soft, lightweight, layered ORC), and SURGICEL® SNoW™ Absorbent Hemostat (structured nonwoven, needle-punched interlocking fibers) and SURGICEL® Powdered Absorbent Hemostat, or Gelitacel® Absorbent Cellulosic Surgical Dressing (Gelita Medical BV, Amsterdam, The Netherlands).

[0114] SURGICEL® powder absorbent hemostat is a powder containing agglomerates of small ORC fiber fragments that can be spread over a large surface area and form a durable clot that does not wash off or rebleed when irrigated.

[0115] Typically, a woven fabric consists of two sets of threads. One set of threads, the warp threads, run along the length of the fabric. The other set of threads, the cross threads or weft threads, are perpendicular to the warp threads. The woven fabric is held together by interweaving the warp and weft threads over and under one another.

[0116] "Nonwoven" refers to a fabric-like material made from long fibers that are bonded together by chemical, mechanical, thermal, or solvent treatment. The term is used in the textile manufacturing industry to describe fabrics such as felt that are not woven or knitted. Thus, the phrase "nonwoven" refers to a sheet, web, or mat of directionally or randomly oriented fibers in which the fibers are not interlocked but are bonded through various means including, for example, friction, cohesion, and / or adhesion. The term "nonwoven" also includes, but is not limited to, bonded, formed, or modified fabrics made by processes other than spinning, weaving, or knitting.

[0117] Typically, but not exclusively, the term "nonwoven" also refers to porous, woven-like materials that are primarily or entirely composed of staple fibers, usually in the form of flat sheets, and assembled into webs, sheets, or batts. The structure of nonwoven fabrics is typically more or less randomly arranged, e.g., based on the arrangement of the staple fibers. The tensile, stress-strain, and tactile properties of nonwoven fabrics are usually due to, e.g., fiber-to-fiber friction and / or adhesion, chemical or physical bonds caused by the entanglement and reinforcement of the staple fibers. Nevertheless, the raw materials used to manufacture nonwoven fabrics may be yarns, scrims, nets, or filaments made by processes including spinning, weaving, or knitting (as described in European Patent Application having Publication No. 1802358(A2)).

[0118] Typically, knitted fabrics are made from only one set of yarns that all run in the same direction. Some knits have yarns that run along the length of the fabric, others have yarns that run across the width of the fabric. Knitted fabrics may be held together by wrapping the yarns around each other. Knitting creates ridges in the resulting fabric.

[0119] As shown in the Examples section below, ORC derived from short fibers ("ORC short") expanded up to about 5 times its original volume, while ORC made with long fiber ORC ("ORC long") expanded up to 3 times its original volume. Increasing the compaction pressure to 2 or 5 tons had no beneficial effect on the expansion rate. The nonwoven fabric showed a superior overall expansion effect. The typical size distribution of ORC fiber types "ORC long" or "ORC short" is as described in the Examples section below (Table 1).

[0120] In some embodiments, the above-mentioned forms of the OC-based materials (eg, nonwoven, knitted, etc.) do not necessarily remain the same as the compressed form of the matrices of the present disclosure.

[0121] The compressed ORC materials A, B, C, and D produced (described in the Examples section below) all exhibited superior expansion rates to the milled powder.

[0122] The compositions of the present invention are non-aqueous compositions, which means that the main liquid in the composition is not water, and the composition has very low water content or no water before being immersed in an aqueous environment.Thus, in some embodiments, the water content of the composition is less than about 10% (w / w).In some embodiments, the water content of the composition is less than about 8% (w / w).In some embodiments, the total water content of the composition is less than about 5%, 4%, 3%, 2%, or 1% (w / w).In some embodiments, the composition does not contain water.In some embodiments, the composition does not contain any solvent.

[0123] In some embodiments, the matrix further comprises a pharma- ceutically acceptable excipient or additive, which may include any pharma- ceutically suitable excipient, such as, but not limited to, calcium salts, human albumin, mannitol, sodium acetate, sodium chloride, sodium citrate dihydrate, gluconate buffer, sucrose, glycine, sodium acetate, histidine, and polyethylene glycol.

[0124] The calcium salt used in the present invention may be in the form of a calcium chloride salt. Alternatively, additional salts such as calcium acetate and / or calcium citrate may be used.

[0125] In some embodiments, the composition may further comprise a biologically active agent. Non-limiting biologically active agents that may be included in the composition include therapeutic agents such as antibiotics, anti-inflammatory agents, growth factors, or clotting factors as described above. For example, the composition may further comprise fibrinogen or thrombin.

[0126] As used herein, "thrombin" refers to the activated enzyme resulting from the proteolytic cleavage of prothrombin (Factor II). Thrombin may be produced by a variety of production methods known in the art, including, but not limited to, recombinant thrombin and plasma-derived thrombin.

[0127] Human thrombin is a 295 amino acid protein composed of two polypeptide chains joined by disulfide bonds. Both human and non-human (e.g., bovine) thrombin can be used within the scope of the present disclosure.

[0128] The term "fibrinogen" is intended to include any type of fibrinogen, including, but not limited to, fibrinogen in cryoprecipitate. Thus, fibrinogen refers to monomeric and dimeric fibrinogen molecules having its monomeric structure (AαBβγ), hybrid molecules, and variants thereof, whether native, modified, or synthetic. The term "fibrinogen" generally refers to fibrinogen of human origin, but may include fibrinogen of any species, particularly mammalian species.

[0129] Any preparation for therapeutic use must be sterile. Particularly when dealing with blood products, the issue of sterility, specifically the issue of viral inactivation, is important. In general, viral inactivation can be carried out by any method, including solvent detergent, heat inactivation, irradiation, and nanofiltration. Typically, viral inactivation standards require the use of two different methods. Furthermore, the US Food and Drug Administration (FDA) standard for sterility requires filtration.

[0130] In another embodiment, the compositions of the present disclosure may be used in conjunction with a backing, pad, scaffold, or matrix to provide mechanical strength to cover the surface of a wound, where the matrix is ​​supported on a pad to facilitate application or tamponade.

[0131] In some embodiments, the matrix is ​​characterized by antimicrobial efficacy. In some embodiments, the matrix is ​​for antimicrobial use, for example, in inhibiting or reducing the formation of a microbial load. As used herein, the term "antimicrobial" is intended to include the destruction or inhibition of the growth of microorganisms, such as pathogenic bacteria. Antimicrobial efficacy and, in some embodiments, may be for use in inhibiting or reducing the formation of a microbial load.

[0132] It is understood that the composition can be applied, for example, by directly applying the composition to the bleeding site. Thus, the composition does not need to be further spread or applied onto a solid surface, object, or other solid medium, such as a strip or film, to be in a suitable form for application to the bleeding site. Nevertheless, a suitable applicator may be used for easy access and handling to apply, position, spread, or attach the composition to the bleeding site.

[0133] As provided herein, OC matrix can be used as an immediate hemostatic agent at the wound site without the need for time-consuming and tedious manual compression. The compression exerted by the expansion of the material itself at the wound site allows the compressed material, after absorption of blood, to stop or reduce bleeding without further external compression.

[0134] In one aspect of the invention, a method of treating a wound is provided, comprising applying (e.g., contacting) a biodegradable hemostatic matrix disclosed in any embodiment thereof onto and / or within a wound of a subject in need of such treatment.

[0135] "Treating a wound" is further meant to encompass reducing blood loss at a bleeding site in tissue, for example, in a patient undergoing surgery. Thus, in some embodiments, the method is for reducing blood loss at a bleeding site in tissue, for example, in a patient undergoing surgery, and includes contacting the bleeding site with a composition of the present disclosure in that embodiment.

[0136] Referring now to FIG. 2, the ability of the composition of the present invention to assume the shape of a wound site while expanding upon exposure to bodily fluids is demonstrated.

[0137] As used herein, the term "subject" is intended to mean any animal, including, but not limited to, a human, a mouse, a rat, a rabbit, a non-human primate, or any other mammal. In some embodiments, the subject is a human (e.g., a human patient). The subject can be male or female.

[0138] Thus, the matrix of the present disclosure in any of its embodiments is for use in controlling bleeding in soft tissues of a subject in need thereof. The term "soft tissue" as used herein refers to body tissue that is not solidified or calcified. This term refers to soft tissue that is vascularized and therefore may be a source of bleeding. Examples of such tissues include, but are not limited to, connective tissues (such as tendons, ligaments, fascia, skin, fibrous tissue, fat, and synovium), muscles, and internal organs. In general, soft tissue is meant to exclude bone tissue.

[0139] In some embodiments, the composition is homogeneous. As used herein, "homogeneous" refers to a uniform composition and texture throughout, i.e., having a density that varies by less than ±20%, less than ±15%, less than ±10%, less than ±5%, less than ±2%, or less than ±1%.

[0140] For example, 0.8 to 1.2 gr / cm 3 It has been found that the desired combination of properties of the matrix of the present disclosure, having a density in the range of 0.1 to 1.0 mm and capable of expanding to at least three times its original volume within four seconds upon contact with an aqueous solution, can be achieved, for example, by compressing the OC material (e.g., a nonwoven material ORC source).

[0141] Accordingly, there is provided a method of making a hemostatic matrix of the present disclosure, according to any embodiment thereof, the method comprising providing a surface area of ​​about 0.2 to about 7 tonnes / cm2 of hemostatic matrix. 2 In some embodiments, the method includes compressing or compacting the OC-based material by applying a pressure in the range of 0.3 to 3.5 tons / cm2 on one or more surfaces.2 In some embodiments, the method includes compressing or molding the OC-based material by applying a pressure in the range of 0.2, 0.3, 0.4, 0.5, 0.5, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.40, 3.41, 3.42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56, 3.57, 3.58, 3.59, 3 .3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7 tonnes / cm 2 (including any value and range therebetween) of pressure to compress or mold the material.

[0142] In another aspect of the present disclosure, a matrix is ​​provided and produced by a method of compressing an OC-based material by applying pressure to its surface as set forth herein. In some embodiments, compression is applied by applying pressure, for example, using a hydraulic press. In some embodiments, the applied pressure is from about 0.2 to about 7 tons / cm. 2 , 1cm 2 0.3 to 3 tons or 0.5 to 2 tons per cm 2 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 , 3, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7 tons (including any values ​​and ranges therebetween).

[0143] In some embodiments of this method, the OC material comprises ORC. In some embodiments of this method, the ORC is in a non-woven form. In some embodiments, the method further comprises mixing the OC material with one or more additives selected from, but not limited to, calcium salts, anti-infective agents, and hemostasis promoting agents.

[0144] As used herein, the term "about" means ±10%.

[0145] The terms "comprises," "comprising," "includes," "including," "contains," "containing," "has," "having" and their conjugations mean "including but not limited to." The term "consisting of" means "including and limited to." The term "consisting essentially of" means that a composition, method, or composition may include additional components, steps, and / or moieties, but only if the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or composition.

[0146] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or does not necessarily exclude the incorporation of features from other embodiments.

[0147] The word "optionally" is used herein to mean "provided in some embodiments and not provided in other embodiments." Any particular embodiment of the invention may include multiple "optional" features, unless such features are inconsistent.

[0148] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0149] Throughout this application, various embodiments of the present invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present invention. Thus, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0150] Whenever a numerical range is given herein, it is meant to include any recited numbers (fractions or integers) within the given range. The phrases "ranging / ranges between" a first designation number and a second designation number, and "ranging / ranges from" a first designation number to a second designation number, are used interchangeably herein and are meant to include the first and second designation numbers and all fractions and integers therebetween.

[0151] As used herein, the term "method" means methods, means, techniques, and procedures for accomplishing a given task, including, but not limited to, such methods, means, techniques, and procedures that are either known or readily developed as well-known methods, means, techniques, and procedures by practitioners in the chemical, pharmacological, biological, biochemical, and medical arts.

[0152] As used herein, the term "treating" includes arresting, substantially inhibiting, slowing or reversing the progression of a disease state, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the appearance of clinical or cosmetic symptoms of a condition.

[0153] As used herein, unless otherwise specified, the terms "by weight," "w / w," "weight percent," or "% by weight" are used interchangeably herein to describe the concentration of a particular substance in the total weight of the corresponding mixture, solution, formulation, or composition.

[0154] As used herein, the term "hemorrhage" refers to the extravasation of blood from any component of the circulatory system. Thus, "hemorrhage" encompasses unwanted, uncontrolled, and often excessive bleeding associated with surgery, trauma, or other forms of tissue damage, as well as unwanted bleeding in patients with bleeding disorders.

[0155] As used herein, the terms "control," "prevent," or "reduce" may be used interchangeably herein in connection with bleeding (including all grammatical inflections thereof) to refer to essentially negating or reducing the extravagated blood rate by 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or even 100% of the initial bleeding rate compared to the situation lacking contact of the composition of the present disclosure in / on the bleeding site. Methods for determining the level of bleeding occurrence are known in the art.

[0156] Additionally, in some embodiments, in the context of bleeding, the terms "control," "prevent," or "reduce" are also meant to encompass at least partially sealing blood vessels at any site of bleeding in soft tissue.

[0157] When a notation similar to "at least one of A, B, and C, etc." is used, such syntax is generally intended in the sense that one of ordinary skill in the art would understand the notation (e.g., "a composition having at least one of A, B, and C" includes, but is not limited to, compositions having only A, only B, only C, both A and B, both A and C, both B and C, and / or all of A, B, and C, etc.). One of ordinary skill in the art will further appreciate that virtually all disjunctions and / or phrases presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to consider the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0158] Although certain features of the invention are described for clarity in the context of separate embodiments, it is understood that they may also be provided in combination in a single embodiment. Conversely, various features of the invention are described for brevity in the context of a single embodiment, but they may also be suitably provided separately or in any suitable subcombination, or in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be construed as essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0159] Various embodiments and aspects of the present invention, as delineated hereinabove and as claimed in the claims section below, find experimental support in the following examples. EXAMPLES

[0160] Reference is made to the following examples, which, together with the above description, illustrate some embodiments of the invention in a non-limiting manner.

[0161] Materials and Methods material Table 1 below shows the ORC morphology used in the exemplary expansion experiments.

[0162] [Table 1] * Tablets "A" and "B" are made from knitted fabric (A=SURGICEL ORIGINAL, B=NU-KNIT) and tablets "C" and "D" are made from either woven or non-woven (non-knit) materials (C=FIBRILLAR, D=SNoW).

[0163] In additional exemplary procedures, the following ORC materials were further tested as described below: SURGICEL, NU-KNIT, FIBRILLAR, SNoW and crushed ORC.

[0164] Sample preparation A 0.5 g sample was weighed from each material. The weighed samples were pressed into a circular tablet mold with a diameter of 1 cm. Compression forces of 0.5, 2, and 5 tons were applied, resulting in ORC tablets with different compression levels.

[0165] The weighed sample was placed in a round pellet die mold with a diameter of 1 cm. In an exemplary procedure, the mold used was a metal cylinder with a diameter of 1 cm. A metal rod with a diameter similar to the mold opening was inserted into the mold and placed on top of the sample material. A force was used on the rod to compress the sample while the rod continued to be inserted into the mold containing the sample. The force was applied by the rod on the vertical axis of the cylindrical mold. The force was applied by a manual hydraulic press until a predetermined force was reached, such as a compression force of 0.5, 2, and 5 tons. Once achieved, the rod was removed and the resulting tablet was removed from the mold.

[0166] method The thickness of each pressed sample was measured using a caliper to calculate its initial volume. A transparent 12 mm diameter graduated cylinder was filled to 10 mL with saline. A 10 mm diameter sample tablet was then dropped from the top of the cylinder into the saline in the graduated cylinder. At the time of dropping, a timer was started. The sample was constrained almost horizontally and began to absorb liquid and expand primarily in the vertical axis. The volume of sample consumed was properly visualized and evaluated through the transparent graduated cylinder. Four seconds after dropping, the rate of expansion was evaluated. The maximum rate of expansion was recorded, as well as the length of time until maximum expansion was achieved.

[0167] Equipment: 1. Caliper - Sylva "SCal pro IP67" 2. 12mm diameter graduated cylinder – "Plasti Brand" 3. Manual Hydraulic Press – Specac Atlas Series 15 Ton Press 4.10mm evacuable pellet die - Specac 5. Digital Timer TM-44 - MICROTEMP ELECTRICS CO.,LTD

[0168] Example 1: Expansion In an exemplary procedure, among other things, the rate and degree of expansion of expandable tablets produced from different processed ORC materials were evaluated. The results provide an estimate of the potential of each type of compressed ORC to function as an effective hemostatic agent in various blood loss scenarios.

[0169] Swelling ratio: The degree of swelling (swelling ratio) is defined as the multiple of the original volume (in mL) at maximum swelling. For example, if the original volume of a tablet is 2 cm 3 and the maximum expansion volume is 8 cm 3 If there is, the expansion factor will be 4.

[0170] Time to maximum swelling: The time it took for tablets to fully swell after exposure to saline was measured. Time was measured for a maximum of 300 seconds.

[0171] The results are summarized in Tables 2A and 2B, which show the swelling rate and time to swelling of ORC tablets exposed to saline (fixed at 4 seconds in Table 2B), and are further illustrated in Figures 3A and 3B.

[0172] [Table 2] * The initial volume was similar for all samples.

[0173] The milled ORC "ORC Short" and "ORC Long" samples showed the smallest expansion volume. Furthermore, when exposed to saline, the fibers dissolve to some extent and begin to disintegrate immediately. (0.785 cm 2When compressed under a pressure of 0.5 tons per tablet (100 sq. cm), "ORC Short" expanded to a maximum of approximately 5 times its original volume and "ORC Long" expanded to 3 times its original volume. Increasing the compression pressure to 2 or 5 tons had no beneficial effect on the expansion rate. However, increasing the compression strength hinders the expansion capacity of the tablets, resulting in the time to maximum expansion exceeding the defined 5 minute time limit of the assay.

[0174] The compressed materials produced, A, B, C, and D, all exhibited better expansion rates than the milled powder.

[0175] Of the knitted fabrics (materials A and B), material B showed slightly better expansion properties than material A, with no obvious effect of increasing pressure on the degree of expansion. However, the time required for maximum expansion was significantly shorter for material A compared to material B at all compression strengths (5-8 s, 10-35 s). Like powdered ORC, in both fabrics, the 0.5 ton compressed tablets expanded faster than the more compressed tablets.

[0176] At 0.5 ton compression, the expansion rate of both fabrics decreased. The time to maximum expansion was very fast for the Material D tablets (5 seconds) for all compression pressures. The Material C tablets showed a direct effect of compression on the "time to maximum expansion", where an increase in tablet pressure directly increased the time to expansion from 3 seconds (0.5 ton) to 16 seconds (5 ton). Materials A and C reached their maximum expansion at the same time (8 seconds at 2 ton compression) (see Figure 3B). Considering the combined results of expansion volume and expansion time (shown in Figures 3A and 3B), 2 ton compression was chosen.

[0177] The results presented in Table 2B, which is further illustrated in Figures 4A-5, show that the ORC density ranges from about 0.8 to 1.2 gr / cm 3 In particular, 0.95 to 1.2 gr / cm 3provided the best expansion after 4 seconds, with "FIBRILLAR" and "SNoW" exhibiting the greatest expansion rates. For comparison, a gauze pad (non-oxidized cellulose) was also tested, which showed a lower expansion coefficient for a given density value compared to the oxidized cellulose sample.

[0178] [Table 3] * Assuming a circular mold of 1 cm, πr 2 Calculated as 0.785cm 2 is given. ** Surface area of ​​cylinder = 2πr 2 +2πrh Materials: "1"-SURGICEL, "2"-NU-KNIT, "3"-FIBRILLAR, "4"-SNoW, "5"-Crushed ORC, "6"-Gauze Pad (Non-oxidized Cellulose)

[0179] FIG. 6 is also based on Table 2B and provides a graph showing maximum expansion volume (mL) in saline versus ORC material density.

[0180] Example 2: In vivo study: porcine spleen biopsy punch model In an in vivo study, the differential hemostatic effects of representative tablets composed of different fabrics (knitted and nonwoven) were investigated.

[0181] In this study, similar expansion times are recommended. Therefore, from the knitted materials, material A was selected (see Table 2A), and from the nonwoven materials, material C was selected (see Table 2A). As described above, both reached their maximum expansion at the same time (8 seconds at 2 ton compression) (see Figure 3B). Considering the combined results of expansion volume and expansion time (see Figures 3A and 3B), 2 ton compression was selected.

[0182] material ORC material C or ORC material A (5 g each) was compressed with a compressive force of 2 tons to obtain a mass of 0.4 mL (cm 3) tablets.

[0183] method Porcine spleen biopsy punch model: Adult female pigs weighing approximately 60 kg were fasted for 24 hours prior to surgical procedures. Animals were anesthetized with 1150-1400 mg ketamine, 115-140 mg xylazine, and 7.5 mg midazolam. Anesthesia was maintained with isoflurane, and the abdomen was opened to expose the spleen.

[0184] Mean arterial blood pressure, body temperature, and heart rate were continuously monitored during the surgical procedure. The experiment was terminated when the mean arterial blood pressure fell below 60 mmHg.

[0185] A biopsy punch, 8 mm in diameter x 3 mm deep, was performed on the spleen and the specimen was excised with surgical scissors. The punch site was allowed to bleed for 30 seconds and the bleeding intensity was visually assessed on a scale of 0 to 5 (described in FIG. 7). "No bleeding" was given a score of 0 and "heavy bleeding" was given a score of 5. The punch site was then wiped with clean gauze to remove excess blood and a single tablet was inserted into the puncture wound. The bleeding rate was then reassessed according to the scheme described in FIG. 7.

[0186] The results are summarized in Table 3 below, which shows the effect of application of ORC tablets on bleeding levels in an 8mm diameter x 3mm depth splenic biopsy punch model.

[0187] [Table 4]

[0188] Application of ORC Material A tablets to a puncture with a bleeding level of grade 3 ("mild" bleeding) reduced the bleeding to a grade 1 level ("exudation"). Application of ORC Material C tablets showed superior efficacy, reducing a bleeding level of grade 4 ("moderate" bleeding) to grade 1 ("exudation"). During application, ORC Material C tablets expanded much more rapidly, demonstrating greater efficacy and faster rate of reducing bleeding than ORC Material A tablets. These results indicate that the texture of the nonwoven compressed fabric properties, which expand to a larger volume and at a faster rate than compressed knit ORC, also shows improved efficacy in hemostasis of puncture bleeding. Application of non-compressed ORC Material C showed reduced efficacy, reducing the bleeding level from 4 ("moderate") to 2 ("mild"), suggesting the advantage of compressed tablets over non-compressed materials in immediate hemostasis of puncture wounds.

[0189] Example 3: In vivo studies: Heparinized porcine spleen biopsy punch model Approximately 60 kg adult female pigs were treated as described above, laparotomy was performed to expose the liver or spleen, and 27,000 IU of heparin was administered prior to the biopsy procedure. The ACT (activated clotting time) test was used to monitor heparinization. Heparin boosts were therefore given to maintain stable ACT levels. Heparin is used as an injectable anticoagulant (through activation of antithrombin III). Thus, this model represents a challenge bleeding model.

[0190] The liver was subjected to a 8 mm diameter x 3 mm depth biopsy punch. The porcine spleen was subjected to a 6 mm diameter x 3 mm depth biopsy punch. In both organs, the specimens were excised with surgical scissors. The punch site was allowed to bleed for 30 seconds and the bleeding intensity (level) was visually assessed on a scale of 0 to 5 as described above. The results are summarized. Table 4 shows the effect of application of ORC tablets on bleeding levels in the 8 mm diameter x 3 mm depth liver biopsy punch model. Table 5 shows the effect of application of ORC tablets on bleeding levels in the 6 mm diameter x 3 mm depth spleen biopsy punch model. The hemostatic effect was evaluated in the porcine liver and porcine spleen. The ORC tablets were manually applied to the wound site.

[0191] [Table 5] * triple

[0192] [Table 6]

[0193] At a biopsy punch size of 8 mm diameter x 3 mm depth (as shown in Table 4), application of non-woven ORC tablets (material C-triple, material D-single) to the liver reduced the bleeding intensity from 4 to 0 (from "moderate" to "no bleeding") and completely stopped the bleeding. Application of the "ORC short" compressed tablet showed little expansion of the tablet and this sample was unable to achieve hemostasis (as shown in Table 4).

[0194] Application of non-woven ORC tablets (material C-single, material D-double) to pig spleens resulted in complete cessation of bleeding from 2 / 3 / 4 (initial bleeding levels) to 0 (as shown in Table 5). Application of "ORC short" compressed tablets (tested in triplicate) showed a reduction in bleeding of 1 or 2.

[0195] These results indicate that compressed tablets made from nonwoven ORC materials exhibit higher efficacy than tablets made from other ORC materials, which could potentially be applied in new surgical scenarios and broaden the scope of application of ORC-based materials.

[0196] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0197] [Embodiment] (1) A biodegradable hemostatic matrix comprising oxidized cellulose (OC), the OC comprising one or more sheets, the matrix having (i) about 0.8 to about 1.2 gr / cm 3 and (ii) is capable of expanding to at least three times its original volume within four seconds upon contact with an aqueous solution at at least one temperature between 10 and 40°C. (2) Approx. 1.2gr / cm 3 2. The matrix of embodiment 1, having a density of (3) 5mm 3 3. The matrix according to embodiment 1 or 2, having a volume of greater than 1000 μm. (4) The matrix according to any one of the preceding embodiments, which is in a compressed state. (5) A matrix according to any one of the preceding embodiments, having a cylindrical, rectangular and / or polygonal shape.

[0198] (6) The matrix according to any one of the preceding embodiments, which is capable of swelling to at least 90% of its maximum swelling volume within 30 seconds after immersion in an aqueous solution. (7) The matrix according to embodiment 6, which is capable of expanding to 15 to 30 times its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 30° C. (8) The matrix according to any one of the preceding embodiments, in a form selected from a tablet and a wound dressing. (9) The matrix according to any one of the preceding embodiments, wherein the OC comprises oxidized regenerated cellulose (ORC). (10) The matrix of embodiment 9, wherein the ORC is in a form selected from a knitted fabric, a nonwoven fabric, a woven fabric, a shredded material, and any combination thereof.

[0199] 11. The matrix of claim 10, wherein the ORC is in the form of a nonwoven fabric. (12) The matrix according to any one of the preceding embodiments, further comprising one or more additives selected from the group consisting of calcium salts, anti-infective agents, and hemostasis-promoting agents. (13) The matrix according to any one of the preceding embodiments, further comprising one or more excipients selected from the group consisting of sodium chloride, mannitol, albumin, and sodium acetate. (14) The matrix according to any one of the preceding claims, wherein the carboxyl content of the OC is in the range of 12% by weight to 21% by weight according to United States Pharmacopeia (USP) 23-NF18. (15) Approx. 0.5~10cm 2 , optionally from about 3 to about 5 cm 2 15. The matrix according to any one of the preceding embodiments, having a total pre-expanded surface area in the range of

[0200] (16) Approx. 0.05 cm 3 ~ approx. 2cm 3 , optionally from about 0.4 to about 0.8 cm 3 15. The matrix according to any one of the preceding embodiments, having a pre-expanded volume in the range of (17) A matrix according to any one of embodiments 1 to 16 for use in controlling bleeding in soft tissues. (18) A matrix according to any one of the preceding embodiments for use in inhibiting or reducing the formation of a microbial load. (19) OC-based material is applied to the surface at a rate of 0.3 to 7 ton / cm 2 19. The matrix according to any one of the preceding embodiments, which has been produced by compressing it by applying a pressure in the range of (20) The matrix of any one of the preceding embodiments, wherein the OC contains less than 8% water, optionally less than 5% water, prior to contact with the aqueous solution.

[0201] (21) The matrix according to any one of the preceding embodiments, which is capable of expanding to at least four times its original volume within four seconds upon contact with an aqueous solution at at least one temperature between 10 and 40° C. (22) The matrix according to any one of the preceding embodiments, which is capable of expanding to at least 5 times its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 40° C. (23) The matrix according to any one of the preceding embodiments, which is capable of expanding to 3 to 6 times its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 40° C. (24) A method for producing a hemostatic matrix according to any one of the first to third embodiments, comprising applying an OC-based material to the surface of the matrix at a concentration of about 0.3 to about 7 ton / cm. 2 compressing by applying a pressure in the range of 25. The method of claim 24, wherein the OC material comprises ORC.

[0202] 26. The method of claim 25, wherein the ORC is in nonwoven form. (27) The method of any one of embodiments 24 to 26, further comprising mixing the OC material with one or more additives selected from the group consisting of calcium salts, anti-infective agents, and hemostasis-promoting agents. (28) A method for treating a wound, comprising applying a biodegradable hemostatic matrix described in any one of embodiments 1 to 23 onto and / or into the wound of a subject in need thereof.

Claims

1. A biodegradable hemostatic matrix comprising oxidized cellulose (OC), said OC comprising oxidized regenerated cellulose (ORC), said matrix being a compressed tablet or pellet having a density ranging from about 0.8 to about 1.2 gr / cm3 in the form of one or more nonwoven sheets, said one or more nonwoven sheets being fibrous and / or filled layered sheets, said compressed tablet or pellet being capable of expanding to 3 to 8 times its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 40°C.

2. The density is from about 0.95 to about 1.2 gr / cm ３ 2. The matrix of claim 1, wherein the .alpha.-methylphenyl.

3. 3. The matrix according to claim 1 or 2, which is capable of expanding to at least four times its original volume within four seconds upon contact with an aqueous solution at at least one temperature between 10 and 40°C.

4. A matrix according to any one of claims 1 to 3, which is capable of expanding to at least 5 times its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 40°C.

5. 3. The matrix according to claim 1 or 2, which is capable of expanding to 3 to 6 times its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 40°C.

6. 6. The matrix according to any one of claims 1 to 5, wherein the compressed tablet or pellet is capable of expanding to 5 to 8 times its original volume within 4 seconds upon contact with an aqueous solution at at least one temperature between 10 and 40°C.

7. 7. The matrix according to claim 6, wherein the compressed tablet or pellet has a maximum expansion ratio of 6 to 8 times.

8. The density is about 1.2 gr / cm ３ The matrix according to any one of claims 1 to 7,

9. 5mm ３ A matrix according to any one of claims 1 to 8, having a volume of more than 1000 μm.

10. A matrix according to any one of claims 1 to 9, in a compressed state.

11. The matrix according to any one of claims 1 to 10, having a cylindrical, rectangular and / or polygonal shape.

12. A matrix according to any one of claims 1 to 11, which is capable of swelling to at least 90% of its maximum swelling volume within 30 seconds after immersion in an aqueous solution.

13. A matrix according to any one of claims 1 to 12 for use in a bandage.

14. The matrix of any one of claims 1 to 13, further comprising one or more additives selected from the group consisting of calcium salts, anti-infective agents, and agents promoting hemostasis.

15. The matrix according to any one of claims 1 to 14, further comprising one or more excipients selected from the group consisting of sodium chloride, mannitol, albumin, and sodium acetate.

16. The matrix according to any one of claims 1 to 15, wherein the carboxyl content of the OC ranges from 12% to 21% by weight according to United States Pharmacopeia (USP) 23-NF18.

17. Approximately 0.5 to approximately 10cm ２ , optionally from about 3 to about 5 cm ２ 17. The matrix of any one of claims 1 to 16, having a total pre-expanded surface area in the range of

18. Approximately 0.05 cm ３ ~ approx. 2 cm ３ , optionally from about 0.4 to about 0.8 cm ３ 17. The matrix according to any one of claims 1 to 16, having a pre-expanded volume in the range of

19. A matrix according to any one of claims 1 to 18 for use in controlling bleeding in soft tissue.

20. A matrix according to any one of claims 1 to 19 for use in inhibiting or reducing the formation of a microbial load.

21. The matrix of any one of claims 1 to 20, wherein the OC comprises less than 8% water, optionally less than 5% water, prior to contact with the aqueous solution.

22. A method of making the matrix according to any one of claims 1 to 21, comprising applying the OC to a surface of the matrix at a density of about 0.3 to about 7 ton / cm2. ２ compressing by applying a pressure in the range of

23. The pressure is about 1 to about 2 tons / cm ２ The method of claim 22, wherein the range is

24. 24. The method of claim 22 or 23, further comprising mixing the OC with one or more additives selected from the group consisting of calcium salts, anti-infective agents, and hemostasis promoting agents.

25. 22. A matrix according to any one of claims 1 to 21 for use in a method of treating a wound, the method comprising the step of applying the matrix onto and / or into the wound of a subject in need thereof.

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