Systems and methods for using tissue-adhesive porous hemostatic products in event of severe surface and chamber bleeding

Abstract

Methods and systems for using a biocompatible and flexible hemostatic sheet comprising a fibrous carrier structure and a reactive electrophilic group capable of reacting with amine groups in tissue and blood, the hemostatic sheet is delivered to tissue at a bleeding site of an organ to resume hemostasis during an open surgical procedure.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 483,051, filed February 3, 2023, the disclosure of which is hereby incorporated by reference in its entirety for all purposes. Technical Field

[0003] The present disclosure relates to devices and methods for reducing bleeding sites using medical products comprising biocompatible, covalently cross-linked polymers. Background Art

[0004] Intraoperative bleeding can cause significant morbidity and mortality and can have several health economic impacts, such as longer operating times, increased resource use, and longer hospital stays. Hemostatic technology is essential during surgery or other invasive procedures to provide hemostasis quickly and efficiently. Failure to achieve hemostasis can prolong surgery, impair wound healing, increase infection, and lead to accidental exposure to blood products if the patient requires a blood transfusion. Hemostatic products are used when standard methods (e.g., temporary packing, electrocautery, and suturing) cannot control bleeding. Topical hemostatic agents such as patches, glues, powders, and sprays are divided into three categories: (1) adhesive, containing fibrinogen and thrombin; (2) mechanical, containing gelatin, collagen, or oxidized cellulose; and (3) sealants containing polyethylene glycol (PEG). Current products have several disadvantages in terms of applicability, user-friendliness, and financial cost. Examples of these disadvantages are partial detachment when applied to irregular tissue surfaces, long waiting times before hemostasis, lower effectiveness in coagulopathy conditions, and increased cost due to reliance on human-derived coagulation components.

[0005] Although different hemostatic agents are effective for less severe exudative bleeding from capillaries and small blood vessels, only a few of these agents can be applied to active, severe bleeding. Patches are known for their ability to achieve hemostasis in the case of severe bleeding, but their use in cavities or recesses is inadequate because they lack the flexibility and homogeneity to be shaped to fill the cavity or conform to highly irregular recesses to uniformly deliver the coagulation matrix. Flowable hemostatic agents are considered to be the standard of care as an adjunct to hemostasis for this type of challenging bleeding, but in the case of severe bleeding, flowable agents require additional doses to complete hemostasis, which reduces efficacy and increases the time to control active bleeding.

[0006] In light of these significant performance shortcomings, there is a need for flexible hemostats that can be suitably used to minimize bleeding during surgical procedures. The solution of the present disclosure addresses these and other problems in the art. Summary of the Invention

[0007] The subject of the present disclosure is the use of a biocompatible and flexible hemostatic sheet for restoring hemostasis to tissue at a bleeding site of an organ during surgery.

[0008] An example method for treating bleeding in a subject during a surgical procedure may include positioning a hemostatic patch in contact with tissue at a bleeding site in a respective subject of a plurality of first subjects, and restoring hemostasis to the tissue within at least three minutes. The hemostatic patch may include a carrier structure and a reactive electrophilic group capable of reacting with amine groups in the tissue and blood.

[0009] The present disclosure includes a method for treating bleeding in a subject during a surgical procedure. The method may include delivering a first hemostatic patch into contact with tissue at a bleeding site of an organ of a corresponding subject in a plurality of first subjects, reacting it with a nucleophilic polymer and amine groups in the tissue and blood; and restoring hemostasis to the organ within at least three minutes. The first hemostatic patch may comprise a three-dimensionally interconnected interstitial space. The three-dimensionally interconnected interstitial space may comprise a plurality of reactive polymer particles, the reactive polymer particles comprising a nucleophilic polymer carrying a reactive nucleophilic group; and an electrophilic polymer carrying at least three reactive electrophilic groups that are capable of reacting with amine groups in the tissue and blood.

[0010] The present disclosure includes a method for treating bleeding in a subject during a surgical procedure. The method may include delivering a first hemostatic patch to a portion of a first subject near or around a bleeding site of an organ of a respective subject in a plurality of first subjects, and achieving hemostasis of the organ within approximately one minute. The first hemostatic patch may include a nucleophilic polymer having a reactive nucleophilic group and an electrophilic polymer having at least three reactive electrophilic groups capable of reacting with amine groups in the nucleophilic polymer and tissue and blood.

[0011] The present disclosure includes a device for treating surgical bleeding in a subject. The device may include a biocompatible, flexible hemostatic patch. The hemostatic patch may include a nucleophilic polymer carrying a reactive nucleophilic group and an electrophilic polymer carrying at least three reactive electrophilic groups that are capable of reacting with amine groups in the nucleophilic polymer and tissue and blood. The hemostatic device may be configured to be delivered to an organ of a subject and restore hemostasis to the organ within approximately three minutes or less after the hemostatic device is positioned in contact with tissue at a bleeding site of the organ.

[0012] The present disclosure includes a device for treating surgical bleeding in a subject. The device may include a biocompatible, flexible hemostatic device for treating surgical bleeding. The hemostatic device may include a water-resistant, adhesive, fibrous carrier structure. The fibrous carrier structure may include three-dimensionally interconnected interstitial spaces having a plurality of reactive polymer particles having an electrophilic polymer; and fibers having a nucleophilic polymer carrying reactive nucleophilic groups. The hemostatic device may be capable of being delivered to an organ of a subject and restoring hemostasis to the organ in approximately three minutes or less by positioning the hemostatic device near or around a bleeding site in the organ.

[0013] To accomplish the foregoing and related ends, certain illustrative aspects are described herein in connection with the following description and accompanying drawings. However, these aspects are indicative of but a few of the various ways in which the principles of the claimed subject matter may be employed, and the claimed subject matter is intended to include all such aspects and their equivalents. Additional advantages and novel features will become apparent from the following detailed description when considered in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The above and additional aspects of the present invention will be further discussed with reference to the following description in conjunction with the accompanying drawings, in which like numbers indicate similar structural elements and features in the various figures. The drawings are not necessarily drawn to scale, with emphasis instead being placed upon illustrating the principles of the invention. The drawings depict one or more specific implementations of the apparatus of the present invention by way of example only and not limitation.

[0015] Figure 1 A patient undergoing open surgical procedure is shown with an example hemostatic patch positioned at the site of bleeding, according to an embodiment of the present disclosure.

[0016] Figure 2A A perspective view of an example hemostatic patch according to an embodiment of the present disclosure is shown.

[0017] Figure 2B and Figure 2C is a structure of example reactive particles embedded in a hemostatic patch according to an embodiment of the present disclosure.

[0018] Figure 3 A diagram showing the verbal and visual descriptors of the Surface Bleeding Severity Scale (SBSS) score and the corresponding intended interventions.

[0019] Figure 4 A representative overview of an example of a research process for the present disclosure is shown.

[0020] Figure 5 is a table summarizing the demographics of an example study of the present disclosure.

[0021] Figure 6A is a table summarizing the disease diagnoses of multiple subjects in the first study of the present disclosure.

[0022] Figure 6B is a table summarizing the types of surgery for multiple subjects in the first study of the present disclosure.

[0023] Figure 7 is a table summarizing treatment details for multiple subjects in the first study of the present disclosure.

[0024] Figure 8 is a table summarizing the characteristics of subjects who underwent use of adjunctive hemostatic agents / techniques to achieve hemostatic control for multiple subjects prior to application of a hemostatic patch in the first study of the present disclosure.

[0025] Figure 9 A table summarizing the hemostatic endpoints for the first treated bleeding site for each Phase II patient of the first study of the present disclosure is provided.

[0026] Figure 10 A table summarizing the hemostatic endpoints for all treated bleeding sites (eg, more than one bleeding site per subject) for Phase II subjects and all patients of the first study of the present disclosure is provided.

[0027] Figure 11 A graphical illustration of the time to hemostasis for multiple subjects following application of the hemostatic patch relative to a comparative device 1 in a second study of the present disclosure is provided.

[0028] Figure 12 is a graphical depiction of the efficacy of a conditioned hemostatic patch according to an embodiment of the present disclosure compared to a blank, Comparative Device 1, and Comparative Device 2 following liver perforation, liver resection, and splenectomy.

[0029] Figure 13A and Figure 13B Shown is a summary of the results of mean hemostasis and rebleeding times for examples of studies of the present disclosure comparing the hemostatic patch to Comparative Device 4 and Comparative Device 5 according to the fourth study of the present disclosure.

[0030] Figure 14 is a table summarizing the initial hemostasis between the hemostatic patch and the comparative device 4 and the number of applications for each device used in the fifth study of the present disclosure.

[0031] Figure 15 is a flow chart of an example method for treating bleeding in a subject during a surgical procedure by delivering a hemostatic patch according to an embodiment of the present disclosure.

[0032] Figure 16is a flow chart of an example method for treating bleeding in a subject during a surgical procedure by delivering a hemostatic patch according to an embodiment of the present disclosure.

[0033] Figure 17 is a flow chart of an example method for treating bleeding in a subject during a surgical procedure by delivering a hemostatic patch according to an embodiment of the present disclosure.

[0034] Figure 18 is a flow chart of an example method for treating bleeding in a subject during a surgical procedure by delivering a hemostatic patch according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0035] Although example embodiments of the disclosed technology are described in detail herein, it should be understood that other embodiments are contemplated. Accordingly, it is not intended that the scope of the disclosed technology be limited to the details of construction and arrangement of components set forth in the following description or illustrated in the accompanying drawings. The disclosed technology is capable of other embodiments and can be practiced or implemented in various ways.

[0036] It should also be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "comprise," "contain," or "include" mean that at least the named compound, element, particle, or process step is present in the composition, article, or process, but do not preclude the presence of other compounds, materials, particles, or process steps, even if such other compounds, materials, particles, or process steps have the same function as the named ones.

[0037] In describing the example embodiments, terminology will be employed for the sake of clarity. It is intended that each term assume its broadest meaning as understood by those skilled in the art, and include all technical equivalents that operate in a similar manner to achieve similar purposes. It should also be understood that reference to one or more steps of a method does not preclude the presence of additional method steps or intermediate method steps between those explicitly identified steps. The steps of the method may be performed in an order different from that described herein without departing from the scope of the disclosed technology. Similarly, it should also be understood that reference to one or more components in a device or system does not preclude the presence of additional components or intermediate components between those explicitly identified components.

[0038] As discussed herein, the vasculature of a "subject" or "patient" can be the vasculature of a human or any animal. It should be understood that the animal can be any suitable type, including but not limited to mammals, veterinary animals, livestock animals, or pet animals. For example, the animal can be a laboratory animal specifically selected to have certain characteristics similar to those of humans (e.g., rats, dogs, pigs, monkeys, etc.). It should be understood that the subject can be, for example, any suitable human patient.

[0039] As discussed herein, an "operator" may include a physician, surgeon, or any other individual or delivery instrument associated with delivering a retrieval device to the vasculature of a subject.

[0040] As discussed herein, "hemorrhage" can be understood as the release of blood from a ruptured blood vessel inside or outside the body. The terms "hemorrhage," "bleeding site," "rupture," "blood flow," "bleeding," and the like are often used interchangeably throughout this disclosure.

[0041] Unless otherwise specified, as used herein, the term "hemostatic patch" refers to a sheet material that has the ability to stop bleeding from damaged tissue. The hemostatic patch of the present invention can achieve hemostasis by turning blood into a gel and / or by forming a seal to close a wound site.

[0042] As used herein, the term "tissue adhesion" refers to the ability of a hemostatic patch to adhere to tissue due to the formation of covalent bonds between the patch and the tissue. The formation of these covalent bonds generally requires the presence of water.

[0043] As used herein, the term "water-resistant" or "insoluble" in relation to a fibrous support structure means that the structure is not water-soluble and does not disintegrate to form a colloidal dispersion in water under neutral pH conditions (pH 7) and a temperature of 37° C. In some examples, the fibrous support structure can absorb up to about 35 times its own weight in an aqueous solution before converting to a colloidal dispersion.

[0044] As used herein, the term "interstitial space" refers to the void ("empty") space within a fibrous support structure. The interstitial space within the fibrous support structure allows for the introduction of reactive polymer particles into the structure. In addition, blood and other bodily fluids can enter the interstitial space, allowing the water-soluble electrophilic polymer within the reactive polymer particles to dissolve.

[0045] The concentration of reactive polymer particles having a diameter in the range of 0.5 μm to 100 μm is expressed as % by weight of the fibrous support structure itself (ie without reactive polymer particles).

[0046] The "water-soluble electrophilic polymer carrying reactive electrophilic groups" employed in accordance with the present invention carries at least three reactive groups capable of reacting with amine groups in tissue and blood by forming covalent bonds. The water-soluble electrophilic polymer has a molecular weight of at least 1 kDa and a solubility of at least 50 g / L in distilled water at 20°C.

[0047] As used herein, the term "water absorption capacity" is a measure of the ability of a hemostatic patch to absorb water. The water absorption capacity is determined by weighing a sample of the dry sheet (weight = Wd) and then immersing the sample in distilled water (37°C) for 45 minutes. Next, the sample is removed from the water and the water attached to the outside of the substrate is removed, and then the sample is weighed again (weight = Ww). Water absorption capacity = 100% x (Ww-Wd) / Wd. The water absorption capacity indicates the porosity of the substrate and its ability to swell in the presence of water.

[0048] As used herein, the term "collagen" refers to the main structural protein in the extracellular space of various connective tissues in animals. Collagen forms a characteristic triple helix of three polypeptide chains. Depending on the degree of mineralization, collagen tissue can be rigid (bone) or compliant (tendon), or have a gradient from rigidity to compliance (cartilage). Unless otherwise specified, the term "collagen" also encompasses modified collagens other than gelatin.

[0049] As used herein, the term "gelatin" refers to a mixture of peptides and proteins produced by partial hydrolysis of collagen extracted from the skin, bones, and connective tissue of animals such as domestic cattle, chickens, pigs, and fish. During the hydrolysis process, the natural molecular bonds between individual collagen chains are broken down into a form that is more easily rearranged.

[0050] As used herein, the term "polyoxazoline" refers to poly(N-acylalkyleneimine) or poly(aroylalkyleneimine), and is also referred to as POx. An example of POx is poly(2-ethyl-2-oxazoline). The term "polyoxazoline" also includes POx copolymers.

[0051] The present disclosure relates to systems, methods and devices for recovering hemostasis to the bleeding site of tissue during open surgical procedures, and particularly for hemorrhage from organs. Certain features, such as a fiber carrier structure, can be designed to be flexibly positioned in and / or above the bleeding site to stabilize bleeding. Certain features of the hemostatic patch of the present disclosure can allow for easier delivery procedures, reduce the time delivered at the bleeding site and reduce hemostasis.

[0052] For example, Figure 1 A schematic diagram of an open surgical procedure is depicted in which an example hemostatic device 200, also known as a hemostatic patch, is positioned at a bleeding site on an organ 10 (particularly the liver). The hemostatic device 200 can be designed to be positioned within or over any internal bleeding site in the body, such as the liver, pancreas, spleen, stomach, kidney, bladder, reproductive organs, lungs, heart, etc. Although not shown, the hemostatic device 200 can also be designed for use during minimally invasive surgery (e.g., laparoscopy) and / or for external use (e.g., on the skin of a subject).

[0053] The studies disclosed herein compared Device 200 (GATT-Patch 10×5 cm; GATT Technologies BV, Nijmegen, The Netherlands) with comparator devices including Comparator Device 1 (FloSeal; Baxter Healthcare, Deerfield, IL, United States); Comparator Device 2 (TachoSil, Corza Medical, Westwood, MA, United States); Comparator Device 3 (Veriset; Medtronic plc, Dublin, Ireland); Comparator Device 4 (Surgifoam; Johnson and Johnson Ethicon, Bridgewater, NJ, United States, which was used in combination with thrombin for more severe bleeding in the studies described herein; and Comparator Device 5 (Hemopatch; Baxter International Inc., Deerfield, IL, United States).

[0054] Figure 2A A pictorial representation of a hemostatic device 200 is depicted. A hemostatic patch 200 according to the present invention may include a water-resistant, adhesive fiber carrier structure that holds small particles. The small particles include Figure 2B The reactive electrophilic polymers depicted in Figure 2C The distribution of polymers with nucleophiles is depicted in The reactive electrophilic polymers are capable of covalently binding to host blood proteins and tissues as well as to reactive nucleophilic groups in the polymer cross-linking moieties and fibrous support structure and thereby inducing hemostasis and / or tissue adhesion.

[0055] Figure 2B The reactive electrophilic polymer in the present invention includes functional NHS-ester side chains that can (i) react with amines at the target bleeding site (e.g., tissue, protein, etc.), (ii) react with Figure 2C The invention relates to a hemostatic patch 200 comprising a plurality of hemostatic polymers, wherein the plurality of hemostatic polymers comprises a plurality of hemostatic polymers, wherein the plurality of hemostatic polymers comprises a plurality of hemostatic polymers, wherein the plurality of hemostatic polymers comprises a plurality of hemostatic polymers, wherein the plurality of hemostatic polymers comprises a plurality of hemostatic polymers, and (iii) reacts with the amines in the gelatin of the hemostatic patch 200 to act as a hemostatic polymer. Crosslinking with the tissue results in adhesion to the tissue. Crosslinking with the gelatin and the crosslinked polymer results in hemostasis within the carrier. The main chain structure (which is composed of tertiary amide groups) is generally stable under physiological conditions, but the presence of ester groups makes the side chains essentially biodegradable. The ester bond also contributes to the degradability of the reactive electrophilic polymer. The reactive electrophilic polymer can include a composition of P(EtOx-OH-NHS) and form particles embedded in the hemostatic patch 200. Figure 2BThe main chain shown in comprises a copolymer (terpolymer) having three monomers. In some examples, P(EtOx-OH-NHS) can be formed in a 60-20-20 ratio (about 60% POx, about 20% OH, and about 20% NHS). In 60% Pox, the "Et" component can be inert and limit post-polymerization activation, while the "Me" component (40%) can be post-polymerization activated. The first monomer can have a chain length m in the range of about 5 to about 5,000 repeating units. The second monomer can have a chain length n in the range of about 5 to about 5,000 repeating units. The third monomer can have a chain length p in the range of about 5 to about 5,000 repeating units. PDI can be in the range of about 1.10 to about 2.50.

[0056] Figure 2C The cross-linked polymers include amine side variations, which can be Figure 2B The electrophilic polymer reacts to act as a crosslinking agent. The backbone structure includes tertiary amide groups and is generally stable under physiological conditions. The crosslinking polymer may include a composition of P(EtOx-NH2). Figure 2C The backbone shown in includes a copolymer (binary copolymer) having two monomers. In some examples, P(EtOx-NH2) can be formed in a 90-10 ratio (about 90% POx and about 10% NH2). The first monomer can have a chain length q in the range of about 5 to about 5,000 repeating units. The second monomer can have a chain length r in the range of about 5 to about 5,000 repeating units.

[0057] Figure 2B The particulate reactive electrophilic polymer depicted in Figure 2C The molecular weight distribution or polydispersity index (PDI) of the polymer crosslinks depicted in the embodiment is less than 2.0 upon release. Premature or excessive crosslinking between NHS-POx and NU-Pox and / or gelatin results in an increase in the PDI. If such crosslinking occurs, there will be fewer readily available NHS groups that can adhere to tissue and reduce the hemostatic control of the hemostatic patch 200.

[0058] The hemostatic patch 200 can restore hemostasis to a bleeding site by positioning the hemostatic patch 200 in contact with tissue at the bleeding site. It should be understood that the hemostatic patch 200 can be used to restore hemostasis to the tissue within three minutes or less (e.g., 30 seconds) after the hemostatic patch 200 is brought into contact with the tissue. Since applicable procedural guidelines vary with respect to the use of hemostatic patches for treating open surgical procedures, it is also conceivable that the device 200 can be delivered via alternative techniques, such as during minimally invasive surgery. The hemostatic patch 200 can be understood to include the features expressly described in Appendix A, which is incorporated herein by reference in its entirety, from U.S. Patent Nos. 10,232,077 and 9,416,228; and U.S. Patent Application Nos. 17 / 573,564; 17 / 573,541; 17 / 573,537; 17 / 573,574; and 17 / 586,428, each of which is incorporated herein by reference in its entirety as if set forth verbatim herein.

[0059] Hemostatic patch 200 comprises a water-resistant, adhesive fibrous support structure that readily absorbs blood, as blood can penetrate the interstitial spaces. This fibrous support structure can be easily impregnated with reactive polymer particles. Unlike liquid impregnation, this dry impregnation does not affect the structural integrity or mechanical properties of the support structure. As blood is absorbed by hemostatic patch 200, the reactive polymer particles within the sheet begin to dissolve once they are 'wetted' by the blood, allowing the electrophilic polymer to react with both reactive nucleophilic groups in the blood and tissue, as well as reactive nucleophilic groups in the fibrous support structure, thereby inducing blood coagulation and tissue sealing, both of which contribute to hemostasis.

[0060] The reactive polymer particles can be uniformly distributed within the interstitial spaces of the fibrous support structure, in the sense that the particle density is substantially the same throughout the support structure. Alternatively, the reactive polymer particles can be unevenly distributed throughout the support structure. For example, if the hemostatic sheet is prepared as a laminate of a thin layer of a fibrous support structure and a layer of reactive polymer particles, the reactive polymer particle density within the sheet may fluctuate. For certain applications, it may be advantageous if the reactive polymer particle density exhibits a gradient, e.g., the reactive polymer particle density is highest near one side of the sheet intended for application to a bleeding wound and lowest near the other side of the sheet.

[0061] The diameter distribution of the reactive polymer particles can be suitably determined by laser diffraction using a Malvern Mastersizer 2000 in combination with a stainless steel sample dispersion cell. The sample dispersion cell is filled with approximately 120 ml of cyclohexane, which is stabilized at a stirring speed of 1800 rpm for 5 to 10 minutes, followed by a background measurement (blank measurement). The sample tube is shaken and rotated horizontally 20 times. Next, approximately 50 mg is dispersed in the sample dispersion cell containing cyclohexane. After the sample is introduced into the dispersion cell, it is stirred at 1800 rpm for one and a half minutes to ensure that all particles are properly dispersed before the measurement is taken. The dispersed particles are not subjected to ultrasonic treatment. The average particle size is expressed as D[4,3], i.e. the volume weighted average diameter (Σn i D i 4 ) / (Σn i D i 3 ).

[0062] In a particularly preferred embodiment, unlike the fibrous tissue sealants described in U.S. Pat. No. 8,545,871, the hemostatic patch of the present invention does not form a hydrogel, i.e., a water-swellable polymer matrix that can absorb large amounts of water to form an elastic gel, until it is wetted after delivery to the bleeding site.

[0063] According to a particularly preferred embodiment, the hemostatic patch 200 is bioabsorbable, meaning that the carrier structure, reactive polymer particles, and any other components of the hemostatic patch 200 are ultimately absorbed into the body. Absorption of the carrier structure and reactive polymer particles typically requires chemical decomposition (e.g., hydrolysis) of the polymers contained therein. Complete absorption of the hemostatic patch 200 by the body is typically achieved within approximately 1 to 10 weeks, preferably within approximately 4 to 6 weeks.

[0064] The hemostatic patch 200 typically has an uncompressed average thickness of 0.5 mm to 25 mm, more preferably, the uncompressed average thickness is in the range of 1 mm to 10 mm, and most preferably in the range of 1.5 mm to 5 mm.

[0065] The size of the hemostatic patch 200 is preferably such that the top and bottom of the sheet each have at least 2 cm 2 , more preferably at least 10 cm 2 and most preferably 25cm 2 -50cm 2Typically, the sheet is rectangular in shape and has a length of 25 mm to 200 mm and a width of 25 mm to 200 mm. Due to its flexibility, the hemostatic patch 200 of the present invention can be appropriately applied to irregularly shaped bleeding sites. If the applied sheet does not completely stop the bleeding, the hemostatic sheet can be applied layer by layer.

[0066] The hemostatic patch 200 can be cut into any suitable shape and size for an open surgical delivery method or for the size of a bleeding site. Additionally or alternatively, due to the fiber carrier structure, the hemostatic patch 200 can be chopped or otherwise formed into a cotton candy-like configuration. During the procedure, the hemostatic patch 200 can be chopped or rolled into a ball and positioned within the cavity at the bleeding site, and then the unchopped patch is placed on the bleeding site to restore hemostasis.

[0067] The hemostatic patch 200 preferably has a viscosity less than 200 mg / cm 3 , more preferably less than 150 mg / cm 3 And most preferably 10 mg / cm 3 -100mg / cm 3 Uncompressed density.

[0068] In one embodiment of the present invention, the reactive polymer particles are uniformly distributed within the interstitial spaces of the fibrous support structure. In another embodiment of the present invention, the hemostatic patch 200 is a laminate comprising alternating layers of fibrous support structure and layers of reactive polymer particles. In the latter embodiment, the reactive polymer particles are preferably incorporated into the layers of the fibrous support structure that separate the layers of reactive polymer particles.

[0069] The hemostatic patch 200 is preferably substantially anhydrous. Typically, the hemostatic patch 200 has a water content of no more than 5% by weight, more preferably no more than 2% by weight, and most preferably no more than 1% by weight. The water absorption capacity of the hemostatic patch 200 is preferably at least 50%, more preferably in the range of 100% to 800%, and most preferably in the range of 200% to 500%.

[0070] The hemostatic patch 200 of the present invention is preferably sterile.

[0071] The reactive polymer particles in the hemostatic patch 200 preferably comprise a water-soluble electrophilic polymer carrying a reactive electrophilic group selected from the group consisting of carboxylates, sulfonates, phosphonates, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrophenylthio esters, acyl halide groups, anhydrides, ketones, aldehydes, isocyanates, thioisocyanates, isocyano groups, epoxides, activated hydroxyl groups, olefins, glycidyl ethers, carboxyl groups, succinimidyl esters, sulfosuccinimidyl esters, maleimido groups, vinylsulfonyl groups, imidoesters, acetoacetates, halogenated acetals, o-pyridyl disulfides, dihydroxyphenyl derivatives, vinyl groups, acrylates, acrylamides, iodoacetamides, and combinations thereof. More preferably, the reactive electrophilic group is selected from carboxylate, sulfonate, phosphonate, pentafluorophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, acyl halide group, anhydride, ketone, aldehyde, isocyanate, thioisocyanate, isocyano group, epoxide, activated hydroxyl group, glycidyl ether, carboxyl, succinimide ester, sulfosuccinimide ester, imidoester, dihydroxyphenyl derivative and their combination.Even more preferably, the reactive electrophilic group is selected from halogenated acetal, orthopyridyl disulfide, maleimide, vinyl sulfone, dihydroxyphenyl derivative, vinyl, acrylate, acrylamide, iodoacetamide, succinimide ester and their combination.Most preferably, the reactive electrophilic group is selected from maleimide, vinyl, acrylate, acrylamide, succinimide ester, sulfosuccinimide ester and their combination.

[0072] Suitable succinimide esters that may be employed include succinimidyl glutarate, succinimidyl propionate, succinimidyl succinamide, succinimidyl carbonate, disuccinimidyl suberate, bis(sulfosuccinimidyl) suberate, dithiobis(succinimidyl propionate), bis(2-succinimidyloxycarbonyloxy)ethyl sulfone, 3,3'-dithiobis(sulfosuccinimidyl-propionate), succinimidyl carbamate, sulfosuccinyl Imino (4-iodoacetyl) aminobenzoate, bis (sulfosuccinimidyl) suberate, sulfosuccinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, disulfobis-sulfosuccinimidyl propionate, disulfosuccinimidyl tartrate; bis [2-(sulfosuccinimidyloxycarbonyloxyethyl sulfone)], ethylene glycol bis (sulfosuccinimidyl succinate), disulfobis (succinimidyl propionate) and combinations thereof.

[0073] Suitable dihydroxyphenyl derivatives that may be employed include dihydroxyphenylalanine, 3,4-dihydroxyphenylalanine (DOPA), dopamine, 3,4-dihydroxyhydrocinnamic acid (DOHA), norepinephrine, epinephrine, and catechol.

[0074] The use of a fibrous support structure in the hemostatic patch 200 provides the advantage that the reactive polymer particles can be uniformly distributed throughout the support structure without difficulty. Such uniform distribution is difficult to achieve in, for example, a foamed support structure.

[0075] The fibers in the fibrous support structure preferably have an average diameter of 1 μm to 500 μm, more preferably 2 μm to 300 μm, and most preferably 5 μm to 200 μm. The average diameter of the fibers can be suitably determined using a microscope. Typically, at least 50% by weight, more preferably at least 80% by weight, of the fibers in the fibrous support structure have a diameter of 1 μm to 300 μm and a length of at least 1 mm. Preferably, at least 50% by weight, more preferably at least 80% by weight, of the fibers in the fibrous support structure have an aspect ratio (ratio of length to diameter) of at least 1000.

[0076] The fiber carrier structure may comprise a felt structure, a woven structure or a knitted structure. Most preferably, the fiber carrier structure is a felt structure. Here, the term "felt structure" refers to a structure produced by laying and pressing fibers together to form an adhesive material.

[0077] According to one embodiment, the fibrous support structure is biodegradable.

[0078] The nucleophilic polymer contained in the fibrous carrier structure can be uniformly distributed throughout the fibers contained in the carrier structure, or it can be applied as an external coating. The presence of the nucleophilic polymer in the carrier structure improves both the adhesion and hemostatic properties of the hemostatic patch 200.

[0079] Preferably, the fibers of the fibrous support structure contain at least 5 wt%, more preferably at least 10 wt% and more preferably at least 50 wt% of the nucleophilic polymer.Most preferably, the fibers consist of said nucleophilic polymer.

[0080] The nucleophilic polymer contained in the fiber of the carrier structure generally comprises at least 2 reactive nucleophilic groups, more preferably at least 5 reactive nucleophilic groups, even more preferably at least 10 reactive nucleophilic groups, most preferably at least 20 reactive nucleophilic groups. These reactive nucleophilic groups are preferably selected from amine groups, thiol groups, phosphine groups and combinations thereof. More preferably, these reactive nucleophilic groups are selected from amine groups, thiol groups and combinations thereof. Most preferably, the reactive nucleophilic group is an amine group. These amine groups are preferably selected from primary amine groups, secondary amine groups and combinations thereof.

[0081] The nucleophilic polymer in the fibers of the fibrous support structure preferably has a nitrogen content of at least 1 wt%, more preferably 5-10 wt% and most preferably 15-25 wt%.

[0082] The nucleophilic polymer is preferably selected from proteins, chitosan, synthetic polymers carrying reactive nucleophilic groups, carbohydrate polymers carrying reactive nucleophilic groups, and combinations thereof. More preferably, the nucleophilic polymer is selected from gelatin, collagen, chitosan, and combinations thereof. Even more preferably, the nucleophilic polymer is gelatin, most preferably cross-linked gelatin.

[0083] Chitosan is a naturally occurring substance, a biodegradable, non-toxic, complex carbohydrate derivative of chitin (poly-N-acetyl-D-glucosamine). Chitosan is a deacetylated form of chitin. The chitosan applied according to the present invention preferably has a degree of deacetylation greater than 70%.

[0084] The fibrous support structure preferably comprises at least 50 wt. %, more preferably at least 80 wt. % and most preferably at least 90 wt. % of fibers comprising a nucleophilic polymer carrying reactive nucleophilic groups.

[0085] In a preferred embodiment, the fibrous support structure comprises at least 50% by weight, more preferably at least 80% by weight and most preferably at least 90% by weight of fibers containing at least 50% by weight of a nucleophilic polymer carrying reactive nucleophilic groups. According to a particularly preferred embodiment, the fibrous support structure comprises at least 50% by weight, more preferably at least 80% by weight and most preferably at least 90% by weight of fibers made of gelatin, collagen or chitosan.

[0086] Preferred collagens do not have telopeptide regions ("atelopeptide collagen"). The collagen employed according to the present invention is preferably selected from the group consisting of microfibrillar collagen, synthetic human collagens such as type I collagen, type III collagen, or a combination of type I and type III collagen. Collagen cross-linked using heat, radiation, or chemical agents such as glutaraldehyde may also be used.

[0087] According to a preferred embodiment, the fibers in the fibrous carrier structure comprise at least 50 wt%, more preferably at least 80 wt% and most preferably at least 90 wt% gelatin. The gelatin in the fibers preferably has a Bloom strength of 200 or higher.

[0088] In a particularly advantageous embodiment, the fibrous support structure comprises at least 50% by weight, more preferably at least 80% by weight and most preferably at least 90% by weight of partially cross-linked gelatin. The use of partially cross-linked gelatin offers the advantage that the fibrous support structure is both sufficiently stable and flexible at body temperature and that swelling of the fibrous support structure does not lead to the formation of a closed-cell fibrous gel structure.

[0089] In preparing the hemostatic patch 200, it may be advantageous to react a portion of the reactive electrophilic groups in the electrophilic polymer of the reactive polymer particles with the reactive nucleophilic groups of the nucleophilic polymer. Thus, the reactive polymer particles can be effectively immobilized within the fibrous support structure.

[0090] According to a preferred embodiment, the reactive nucleophilic groups of the nucleophilic polymer in the fibers of the fibrous support structure include amine groups, and the reactive electrophilic groups of the electrophilic polymer in the reactive polymer particles are selected from carboxylates, sulfonates, phosphonates, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrothiophenyl esters, acyl halide groups, acid anhydrides, ketones, aldehydes, isocyanates, thioisocyanates, isocyano groups, epoxides, activated hydroxyl groups, glycidyl ethers, carboxyl groups, succinimide esters, sulfosuccinimide esters, imidoesters, dihydroxyphenyl derivatives and combinations thereof.

[0091] According to another preferred embodiment, the reactive nucleophilic group of the nucleophilic polymer comprises a thiol group, and the reactive electrophilic group of the electrophilic polymer in the reactive polymer particles is selected from the group consisting of halogenated acetals, orthopyridyl disulfides, maleimides, vinyl sulfones, dihydroxyphenyl derivatives, vinyl groups, acrylates, acrylamides, iodoacetamides, succinimide esters, sulfosuccinimide esters, and combinations thereof. More preferably, the reactive electrophilic group is selected from the group consisting of succinimide esters, sulfosuccinimide esters, halogenated acetals, maleimides, or dihydroxyphenyl derivatives, and combinations thereof. Most preferably, the reactive electrophilic group is selected from the group consisting of maleimides, or dihydroxyphenyl derivatives, and combinations thereof.

[0092] In a preferred embodiment of the present invention, the fibrous support structure does not contain oxidized regenerated cellulose.

[0093] Research Overview

[0094] The present disclosure may be more clearly understood through the corresponding studies discussed more specifically below with respect to open surgical procedures in hemorrhage at various organs. It should be understood that the data presented herein are for illustrative purposes and should not be construed as limiting the scope of the disclosed technology in any way or to exclude any alternative or additional embodiments.

[0095] Figure 3The verbal and visual descriptors of the Surface Bleeding Severity Scale (SBSS) score and a chart of the corresponding expected intervention are shown. The SBSS is a validated bleeding scale developed for coordinating the assessment of bleeding severity and assessing hemostasis. The SBSS consists of 6 subscales of bleeding (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe; not immediately life-threatening, 5=extreme; immediately life-threatening). The scoring has been successfully used to train surgeons to identify the severity of bleeding associated with the inclusion and exclusion criteria in clinical studies, and to assess the endpoint of hemostasis for performance evaluation. The hemostatic patch 200 will be used as an auxiliary means of hemostasis for minimal, mild, moderate bleeding sites defined by the Surface Bleeding Severity Scale (SBSS) 1-3.

[0096] The studies herein use the SBSS as a validated bleeding scale in preclinical evaluation and clinical studies of the hemostatic patch 200. Furthermore, because the SBSS will be considered the primary validated bleeding scale by which the hemostatic patch 200 will be determined to be safe and function as intended, the SBSS will be used in externally facing documentation (e.g., instructions for use, summaries of safety and clinical performance, etc.) to delineate the clinical indications for the hemostatic patch 200.

[0097] Study 1: Prospective Study to Evaluate the Safety and Performance of the Hemostatic Patch 200 for Hemostasis During Open Liver Surgery Prospective, multicenter, single-group clinical study

[0098] A first-in-human clinical study was conducted at three clinical sites in the Netherlands to collect clinical safety and performance data on the use of the Hemostatic Patch 200 during internal surgery, specifically liver surgery. The study was conducted in accordance with ISO14155:2020, the Declaration of Helsinki, and any national or local regulations. Written informed consent was obtained from all patients before entering the study. The study ended in January 2022. The relevance of this dataset was evaluated in accordance with MDCG 2020-6, and an overview of the data considered relevant to this clinical evaluation is provided below. This is a pre-marketing, prospective, single-arm, multicenter, first-in-human clinical study. The clinical study was divided into 2 phases:

[0099] Phase I of the clinical study was conducted with a small cohort of subjects in which the initial safety of the Hemostatic Patch 200 was evaluated. A total of 8 subjects were treated in Phase 1, after which recruitment to the clinical study was suspended. The Data Monitoring Committee (DMC) reviewed the safety of this subgroup of subjects and decided to allow the study to continue.

[0100] Phase II of the clinical study enrolled 39 subjects who were treated with the Hemostatic Patch 200. Phase II was used to evaluate the safety and performance of the Hemostatic Patch 200.

[0101] In both Phase I and Phase II, subjects followed the same clinical study pathway. Phase I subjects were analyzed for safety only, while Phase II subjects were analyzed for both safety and performance.

[0102] Main objectives and hypotheses

[0103] The goal of this study was to evaluate the clinical safety and performance of the Hemostatic Patch 200 during open liver surgery.

[0104] The hemostatic patch 200 is expected to achieve hemostasis in the majority of patients within the specified timeframe and have a favorable safety profile. The hypothesis is defined as follows: The percentage of cases in which hemostasis is achieved at 3 minutes using the hemostatic patch 200 is significantly greater than the literature-based performance goal (PG) of 65.4% (i.e., whether the hemostatic patch 200 is non-inferior to the standard of care). Therefore, the statistical null (H0) hypothesis and the alternative (H1) hypothesis are as follows:

[0105] H0: pGATT ≤ 65.4%;

[0106] H1: pGATT>65.4%

[0107] Primary performance endpoint

[0108] The primary performance endpoint was defined as non-inferiority of the Hemostatic Patch 200 compared to the standard of care in the percentage of cases achieving hemostasis at 3 minutes (ie, demonstrating that the Hemostatic Patch 200 was significantly greater than the literature-based performance target of 65.4%).

[0109] Hemostasis was defined by a grade of 0 (none / dry) on the SBSS. The SBSS provides a validated score for assessing bleeding at the target site and consists of 6 subscales (0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe; not immediately life-threatening, 5 = extreme; immediately life-threatening). Prior to the study, investigators were trained on the assessment scale to provide consistent assessment of bleeding at the target site.

[0110] The achievement of hemostasis is verified every 30 seconds, starting from the time the hemostatic patch 200 is positioned and pressure is initiated. If hemostasis is not achieved after 5 minutes of application (SBSS 1-5), the treatment is considered a failure and additional hemostatic agents or techniques may be used.

[0111] Secondary performance endpoints

[0112] The following secondary endpoints were defined:

[0113] Average time to hemostasis (seconds);

[0114] • Percent hemostasis at 30, 60, 90, 120, and 150 seconds.

[0115] No formal hypothesis testing was performed for secondary performance end points.

[0116] Safety endpoints

[0117] The safety of the hemostatic patch 200 was assessed by the nature, severity, and incidence of device-related adverse events. Adverse events may include:

[0118] Toxic response

[0119] Thromboembolic events

[0120] (Re)bleeding

[0121] Allergic reaction

[0122] ·pain

[0123] New surgery

[0124] ·Infect

[0125] Arterial or venous occlusion / organ ischemia

[0126] Damage to organs and blood vessels

[0127] Pulsating hematoma

[0128] Intestinal closure

[0129] Biliary tumor

[0130] Packaged or rolled devices

[0131] No formal hypothesis testing was performed for the safety endpoints of this clinical study. The adverse events identified with the Hemostatic Patch 200 were compared with current knowledge and state-of-the-art hemostatic methods during open liver surgery to assess whether the device is associated with acceptable safety outcomes.

[0132] Exploratory endpoints

[0133] In addition to the primary endpoint, the following exploratory endpoints were recorded:

[0134] Operation time (minutes)

[0135] Blood loss during surgery (mL)

[0136] Blood transfusion during hospitalization (mL)

[0137] SBSS at the target bleeding site (0-5)

[0138] Use of adjunctive hemostatic agents / techniques (eg, cautery, suturing, or stapling)

[0139] The amount of material required and the bleeding surface

[0140] User satisfaction (questionnaire survey)

[0141] Statistical analysis

[0142] Descriptive statistics for each variable are presented. Continuous variables were summarized using descriptive statistics (number of subjects, mean, median, quartiles, standard deviation, minimum, and maximum). Categorical variables were summarized using the frequency and percentage of subjects in each category.

[0143] result

[0144] Figure 4 A representative overview of an example of a research process for the present disclosure is shown. Inclusion criteria include subjects undergoing elective open liver surgery. Preoperative inclusion criteria also include subjects (i) planning to undergo elective open surgery on the liver; (ii) being willing and able to give written informed consent to participate in the investigation; (iii) being over 18 years old at the time of recruitment; and (iv) having been informed of the nature of the clinical study. Intraoperative inclusion criteria include subjects in which the investigator or operator is able to identify a target bleeding site at the liver resection plane for which any applicable conventional hemostatic means (e.g., suturing, ligation, or cauterization) is ineffective or impractical, and local hemostatic agents are selected to control hemostasis. Intraoperative inclusion also includes subjects with a target bleeding site with a surface bleeding severity score (SBSS) of 1, 2, or 3.

[0145] Recruited 56 subjects in total at 3 research centers, wherein 8 subjects were in phase I, and 39 subjects were in phase II. All 56 subjects provided written informed consent. A total of 9 subjects withdrew before treatment (2 subjects' screening failures, 5 subjects did not meet the protocol qualifications, and 2 subjects withdrew for other reasons). Therefore, the safety colony includes 47 subjects, and the full analysis set (FAS) includes 39 subjects. According to the FAS subject without the main scheme deviation defined as protocol (PP), data were analyzed according to the treatment received, including 37 subjects. 97.9% (46 / 47) subjects completed a 6-week follow-up visit.

[0146] Demographics

[0147] The mean age of the included subjects was 59.7 ± 13.2 years ( Figure 5The majority of the included subjects were male (70.2%, 33 / 47) and of European, Middle Eastern, or North African origin (white, 91.5%, 43 / 47). Figure 6A The disease diagnoses summarized in the data included colorectal cancer metastasis (66.0%, 31 / 47), hepatocellular carcinoma (10.6%, 5 / 47), cholangiocarcinoma (8.5%, 4 / 47), non-colorectal cancer metastasis (8.5%, 4 / 47), and other diagnoses (6.4%, 3 / 47). Other diagnoses included intrahepatic gallstones (n=1), ablated lesions in cirrhotic patients (n=1), and partially cystic / solid ablated lesions (n=1).

[0148] Most subjects did not use Ascal (93.6%, 44 / 47) or other antithrombotic medications (93.6%, 44 / 47). Allergies to one of the components of the Hemostatic Patch 200 were largely unknown. For most subjects, baseline laboratory values ​​were within normal ranges.

[0149] Figure 6B is a table summarizing the surgical characteristics of multiple subjects in the first study of the present disclosure. Between the two phases, the type of procedure mainly included non-anatomical wedge resection, accounting for 31.9% (15 / 47). Approximately 21.3% underwent right hepatectomy (10 / 47), while 14.9% underwent segmentectomy (7 / 47) or bi-segmentectomy (7 / 47). The remaining subjects underwent tri-segmentectomy (6.4%; 3 / 47), left hepatectomy (2.1%; 1 / 47), or other (8.5%; 4 / 47).

[0150] Treatment details

[0151] In the FAS population, the mean operative time was 221.4 ± 149.74 minutes. Figure 7 is a table summarizing the treatment details of multiple subjects in the study described herein. The type of liver parenchyma was cirrhosis in 7.7% (3 / 39). Pedicle occlusion (Pringle maneuver) was used in 41% (16 / 39) and no other inflow reduction was used in the other patients. The method of resection was Cavitron ultrasonic surgical aspiration (CUSA) in 71.8% (28 / 39) and CUSA combined with bipolar, ligation, ultrasonic scalpel and diathermy in the remainder, except for one patient who did not undergo resection and used a hemostatic patch 200 to stop bleeding from the injury that occurred during radiofrequency ablation. The analysis of the use of adjunctive hemostatic agents / techniques before the application of the hemostatic patch 200 is summarized in Figure 8The use of cautery in 15 subjects (15 / 39; 38.5%), clamps in 9 subjects (9 / 39; 23.1%), suturing / ligation in 7 subjects (7 / 39; 17.9%), and other undefined hemostatic agents / techniques in one subject (1 / 39; 2.6%) was shown. SBSS at the target bleeding site was minimal (SBSS1) in 9 subjects (9 / 39; 22.1%), mild (SBSS2) in 16 subjects (16 / 39; 41.0%), and moderate (SBSS3) in 14 subjects (14 / 39; 35.9%). 2 The average size of the hemostatic patch 200 applied to the bleeding surface was 8.7±10.70 cm 2 .

[0152] The average user satisfaction, as reported by surgeons who completed the System Usability Scale (SUS) rating, was 88.4 ± 7.64 (on a scale of 0-100), indicating high user satisfaction.

[0153] Main performance analysis

[0154] The primary endpoint of the study was to determine whether the Hemostatic Patch 200 was non-inferior to the standard of care in terms of the percentage of patients achieving hemostasis at 3 minutes. The performance target of 65.4% was based on a weighted average of hemostasis at 3 minutes in 6 RCTs conducted with the benchmark device.

[0155] Figure 9 A table summarizing the hemostatic endpoints for the first treated bleeding site for each Phase II patient is provided. In approximately 82.1% (32 / 39) of the subjects, hemostasis was achieved within 30 seconds of the hemostatic patch 200 being placed at the bleeding site. Within 1 minute, 94.9% of the subjects achieved hemostasis (37 / 39). In the FAS population, 38 of the 39 patients (97.4%, 95% CI: 84.61, 99.87) achieved hemostasis at 3 minutes using the hemostatic patch 200. In the PP population, all patients (37 / 37; 100%, 95% CI: 87.97, 100) achieved hemostasis at 3 minutes. In all but one subject (38 / 39; 97.4%), equal to or less than 1 hemostatic patch 200 was applied to each bleeding site. In one subject, >1 to 2 hemostatic patches 200 were applied to each bleeding site. The mean blood loss during surgery was 674.7 ± 594.14 mL, and one patient received a blood transfusion (1250.0 ± 0.00 mL) during hospitalization.

[0156] Figure 10A table summarizing the hemostatic endpoints of all treated bleeding sites (e.g., more than one bleeding site per subject) for Phase II subjects and all patients is provided. In approximately 79.7% (43 / 54) of the bleeding sites in Phase II subjects, hemostasis was achieved within 30 seconds of the hemostatic patch 200 being placed at the bleeding site. Within 1 minute, 92.7% of the bleeding sites achieved hemostasis (50 / 54), and within 3 minutes, all bleeding sites except two bleeding sites achieved hemostasis (96.3%; 52 / 54). In approximately 82.7% (52 / 63) of the bleeding sites in all subjects, hemostasis was achieved within 30 seconds of the hemostatic patch 200 being placed at the bleeding site. Within 1 minute, 93.7% of the bleeding sites achieved hemostasis (59 / 63), and within 3 minutes, all bleeding sites except two bleeding sites achieved hemostasis (96.8%; 61 / 63).

[0157] The Hemostatic Patch 200 was shown to be statistically non-inferior to the standard of care for achieving hemostasis at 3 minutes in both the FAS and PP populations (P < 0.001). The percentage of bleeding sites that achieved hemostasis at 3 minutes using the Hemostatic Patch 200 was 96.3% (52 / 54) in the FAS population, 98.0% (51 / 52) in the PP population, and 96.7% (61 / 63) in the safety population.

[0158] Secondary End Point Analysis

[0159] The first secondary endpoint was the mean time to hemostasis (in seconds). The mean time to hemostasis was 54.6 ± 107.48 seconds for subjects in the FAS population and 38.1 ± 26.12 seconds for subjects in the PP population (not shown). The second secondary endpoint was the percentage of hemostasis at 30, 60, 90, 120, and 150 seconds. In the FAS population, the percentage of hemostasis was 82.1% (32 / 39) at 30 seconds and 94.9% (37 / 39) at 60, 90, 120, and 150 seconds. One (1) subject in the FAS group failed to show hemostasis at 5 minutes. In the PP population, the percentage of hemostasis was 83.8% (31 / 37) at 30 seconds and 97.3% (36 / 37) at 60, 90, 120, and 150 seconds. All subjects in the PP population achieved hemostasis at 5 minutes.

[0160] Overall safety analysis

[0161] AE analysis was performed on the safety population. The severity and causality of the study device or procedure were assessed. In total, 28 of 47 subjects (59.6%) experienced AEs, and 7 of 47 subjects (14.9%) experienced SAEs. The majority of these subjects experienced AEs related to the study protocol (24 subjects, 51.1%). Some subjects experienced AEs possibly related to the device (3 subjects, 6.4%); no events were possibly related to the device or had a causal relationship to the device.

[0162] Of the 7 subjects who experienced an SAE, the SAE was related to the study protocol in 6 subjects (12.8%), and one SAE was also device-related in one subject (2.1%). Among the 28 subjects with AEs, the average number of AEs was 1.6 ± 0.84. Most subjects experienced no AEs (19 subjects; 40.4%) or one AE (17 subjects; 36.2%). Other subjects experienced 2 AEs (7 subjects, 14.9%), 3 AEs (3 subjects, 6.4%), or 4 AEs (1 subject, 2.1%).

[0163] There were 44 AEs in total in 28 AE subjects. Most subjects experienced gastrointestinal diseases (5 subjects; 10.6%), hepatobiliary diseases (15 subjects; 31.9%), infections and infestations (8 subjects, 17.0%) and / or AEs related to injuries and surgical complications (4 subjects; 8.5%). In a total of 44 AEs, 38 AEs were mild, 3 AEs were moderate, and 3 AEs were severe. Among the 28 subjects with AEs, 26 subjects experienced mild AEs (55.3%), 3 subjects experienced moderate AEs (6.4%), and 3 subjects experienced serious AEs (6.4%). 3 serious AEs involved ascites, liver failure, and abdominal abscesses. None of the AEs resulted in study withdrawal, and there were no deaths during the trial process.

[0164] A total of 36 of the 44 AEs were procedure-related. Three (3) AEs were also device-related. The three AEs that were possibly device-related involved one subject with a bilioma, one subject with a perihepatic abscess, and one subject with a postoperative hematoma. There were no events that were possibly device-related or causally related to the device. Of note, all adverse events were also common complications of liver surgery and, in addition to being possibly device-related, were also marked as possibly procedure-related (e.g., abscess and bilioma) or causally related to the procedure (e.g., hematoma).

[0165] One device-related AE involving a perianpatic abscess was also considered an SAE. This event involved a subject who underwent a CT scan due to upper abdominal pain. The CT scan revealed a perianpatic abscess. The patient was readmitted to the hospital, and radiographic drainage of the abscess was performed; therefore, this event was considered an SAE. No microorganisms were found in the fluid. The event resolved 4 days later without sequelae. This event was possibly device-related, as a relationship could not be excluded.

[0166] Follow-up data: Ultrasound imaging

[0167] At the 6-week follow-up visit, a mean of 44.8 ± 8.57 days after surgery, subjects underwent imaging of the resection area to identify any signs of device encapsulation, rolled-up device, or biliary aneurysm or pseudoaneurysm. In the majority of subjects (43 / 46; 93.5%), the imaging method was ultrasound imaging per protocol; the remaining subjects (3 / 46; 6.5%) were imaged using CT scans as clinically indicated for these subjects. Imaging results showed that no subject had signs of device encapsulation, rolled-up device, or pseudoaneurysm (0 / 46; 0.0%).

[0168] For all subjects with imaging results (n=46), including those with clinically indicated CT scans (n=3) and conventional ultrasound imaging (n=43), the answer to the question "Evidence of biliary tract infection" was given as "yes" in 10 subjects (10 / 46; 21.7%) based on the imaging results. In addition to the biliary tract infection diagnosed in 3 subjects based on clinically indicated CT scans, 7 subjects (7 / 43; 16.3%) had evidence of biliary tract infection as indicated on conventional ultrasound imaging performed at 6 weeks. After further analysis, the imaging biliary tract infection was evaluated as possible biliary tract infection (n=3), suspected partial biliary tract infection (n=1), effusion of seroma or biliary tract infection (n=1), effusion of hematoma / biliary tract infection (n=1), and biliary tract infection (n=1). Conventional ultrasound imaging at 6 weeks further indicated that 4 subjects had signs of hematoma (4 / 43; 9.3%). After further analysis, imaging hematomas were assessed as effusion with partial hematoma (n=1), effusion, possible hematoma (n=1), small hematoma (n=1), and possible encapsulation of hematoma (n=1). All events were classified according to the worst-case event mentioned in the imaging report, but all events were considered mild adverse events, and none of these events required any further medical intervention. None of these events was confirmed as a biliary tract or hematoma by percutaneous or surgical drainage, and therefore, were most likely small sterile effusions.

[0169] Usability Questionnaire

[0170] As reported by surgeons who completed the System Usability Scale (SUS) rating, the average user satisfaction was 86.2 ± 9.80 (on a scale of 0-100), indicating high user satisfaction. The results of the user satisfaction questionnaire also showed that users were satisfied with the hemostatic patch 200. Of the 27 questions in the medical device-specific user satisfaction questionnaire, 24 questions were answered with a neutral, affirmative, or very affirmative response by all users (47 / 47; 100%). The other three questions were answered with a neutral, affirmative, or very affirmative response by 91.5% (43 / 47) to 97.7% (46 / 47) of users. Of all 10 questions on the user satisfaction questionnaire on SUS, 9 questions were answered with a neutral, affirmative, or very affirmative response by all users (47 / 47; 100%), and one question was answered with a neutral, affirmative, or very affirmative response by the majority of users (44 / 47; 93.6%).

[0171] in conclusion

[0172] The initial first-in-human clinical study of the Hemostatic Patch 200 was conducted in accordance with ISO 14155:2020 and in accordance with regional and ethical principles derived from the Declaration of Helsinki and its subsequent revisions, adopted by the 18th World Medical Congress in Helsinki, Finland in 1964. The design of the study (e.g., follow-up duration, patient population) was considered adequate to evaluate the safety and performance of the Hemostatic Patch 200 for its intended use as provided in the IFU (particularly for liver surgery). The study was considered to be of acceptable quality based on the evaluation criteria in the literature review protocol (LRP) for data from a prospective cohort (i.e., non-randomized, prospective; Level II).

[0173] Most patients were approximately 60 years old, 30% were female, and 91.5% were white / Caucasian. The indication for surgery was colorectal metastases in 66% of patients, and 6.4% had cirrhosis. The population included in this trial represents a similar population to that seen in other hemostasis trials in liver surgery.

[0174] The primary performance endpoint is defined as the non-inferiority of the percentage of subjects who achieved hemostasis with the hemostatic patch 200 at 3 minutes compared to the standard of care. For achieving hemostasis at 3 minutes in both the FAS and PP populations, the hemostatic patch 200 was shown to be statistically non-inferior to the standard of care. The percentage of subjects who achieved hemostasis using the hemostatic patch 200 at 3 minutes was 97.4% in the FAS population and 100% in the PP population. This hemostasis rate was significantly higher than the literature-based performance target of 65.4%. Analysis of secondary endpoints showed that the average time to hemostasis was 54.6 ± 107.48 seconds for the subjects in the FAS population and 38.1 ± 26.12 seconds for the subjects in the PP population. Almost all subjects (94.9% in the FAS population and 97.3% in the PP population) achieved hemostasis at 60 seconds. In the PP population, all subjects achieved hemostasis at 5 minutes. In the FAS population, one subject did not achieve hemostasis upon initial application of the hemostatic patch 200. The subject did initially achieve hemostasis, but a hematoma was observed within 5 minutes. The hematoma was removed according to the instructions for use of the hemostatic patch 200, and additional hemostatic patches 200 were applied, after which hemostasis was achieved.

[0175] The safety of the Hemostatic Patch 200 was assessed by the nature, severity, and incidence of device-related AEs in the safety population. In total, 28 of the 47 subjects (46.8%) experienced AEs, and 7 of the 47 subjects (14.9%) experienced SAEs. There were a total of 44 AEs, of which 36 were procedure-related and 3 of these were also device-related. There were a total of 7 SAEs, of which 6 were procedure-related and one was also device-related. This finding is consistent with the literature on benchmark devices, showing that 42%-100% of subjects experienced at least one AE during liver resection surgery. In addition, these studies showed that most AEs were primarily associated with surgical complications and were not related to the hemostatic product used, which is similar to the findings in the current study. For the Hemostatic Patch 200, the incidence of device-related AEs was 6.4%, which is considered to be below the acceptance criteria for safety (≤7.3%). Device-related AEs included bile duct (n=1), perihepatic abscess (n=1), and postoperative hematoma (n=1); all of which were conservatively adjudicated based on the worst-case scenario, where a relationship to the device could not be ruled out. The reported AEs for the Hemostatic Patch 200 were consistent with those reported for the benchmark device, as these included the risks of bile leakage, hematoma, localized intraperitoneal effusion, peritoneal abscess, liver abscess, and postoperative abscess, as well as other risks, as expected in the setting of major abdominal surgery.

[0176] At the 6-week follow-up, a routine ultrasound of the liver was performed. Three (3) subjects underwent CT scanning for clinical reasons and were diagnosed with biliary tract infections (3 / 47; 6.4%) and abscesses (1 / 47; 2.1%). The results of the other 43 patients who underwent routine ultrasound imaging showed that there were signs of biliary tract infections in 7 subjects (7 / 43; 16.3%), so a total of 10 subjects (10 / 47; 21.3%) were diagnosed with biliary tract infections. This finding on imaging is usually reported as visible perihepatic fluid, which may be a biliary tract infection, but there is no confirmation that the fluid is actually bile. None of these events were confirmed as biliary tract infections by percutaneous or surgical drainage and, therefore, were most likely small, sterile effusions. Based on the worst-case scenario principle, these fluid events were reported as biliary tract infections, where if a biliary tract infection was suspected, it was reported as a biliary tract infection. In addition, no medical action was required based on routine imaging, and none of these events resulted in any clinical sequelae. Three patients (3 / 47; 6.4%) presented with a biliary tumour based on clinical presentation. It is important to note that bile leakage is a common complication of liver resection. In fact, bile leakage is one of the most common complications after liver resection. Even in randomized trials of sealant products to reduce postoperative bile leakage, this event was frequent.

[0177] In the current clinical study, the hemostatic patch 200 was used as a hemostatic device and was therefore applied only to the target bleeding site rather than the entire resection area, and bile leakage may have occurred from the exposed resection area that was not covered by the hemostatic patch 200. The confirmed clinical rate of bile leakage that occurred in this study (6.4%) is consistent with the published literature. Most bilioma-related events are considered clinically insignificant and do not require intervention and can be considered purely imaging findings and are most likely tiny sterile effusions because no confirmation was made that the fluid was actually bile by percutaneous or surgical exploration. In fact, in a previous clinical trial in which routine imaging was performed after liver surgery, similar to the current trial protocol using scheduled ultrasound, postoperative CT scans determined that 27% of patients had 100 mL or more of effusion at the resection surface. A meta-analysis conducted to set acceptance criteria for effusions found on imaging reported that an average of 18.0% (95% CI: 6.7%, 40.1%) of patients had effusions, and studies of the hemostatic patch 200 showed a rate of 21.7%, which is acceptable and the hemostatic patch 200 can be considered safe.

[0178] This clinical study presents the first human results of the Hemostatic Patch 200. The safety and performance of the Hemostatic Patch 200 were evaluated in adult subjects undergoing elective open liver surgery. Clinical data show that the Hemostatic Patch 200 is safe and effective for use in open liver surgery in adult subjects. The performance acceptance criteria of achieving hemostasis ≥ 65.4% were met, and the performance of the Hemostatic Patch 200 (97.4%) was considered to be comparable and significantly higher when compared to the benchmark device. The administration of the Hemostatic Patch 200 further did not cause any new or unique safety issues. The incidence (≤7.3%) and type of AEs associated with the use of the Hemostatic Patch 200 were comparable to the AEs associated with the use of the benchmark device as described in the prior art literature, indicating that the Hemostatic Patch 200 is associated with acceptable safety results.

[0179] Study 2: Results of Non-GLP Hemostatic Patch 200 versus Comparative Device 1 in a Porcine Kidney Bleeding Model

[0180] The objective of this study was to evaluate the acute hemostatic performance of the Hemostatic Patch 200 in a porcine kidney severe compartment hemorrhage model relative to the standard of care, Comparative Device 1 (FloSeal 5 mL; Baxter Healthcare, Deerfield, Illinois, United States), but modified with heparinization to represent drug-induced or in-use coagulopathy conditions.

[0181] Four pigs underwent surgery on their kidneys, with heparinization performed at a target effective clotting time (ACT) 1.5 to 2.5 times higher than baseline. In each kidney, six reproducible ablation lesions (i.e., 3 on the anterior surface and 3 on the posterior surface) were created using a 10 mm diameter biopsy punch and a depth of approximately 10 mm; the perforated tissue was cut using scissors. Alternating treatment was then initiated with either contrast device 1 or hemostatic patch 200 (GATT-patch, 10 cm × 5 cm; GATT Technologies BV, Nijmegen, The Netherlands), resulting in three applications of contrast device 1 and three applications of hemostatic patch 200 for each kidney.

[0182] Use Contrast Device 1 according to the instructions: Fill the chamber and begin applying pressure for 2 minutes with saline-moistened gauze. Check for hemostasis 2 minutes after carefully removing the gauze so as not to disturb or disrupt the hemostatic matrix. If bleeding persists, apply an additional Contrast Device 1 and then reapply pressure for 2 minutes with saline-moistened gauze. Repeat this procedure up to 3 times with Contrast Device 1: If bleeding persists after 3 applications, the treatment is considered a failure. If hemostasis is achieved at any time and maintained for 8 minutes, the treatment is considered a success.

[0183] For ablation lesions treated with the hemostatic patch 200, a patch of approximately 3 cm-3.5 cm × 3 cm-3.5 cm is placed in the chamber and a patch cut into a circular shape with a diameter of approximately 4 cm is immediately applied topically to the top of the bleeding so that it overlaps at least 1 cm on all sides with non-bleeding tissue according to the IFU. Thirty seconds of pressure with saline-moistened gauze is started, after which hemostasis is checked by carefully removing the gauze. If bleeding persists, another 30 seconds of pressure is applied. If bleeding persists again, the hemostatic patch 200 is removed and a second treatment using the same method is applied. If hemostasis is achieved at any time and maintained for 8 minutes, the treatment is successful.

[0184] The hemostasis time for both the comparative device 1 and the hemostatic patch 200 was considered to be the latest time when hemostasis was achieved and maintained from the initial application to 8 minutes. The severity of bleeding was determined by two trained investigators who were certified in determining bleeding severity on a scale of 0-5 based on the surface bleeding severity scale.

[0185] A total of 48 ablation lesions were created and treated with Hemostatic Patch 200 (n=25) and Comparison Device 1 (n=23). The imbalance in the number of ablation lesions in each treatment group was caused by the unavailability of Comparison Device 1 at the end of one of the protocols, where the ablation lesion was treated with Hemostatic Patch 200 instead. The majority of bleeding was severe or life-threatening (n=43; 90%), while the remaining bleeding was moderate (n=5; 10%). The heparinization regimen resulted in prolonged ACT values ​​that met the target of 1.5-fold to 2.5-fold baseline for all treatment applications.

[0186] In the 23 bleeds treated with the comparative device 1 and the 25 bleeds treated with the hemostatic patch 200, hemostasis at 8 minutes was 39% versus 100%, respectively. Figure 11 As shown in the , hemostasis after the initial IFU-indicated application time of 2 minutes for the comparative device 1 and 30 seconds for the hemostatic patch 200 was 4% (n=1 / 23) versus 88% (n=21 / 25), respectively. A second application of the comparative device 1 was required in 96% (n=22 / 23) and resulted in an additional 9% (2 / 23) successful hemostasis rate, while a third application was required in 87% (n=20), ultimately resulting in a 39% hemostasis success rate at 8 minutes. After the hemostatic patch 200 was applied, an additional 30 seconds of pressure was applied in 4% (n=1 / 25), resulting in a 92% successful hemostasis rate. An additional 30 seconds of pressure was applied again in 4% (n=1 / 25), resulting in a 96% successful hemostasis rate at 3 minutes. In only one case was it necessary to remove the initial hemostatic patch 200 application and perform a new application, which resulted in successful hemostasis before 6 minutes.

[0187] Hemostatic patch 200 can quickly and reliably achieve hemostasis in severe renal cavity bleeding, while comparative device 1 does not appear to be a solution in these challenging cases. This data provides evidence for several important aspects of hemostatic patch 200:

[0188] 1. The performance of the hemostatic patch 200 is unrelated to the use of anticoagulants that cause coagulopathy, because high hemostatic performance was achieved using the hemostatic patch 200, and all bleeding treated in this study was under heparinized conditions;

[0189] 2. The performance of the hemostatic patch 200 on the kidney was robust and, when viewed alongside other studies that have been conducted with the hemostatic patch 200 as further detailed in this document, demonstrates its ability to be used in a wide range of clinical scenarios;

[0190] 3. Compared to the standard of care of flowable hemostatic matrices for treating highly irregular tissue surfaces (represented here by luminal ablation lesions), the hemostatic patch 200 presents a superior option due to its flexibility and pliability;

[0191] 4. While the initial indication for Hemostatic Patch 200 is proposed for minimal, mild, and moderate bleeding, this study supports the use of Hemostatic Patch 200 in severe bleeding for potential future regulatory approval; and

[0192] 5. As described in its IFU, a 30 second application time of the hemostatic patch 200 was sufficient to achieve hemostasis in the vast majority of cases (eg, 88%), similar to the hemostasis achieved in other preclinical and clinical studies described in further detail in this document.

[0193] Study 3: An ex vivo porcine liver perfusion model using whole blood was used to compare the hemostatic patch 200 with the control device 2 and the control device 3. Set 3 for comparison

[0194] An ex vivo porcine liver perfusion model using whole blood was developed primarily to evaluate the effects of hemostatic agents (Hemostatic Patch 200, Hemostatic Patch Prototype, and other competitive hemostatic agents) on bleeding during liver surgery without the need for intensive animal studies.

[0195] To validate the ex vivo model, livers and blood were obtained from sacrificed pigs. Ten (10) liters of blood were collected and a standard in vitro organ system (ECOPS, Organ Assist, Groningen, the Netherlands) was filled and perfused with blood to circulate through the bypass. Fresh heparinized blood was used to simulate in vivo conditions as closely as possible. Five (5) ex vivo liver perfusion protocols were performed to validate the model. The liver was mounted on a perfusion machine and oxygenation, pH, temperature, and blood pressure were maintained within in vivo boundaries. Blood was circulated through the liver at a rate of 500 ml / min and a pressure of 5 mmHg-10 mmHg. The liver was then subjected to standard perforated ablation lesions to observe hemostasis using two commonly used patches: Comparative Device 2 (TachoSil; Corza Medical, Westwood, MA, United States) and Comparative Device 3 (Veriset; Medtronic plc, Dublin, Ireland). In addition, in vivo heparinization experiments were performed to compare the efficacy of the hemostatic patches on liver ablation lesions similar to the ex vivo model.

[0196] Initial testing showed that three perfusions could be continued for 4 hours and two (2) perfusions could be continued for 3.5 hours. In all livers, color and temperature returned to approximately normal within 30 minutes after the start of perfusion. When the hemostatic performance of Comparative Device 2 and Comparative Device 3 was compared between use in an isolated liver perfusion model and an in vivo heparinized porcine model, there was no significant difference in the percentage of administrations that resulted in successful hemostasis within 3 minutes. In addition, relevant blood gas measurements, coagulation parameters (partial thromboplastin time, prothrombin time, and fibrinogen) and platelet aggregation time and clot formation time obtained with the isolated model showed comparable results to the in vivo measurements and remained constant over a 4-hour period. Although there were some observed differences between the in vivo and isolated models, such as glucose and red blood cell measurements, these differences were determined not to affect the evaluation of the topical hemostatic product for up to 4 hours. Therefore, this validation testing showed that the isolated model could be used for 4 hours with consistent coagulation parameters comparable to the in vivo heparinized porcine model.

[0197] This model validation test established the following test parameters for future use of the ex vivo model: Two (2) livers and 10 liters of heparinized blood (5000 units / L) were collected at the slaughterhouse. The livers were shipped on ice and the blood was shipped at ambient temperature. Within 2 hours of collection, the livers were inspected for ablation lesions, which were sealed with gloves and cyanoacrylate glue. The perfusion parameters were: flow rate 600 ml / min; pressure 10 mmHg-12 mmHg; blood temperature 37°C (±1°C); oxygenant 0.25 liters per minute. After checking the color and temperature, product testing could be performed.

[0198] When comparing hemostatic patches in clinical use to in vitro models, success rates were lower in challenging in vitro models. For example, for Comparative Device 2, indicated as an adjunct to hemostasis during liver surgery, pooled results from three randomized clinical trials showed that 174 of 233 subjects (74.7%) in the Comparative Device 2 treatment group achieved hemostasis at 3 minutes.

[0199] Figure 12 FIG2 is a graphical depiction of the efficacy of the conditioned hemostatic patch compared to a blank, Comparative Device 1, and Comparative Device 2 after liver perforation, liver resection, and splenectomy. As shown, the hemostatic patch 200 achieved hemostasis (light gray) within 10 seconds of pressure for all perforation and resection bleeds and sustained hemostasis at three minutes. Application of Comparative Device 3 was successful within three minutes in all cases, however, it was successful within 10 seconds in 50% of liver perforation bleeds, 67% of liver resections, and 50% of splenectomies. Application of Comparative Device 2 and the GFC blank was successful in only 18% and 67% of perforation bleeds at three minutes (0% and 33% at 10 seconds), in 18% and 18% of liver resections at three minutes (18% and 18% at three minutes), and in 0% and 0% of splenectomies at three minutes. Considering all liver and spleen punctures and resections, Hemostatic Patch 200 achieved 100%, 42.8%, 7.1%, and 14.3% hemostasis within 10 seconds, and 100%, 100%, 14.3%, and 35.7% hemostasis at 3 minutes, respectively, relative to Comparative Device 3, Comparative Device 2, and GFC-Blank.

[0200] Study 4: GLP Study of Hemostatic Patch 200 Compared to Comparative Devices 4 and 5 in a Porcine Model Evaluation of efficacy and safety after functional administration of blood organ

[0201] Twenty-six (26) sows were recruited and successfully implanted. Nine (9) were assigned to the 72-hour cohort, eight (8) were assigned to the 4-week cohort, and nine (9) were assigned to the 8-week cohort. Eight (8) liver bleeding sites were created per animal, for a total of 208 bleeding sites, and no sites were excluded based on bleeding severity scores. One hundred and thirteen (113) sites (54.3%) were scored as 2 or 3 (mild-moderate) bleeding severity, and 90 sites (43.3%) were scored as 1 (minimal) bleeding severity. Five (5) sites (2.4%) were scored as 0.5 bleeding severity. These bleeding severity scores correspond to the company's validated Surface Bleeding Severity Scale (SBSS). Specifically, 113 sites exhibited an SBSS of 2-3, and 95 sites exhibited an SBSS of 1.

[0202] Organs were placed intravitally to observe hemostasis with two commonly used hemostats: Comparative Device 4 (Surgifoam, Johnson and Johnson Ethicon, Bridgewater, NJ, United States), with topical RECOTHROM thrombin used in combination with each application of Comparative Device 4 and Comparative Device 5 (Hemopatch, Baxter International Inc., Deerfield, IL, United States).

[0203] During the implantation procedure, notice an adverse event, but it is irrelevant to the use or use of control products, and occurs after the surgeon's mistake. Although the inferior vena cava was cut by surgical instruments, it was successfully repaired and completed the assessment to products, and can not affect research data or animal health. For overall products, use, treat 80 positions (10 animals) with hemostatic patch 200, treat 80 positions (10 animals) with contrast device 4, and treat 47 positions (6 animals) with contrast device 5.

[0204] For Hemostatic Patch 200, the time to hemostasis was 1 minute for 79 of 80 sites (98.8%); for Comparative Device 4, the time to hemostasis was 1 minute for 75 of 80 sites (93.8%); and for Comparative Device 5, the time to hemostasis was 1 minute for 41 of 48 sites (85.4%). The average time to hemostasis for each implant is summarized in Figure 13A and Figure 13B middle.

[0205] In total, there were 10 rebleedings after hemostasis was achieved, 6 rebleedings with Comparative Device 5, 3 rebleedings with Comparative Device 4, and 1 rebleeding with Hemostatic Patch 200. 30 minutes (±5 minutes) after application, there was no sign of rebleeding for any of the injury sites.

[0206] In summary, the performance of Hemostatic Patch 200 successfully demonstrated non-inferiority compared to the Comparative Device 4 and Comparative Device 5 hemostatic devices when comparing hemostasis time and rebleeding events at implantation and termination in the 72-hour, 4-week, and 8-week cohorts.

[0207] The swelling of the material at 30 minutes (±5 minutes) after treatment was similar between the hemostatic patch 200 and the comparative device 5, with a score of "0" indicating swelling less than the initial thickness (100% for the hemostatic patch 200; 83% for the comparative device 5; and 7.5% for the comparative device 4). The remaining 17% of the comparative device 5 sites were considered to have a score of "1" (no swelling). For the comparative device 4, 90% of the sites scored '1' (no swelling), and it was also the only product with a score of '2' in 2.5% of the applications (2 sites out of 80 sites), indicating slight swelling.

[0208] At 72 hours, the incidence of severe adhesions was similar across both the Hemostatic Patch 200 (81%) and the Comparative Device 4 (86%), and was slightly less dramatic with the Comparative Device 5 (50%). At both 4 and 8 weeks, severe adhesions were present across all test and control articles, with a distribution indicating secondary effects from the surgical procedure. Clinical pathology data did not present any evidence of active intravascular hemolysis or coagulation changes associated with the use of the Hemostatic Patch 200.

[0209] Histologically, no discernible adhesion was noted at any liver treatment site across all test and control articles at either 72 hours or 4 weeks. At 4 weeks, there was evidence of adhesion of the hemostatic patch 200 in 17 adjacent diaphragmatic sites, and evidence of adjacent adhesion of the comparative device 4 in 17 diaphragmatic sites. The comparative device 5 did not exhibit any microscopic findings of adhesion at 4 weeks. At 8 weeks, there was no evidence of any adhesion at any liver treatment site for all test and control articles, with one exception (histology score of '1').

[0210] Finally, no test article migration was observed using the hemostatic patch 200 in any cohort.

[0211] Finally, there were no safety issues with the Hemostatic Patch 200 compared to the controls that were evaluated overall at autopsy. Evaluations of local tissue effects at all time points after treatment showed that the Hemostatic Patch 200 exhibited a histological response consistent with acceptable biocompatibility. The average reactivity score for the Hemostatic Patch 200 at all time points after treatment was lower than that of both Comparative Device 4 and Comparative Device 5. The controls support the conclusion that the Hemostatic Patch 200 was not reactive relative to either control product. Mineralization was not part of the histological response of the Hemostatic Patch 200 at any time point, and after 72 cohorts, no material remained at 4 or 8 weeks after treatment, indicating complete bioabsorption by 4 weeks. Finally, histological evaluations of non-target organs were not significant, indicating that there were no systemic toxic effects from the Hemostatic Patch 200 or Comparative Devices 5 and 4.

[0212] Study 5: Open Implantation Study and Laparoscopic Application of Hemostatic Patch 200 in a Porcine Model Comparison of GLP assessments of efficacy and safety

[0213] To evaluate the use of Hemostatic Patch 200 in an open GLP study, a GLP preclinical study was conducted to assess the efficacy and safety of Hemostatic Patch 200. This study aimed to demonstrate that Hemostatic Patch 200 performed as expected in an open surgical setting by evaluating hemostatic performance, rebleeding rate, safety, and degradation, and comparing these to the results of a minimally invasive surgery (MIS) study.

[0214] In both the open-label GLP study and the laparoscopic GLP study, baseline bleeding severity was distributed across the range of minimal, mild, and moderate bleeding, and the distribution was similar, as shown in Table 1. Figure 14 As shown in .

[0215] Four healthy pigs were successfully utilized in this study. A total of 24 test article sites and 8 control article sites were treated. Due to high baseline SBSS scores (4), two bleeding sites were created but not treated / assessed. These sites were treated with a combination of cauterization, which was insufficient to reduce bleeding and insufficient to stop bleeding when they were still SBSS 4. Regarding the pre-treatment SBSS scores for the test article treatments, 37.5% (9 of 24) had a score of "1", 45.8% (11 of 24) had a score of "2", and 16.7% (4 of 24) had a score of "3". Regarding the pre-treatment SBSS scores for the control article treatments, 25.0% (2 of 8) had a score of "1", 37.5% (3 of 8) had a score of "2", and 37.5% (3 of 8) had a score of "3". All test and control article treatments were hemostatic, with an SBSS score of "0" at the 30- to 40-second post-treatment bleeding assessment, and all test and control article treatments remained hemostatic throughout the five-minute post-treatment assessment period, with the exception of the test article treatment for Lesion 3. For this animal, an SBSS score of "1" was observed at the 3-minute assessment, yet the injury was found to be hemostatic at the 5-minute assessment without any additional compression time or additional product; therefore, this appears to represent a data collection error.

[0216] Endpoint 1: Overall animal health (mortality)

[0217] Overall animal health (mortality), defined as overall animal health, was assessed by review of physical examinations, clinical observations, clinical pathology, and medical treatment.

[0218] The success criterion established for Endpoint 1 is that there will be no clinically significant adverse events resulting in early death or mortality due to treatment with the test article. All assessments indicate that the animals remain in good overall health throughout the duration of the study. There are no deaths or major adverse events that affect the health or welfare of the animals.

[0219] Endpoint 2: Study the operation and performance of the product

[0220] The handling and performance of the study article were evaluated by the study surgeon based on four parameters. The four parameters evaluated were: (1) Introduction through the trocar: Acceptable if introduced into the body without sticking to the trocar to the extent that it could no longer be used at the bleeding site, (2) Navigation to the bleeding site: Acceptable if it did not stick to other organs / areas while moving to the bleeding site to the extent that it could no longer be used at the bleeding site, (3) Preparation for application: Acceptable if the patch could be unfolded and positioned at the bleeding site, and (4) Application: Acceptable if it was placed on the bleeding site and pressure was applied with wet gauze. No success criteria were established for Endpoint 2. However, the surgeon's responses to all criteria were positive, indicated as "Acceptable" for both animals treated with the test article (n=3) and the control article (n=1).

[0221] Endpoint 3: Study Article Migration

[0222] Migration of the study article was assessed by visual migration via light microscopy and histopathology. Visual migration was qualitatively assessed by the assistant surgeon at the day 3 follow-up procedure and at the termination of the procedure. Histopathology, performed by the study pathologist, evaluated sites on the liver and other tissues distal to the application of the study article for any indication of migration of the study article.

[0223] No success criteria were established for the visual migration assessment, however, in general, there was no evidence of migration of the test article (n=24) or control article (n=8) from any treated site on day 3 and at the termination of the procedure. The success criterion for the histopathological assessment of study article migration was the absence of the test article at untreated sites collected for histology. Histopathology found no evidence of migrated study article in untreated liver sections.

[0224] End 4: Successful hemostasis

[0225] Before treatment, after treatment and at termination, hemostasis success was assessed by assessing the bleeding site using the Surface Bleeding Severity Scale (SBSS). In addition, at the end of treatment (before closure), during the 3rd day follow-up procedure and at termination, visual assessment of rebleeding was used to assess hemostasis success. The success criterion for endpoint 4 was that hemostasis (SBSS score of "0") after applying the test article would be proven to be effective without evidence of rebleeding at the time of termination. The SBSS score range before treatment with the test and control articles was 1 to 3. All test article treatments (n=24) and control article treatments (n=8) achieved hemostasis by 5-minute post-treatment SBSS assessment, with 16.7% of the hemostatic patches 200 and 37.5% of the controls needing to place additional products for hemostasis, and on the treatment day, there was no evidence of rebleeding after returning to normal intra-abdominal pressure within 30 minutes. In addition, there was no evidence of rebleeding on the 3rd day or when the termination procedure was performed. Therefore, the success criterion for this endpoint was met.

[0226] End point 5: Time to hemostasis

[0227] Hemostasis time is defined as the time in which the SBSS score is reached and maintained at "0" during the entire post-treatment assessment period. SBSS was used to assess bleeding at each treatment site 30 seconds, 1 minute, 3 minutes, and 5 minutes after treatment with the test article or control article. In the case where additional test / control article applications are required, hemostasis time is relative to final test / control article applications. For test article treatment, additional test article applications were required in 4 of 24 treatments (16.7%) to achieve hemostasis (i.e., the second patch for these cases), mainly because the patch did not fully cover the bleeding site. For control article treatment, additional control article applications were required in 3 of 8 treatments (37.5%) (i.e., the second patch in 2 cases, and the third patch in 1 case), mainly because the patch did not adhere to the tissue. Success criteria were not established for endpoint 5. However, in summary, for the test article treatment, the time to hemostasis was 30 seconds for 95.8% (23 of 24) of the treatments and 5 minutes for 4.2% (1 of 24) of the treatments. For the control article treatment, the time to hemostasis was 30 seconds for 100% (8 of 8) of the treatments. Based on these results, the time to hemostasis was similar between the test article treatments and the control article treatments.

[0228] Endpoint 6: Adhesion Formation

[0229] Adhesion is formed and adhesion degree / severity score is given. Observed adhesion is also collected and residues and / or other tissue responses of the research product are assessed. Success criteria are not established for endpoint 6. However, in summary, at the time of termination, all test and control product treatment sites received an adhesion score of "1," which is defined as thin, film-like adhesion that can be destroyed by minimal finger manipulation. This indicates that adhesion is negligible for the test product treatment site, and the response is no different from the control product treatment site.

[0230] Endpoint 7: Local tissue response to the study product

[0231] At gross necropsy, local tissue responses to the study article were evaluated by assessing the presence of any clinically significant abnormalities in tissues treated with the study article. At gross necropsy, one of 24 test article-treated sites (4.2%) was assessed for the presence of residual study article, while seven of eight control article-treated sites (87.5%) were assessed for the presence of residual study article. In addition, local tissue responses to the study article were assessed using histopathological assessment of inflammatory response, mineralization, and the amount of study article retained at the treatment site. Using histopathology, residual test article was observed in 8 / 24 sections, with all eight sites observed to have 1%-25% test article remaining compared to the amount at baseline. Further examination revealed that one site had approximately 1% test article remaining, five sites had approximately 1%-5% test article remaining, one site had approximately 5% test article remaining, and one site had approximately 5%-10% test article remaining. Mineralization was observed in 3 / 24 sections, foreign debris was observed in 16 / 24 sections, and hemorrhage was observed in 22 / 24 sections. The remaining control product was observed in 3 / 8 sections and was deeply basophilic in morphology, with 2 sites having 1%-25% of the control product and 1 site having 76%-100% of the control product compared to the amount at baseline. Mineralization was observed in 1 / 8 sections, foreign debris was observed in 6 / 8 sections, and hemorrhage was observed in 7 / 8 sections. No success criteria were established for endpoint 7, however, in summary, all recorded macroscopic lesions may reflect areas of inflammation and fibrosis and are expected findings for a given model. Mononuclear cell infiltrates are also common background findings in pigs and are not considered to be related to the test product. Similar amounts of inflammation (and reactivity scores), mineralization, foreign debris, and hemorrhage were observed between the control and test product sites. No significant or unexpected findings were found in the hepatic lymph nodes. Histological evidence of remaining test article was observed at similar rates between the test article (33.3%) and control article (37.5%), however the amount of remaining test article was lower than the amount of remaining control article.

[0232] In both the open GLP study and the laparoscopic GLP study, the Hemostatic Patch 200 and the comparative device 4 + thrombin resulted in hemostasis at all bleeding sites: in the laparoscopic GLP study, the Hemostatic Patch 200 achieved 96% hemostasis at 30 seconds and 100% hemostasis at 60 seconds, compared to 98.8% hemostasis at 60 seconds and 100% hemostasis at 2 minutes in the open GLP study. In the laparoscopic GLP study, additional patches were required in both the Hemostatic Patch 200 (17%) group and the comparative device 4 + thrombin (38%) group; the rate of additional patches required for initial hemostasis in the open GLP study was n = 0 for the Hemostatic Patch 200 and n = 2 for the comparative device 4 + thrombin. In the Hemostatic Patch 200 group, this was because the initial Hemostatic Patch 200 did not cover the entire bleeding site; this was not observed in the open GLP study. In the comparative Device 4+Thrombin group, this was because the patch did not adhere well enough to the tissue; this was also observed in the open-label GLP study in one bleeding site (n=1 / 80, 1.3%).

[0233] Although hemostasis was achieved with both therapies and no rescue therapy was required, there was a greater need for additional patch placement in the laparoscopic GLP study compared to the open GLP study for both the Hemostatic Patch 200 group and the Comparative Device 4 + Thrombin group. This may be due to the small size of the patch relative to the size of the biopsy punch (e.g., if perfectly placed, a 2.5 cm × 2.5 cm patch on an 8 mm biopsy punch results in only 8.5 mm of overlap of non-bleeding tissue, which is different from the 1 cm recommended in the instructions for use of the Hemostatic Patch 200); although the size of the patch was similar in the open GLP study, the open surgical approach allowed for better visualization and more direct patch placement. In addition, it is generally believed that administration in a laparoscopic setting is more difficult because the visual field and angle on the bleeding site are not always optimal. In addition, the surgeon performing the operation currently has no conventional experience in laparoscopic surgery and may therefore expect a certain degree of imprecise administration. Indeed, additional minimally invasive studies of the Hemostatic Patch 200 found that in an acute laparoscopic non-GLP study performed by surgeons who routinely perform laparoscopic surgery, the same-sized 2.5 cm x 2.5 cm Hemostatic Patch 200 was adequately placed to overlap the bleeding site in all 16 of 16 8 mm biopsy punch bleeds. Notably, in additional studies of the use of the Hemostatic Patch 200 in a robotic partial liver resection model, in which surgeons chose to apply larger portions of the Hemostatic Patch 200 (ranging from 3 cm x 5 cm to 10 cm x 5 cm) that had sufficient overlap on clinically representative bleeding, all applications adequately covered the bleeding site.

[0234] In this study, seven surgeons who performed various minimally invasive procedures with the Hemostatic Patch 200 completed a usability questionnaire. All surgeons responded with "strongly agree" or "agree" on a 5-point Likert scale to the following statements regarding the Hemostatic Patch 200:

[0235] The hemostatic patch 200 can be introduced through a trocar without being damaged, broken, or rolled up to the point where it can no longer be used (n=6 "strongly agree" and n=1 "agree")

[0236] The hemostatic patch 200 can be navigated to the bleeding site without sticking to other structures or becoming too wet to the point where it can no longer be used (n=6 "strongly agree" and n=1 "agree")

[0237] The hemostatic patch 200 can be adequately positioned over the bleeding site using minimally invasive tools (n=7 “strongly agree”)

[0238] • Sufficient pressure can be provided with minimally invasive tools to adhere the hemostatic patch 200 to tissue (n=7 "strongly agree").

[0239] In the open GLP study, there was only one case of rebleeding following the application of the hemostatic patch 200 that occurred during surgery (e.g., 1.3%). In the laparoscopic GLP study, there was no rebleeding due to hemostatic failure of the hemostatic patch 200. There was one accidental injury to the treatment site by the laparoscopic instrument, which required the application of a new hemostatic patch 200 40 minutes after the initial treatment. Notably, the assessment of rebleeding in the laparoscopic GLP study included a 30-minute period of normal intra-abdominal pressure to simulate the immediate postoperative period, during which the risk of rebleeding is highest, and no rebleeding occurred during this period. There was no evidence of rebleeding at 72-hour sacrifice in the open GLP study and at a 72-hour laparoscopic re-examination in the laparoscopic GLP study, nor at later time points of 4 and 8 weeks in both studies. In summary, the laparoscopic GLP study demonstrated that the use of the hemostatic patch 200 in a minimally invasive setting results in a similar degree of sustained hemostasis as when the hemostatic patch 200 is used during open surgery.

[0240] In both the open GLP study and the laparoscopic GLP study, there was no evidence of product migration at any of the multiple time points during surgery, at 72 hours of sacrifice and laparoscopic review, and at later time points of 4 and 8 weeks. The data from the laparoscopic GLP study provided evidence that appropriate pressure was applied during application of the hemostatic patch 200, such that it adhered adequately to the tissue and did not migrate, similar to the results in the open GLP study.

[0241] In the open GLP study, as determined by 72-hour sacrifice, overall severe adhesions were present in 81% of the Hemostatic Patch 200 sites and 86% of the Comparative Device 4+Thrombin sites, compared to 50% of the Hemostatic Patch 200 sites and 100% of the Comparative Device 4+Thrombin sites in the laparoscopic GLP study. In the open GLP study, these adhesions were all graded as '1' (thin, film-like adhesion; disrupted by minimal finger manipulation). Due to the laparoscopic approach with a 3-day re-examination in the laparoscopic GLP study, the nature of the adhesions was not scored at this time. At the 4-week endpoint, the open GLP study found severe adhesions in all Hemostatic Patch 200 and Comparative Device 4+Thrombin sites, and this was also found in the laparoscopic GLP study. The nature of the adhesions indicated that the laparoscopic GLP study was associated with a lower adhesion grade at the 4-week endpoint compared to the open GLP study. Notably, the open-label GLP study found that at 8-week sacrifice, 83.3% of the Hemostatic Patch 200 and 91% of the Comparative Device 4+Thrombin sites had an adhesion score of '2' and 8.3% and 9.0% had a score of '3', respectively, suggesting that long-term adhesion is not expected to be greater in the case of the Hemostatic Patch 200 compared to the Comparative Device 4+Thrombin.

[0242] Given that the majority of animals in both the open GLP study and the laparoscopic GLP study showed adhesion regardless of the hemostatic treatment used, and the overall clinical evidence for the presence of adhesions following intraperitoneal surgery for various indications, it can be concluded that the Hemostatic Patch 200 itself does not appear to be associated with an increase in post-operative adhesions. Visual (unclear) inspection of the treatment sites at 4 weeks in both the open GLP study and the laparoscopic GLP study showed that most treatment sites did not show any residue of the Hemostatic Patch 200, with possible residue visible in 21% of the open GLP study and 4% of the laparoscopic GLP study.

[0243] During histopathology, it was confirmed in the open-label GLP study that degradation of the Hemostatic Patch 200 occurred prior to the 4-week sacrifice of the animals, as there was no microscopic evidence of the Hemostatic Patch 200 at the bleeding site. Although histological data are not currently available from the laparoscopic GLP study, data from visual inspection of the treatment site indicate that the expected degradation time of 4 weeks was also confirmed in the laparoscopic GLP study.

[0244] Results from the laparoscopic GLP study confirmed that the Hemostatic Patch 200 could be satisfactorily introduced through a minimally invasive trocar, navigated to the bleeding site, and applied to the bleeding site; surgeons rated all usability data elements as 'acceptable.' Compared to use of the Hemostatic Patch 200 in an open surgical setting, laparoscopic use of the Hemostatic Patch 200 demonstrated similar performance to the open GLP study in terms of hemostasis, rebleeding, product migration, adhesion formation, and product degradation. Based on these preliminary results, the minimally invasive use of the Hemostatic Patch 200 is considered safe and effective, but additional clinical and histopathological results in the final report of the laparoscopic GLP study are expected to further confirm this conclusion.

[0245] Figure 15 A method 1500 for treating bleeding in a subject during an open surgical procedure is depicted. Method 1500 may include, at step 1510, delivering a hemostatic patch 200 into contact with tissue at a bleeding site in a respective subject of a plurality of first subjects. Although not depicted in method 1500, an operator may also position the hemostatic patch 200 within a chamber at the bleeding site. Method 1500 may optionally include, at step 1520, applying pressure to the hemostatic patch 200 for approximately 30 seconds. Method 1500 also includes, at step 1530, restoring hemostasis to the tissue within at least three minutes.

[0246] Figure 16 A method 1600 for treating bleeding in a subject during an open surgical procedure is depicted. Method 1600 may include, at step 1610, positioning a first hemostatic patch 200 in contact with tissue at a bleeding site of an organ of a respective subject from a plurality of first subjects. The first hemostatic patch 200 may comprise a carrier structure and reactive electrophilic groups capable of reacting with amine groups in tissue and blood. Although not depicted in method 1600, an operator may also position the hemostatic patch 200 within a chamber at the bleeding site. Method 1600 may optionally include applying pressure to the hemostatic patch 200 for approximately 30 seconds as described above. Method 1600 also includes, at step 1630, reducing the time to achieve hemostatic control of active bleeding from the bleeding site of the organ by positioning the first hemostatic patch 200 in contact with tissue of the plurality of first subjects, as compared to a plurality of second subjects treated by delivering the first comparison device. The first comparison device may include comparison device 1, as described in more detail with respect to the second study described herein.

[0247] Figure 17A method 1700 for treating bleeding in a subject during an open surgical procedure is depicted. The method 1700 may include delivering a first hemostatic patch 200 into contact with tissue at a bleeding site of an organ of a respective subject in a plurality of first subjects at step 1710. The first hemostatic patch 200 includes a three-dimensionally interconnected interstitial space having a plurality of reactive polymer particles. Figures 2A to 2C The reactive polymer particles shown in more detail include a nucleophilic polymer that carries a reactive nucleophilic group; and an electrophilic polymer that carries at least three reactive electrophilic groups that can react with amine groups in the nucleophilic polymer and tissue and blood. Although not depicted in method 1700, the operator can also position the hemostatic patch 200 in the chamber at the bleeding site. Method 1700 may optionally include applying pressure to the hemostatic patch 200 for approximately 30 seconds as described above (step 1720). Method 1700 also includes, at step 1730, reducing the time for hemostatic control of active bleeding from the bleeding site of an organ by positioning the first hemostatic patch 200 in contact with the tissue of a plurality of first subjects, compared to a plurality of second subjects treated by delivering a second contrast device. Alternatively or additionally, method 1700 includes reducing the time to hemostatic control of active bleeding from a bleeding site of an organ by positioning first hemostatic patch 200 in contact with tissue of the plurality of first subjects as compared to the plurality of third subjects treated by delivering a third contrast device, at step 1740. The second contrast device may include contrast device 2, and the third contrast device may include contrast device 3, as described in more detail with respect to the third study described herein.

[0248] Figure 18 A method 1800 for treating bleeding in a subject during an open surgical procedure is depicted. The method 1800 may include delivering a first hemostatic patch 200 to contact a bleeding site of an organ of a respective subject in a plurality of first subjects at step 1810. The first hemostatic patch 200 includes a three-dimensionally interconnected interstitial space having a plurality of reactive polymer particles. Figures 2A to 2CThe reactive polymer particles shown in more detail include a nucleophilic polymer that carries a reactive nucleophilic group; and an electrophilic polymer that carries at least three reactive electrophilic groups that can react with amine groups in the nucleophilic polymer and tissue and blood. Although not depicted in method 1800, the operator can also position the hemostatic patch 200 in the chamber at the bleeding site. Method 1800 may optionally include applying pressure to the hemostatic patch 200 for approximately 30 seconds as described above (step 1820). Method 1800 also includes, at step 1830, reducing the time for hemostatic control of active bleeding from the bleeding site of an organ by positioning the first hemostatic patch 200 in contact with the tissue of a plurality of first subjects, compared to a plurality of second subjects treated by delivering a fourth contrast device. Alternatively or additionally, method 1800 includes reducing the time to hemostatic control of active bleeding from a bleeding site of an organ by positioning first hemostatic patch 200 in contact with tissue of the plurality of first subjects as compared to the plurality of third subjects treated by delivering a fifth contrast device, at step 1840. The fourth contrast device may include contrast device 4, and the fifth contrast device may include contrast device 5, as described in more detail with respect to the fourth study described herein.

[0249] The disclosed technology described herein can be further understood in accordance with the following terms:

[0250] Item 1: A method for treating bleeding in a subject during a surgical procedure, the method comprising: positioning a hemostatic patch in contact with tissue at a bleeding site in a corresponding subject of a plurality of first subjects, the hemostatic patch comprising: a carrier structure and reactive electrophilic groups capable of reacting with amine groups in the tissue and blood; and restoring hemostasis to the tissue within at least three minutes.

[0251] Item 2: The method according to Item 1, wherein the hemostatic patch further comprises: a three-dimensionally interconnected interstitial space, the three-dimensionally interconnected interstitial space comprising a plurality of reactive polymer particles, the reactive polymer particles comprising: an electrophilic polymer, the electrophilic polymer carrying the reactive electrophilic group; and a nucleophilic crosslinker, the nucleophilic crosslinker containing a reactive nucleophilic group, the reactive nucleophilic group being capable of reacting with the reactive electrophilic group of the electrophilic polymer while forming a covalent bond.

[0252] Clause 3: The method of Clause 1 or 2, further comprising achieving hemostasis within approximately three minutes in at least 84.6% of the subjects after positioning the hemostatic patch in contact with the tissue at the bleeding site of the respective subject.

[0253] Clause 4: The method of Clause 1 or 2, further comprising achieving hemostasis within about one minute in at least 81.4% of the subjects after positioning the hemostatic patch in contact with the tissue at the bleeding site of the respective subject.

[0254] Clause 5: The method of Clause 1 or 2, further comprising achieving hemostasis within approximately 30 seconds in at least 65.9% of the subjects after positioning the hemostatic patch in contact with the tissue at the bleeding site of the respective subject.

[0255] Clause 6: The method of any one of clauses 1 to 5, wherein the bleeding site is located in one of the following locations: liver, pancreas, spleen, stomach, gastrointestinal tract, kidney, bladder, reproductive organs, lung, mediastinum, breast, lymph node, thymus, muscle, fat, heart, blood vessel, iliac artery, carotid artery, vena cava or brain.

[0256] Clause 7: The method according to any one of clauses 1 to 6 further comprising: restoring hemostasis to the tissue, wherein the tissue exhibits a bleeding severity equal to or less than 5 at the bleeding site of the tissue, the bleeding severity being determined by the Surface Bleeding Severity Scale (SBSS).

[0257] Clause 8: The method of clause 1, wherein the hemostatic patch is configured to completely degrade within approximately six weeks.

[0258] Clause 9: The method of Clause 8, further comprising: allowing the hemostatic patch to degrade after restoring hemostasis to the tissue.

[0259] Item 10: The method of any one of Items 2 to 9, wherein the electrophilic polymer comprises at least three reactive electrophilic groups capable of reacting with the nucleophilic crosslinker and amine groups in the tissue and blood.

[0260] Item 11: The method of Item 10, wherein the electrophilic polymer is selected from the group consisting of polyoxazoline, polyethylene glycol, polyvinyl pyrrolidone, polyurethane, and combinations thereof.

[0261] Item 12: The method of Item 11, wherein the electrophilic polymer is a polyoxazoline.

[0262] Item 13: The method according to Item 10, wherein the reactive electrophilic group is selected from the group consisting of: carboxylate, sulfonate, phosphonate, pentafluorophenyl ester, p-nitrophenyl ester, p-nitrophenylthio ester, acyl halide group, acid anhydride, ketone, aldehyde, isocyanate, thioisocyanate, isocyano group, epoxide, activated hydroxyl group, olefin, glycidyl ether, carboxyl group, succinimide ester, sulfosuccinimide ester, maleimido group, vinylsulfonyl group, imidate, acetoacetate, haloacetal, o-pyridyl disulfide, dihydroxyphenyl derivative, vinyl group, acrylate, acrylamide, iodoacetamide and combinations thereof.

[0263] Clause 14: The method of any one of Clauses 10 to 13, wherein the hemostatic patch comprises a molar ratio of electrophilic polymer to nucleophilic polymer ranging from about 1.0:0.10 to about 1.0:0.40.

[0264] Clause 15: The method of any one of Clauses 1 to 14, wherein the hemostatic patch further comprises a blue colorant.

[0265] Item 16: A method for treating bleeding in a subject during a surgical procedure, the method comprising: positioning a first hemostatic patch in contact with tissue at a bleeding site of an organ of a corresponding subject among a plurality of first subjects, the first hemostatic patch comprising: a carrier structure and reactive electrophilic groups capable of reacting with amine groups in the tissue and blood; and restoring hemostasis to the organ within at least three minutes.

[0266] Clause 17: The method of clause 16, further comprising: reducing the time for hemostatic control of active bleeding from the bleeding site of the organ by positioning the first hemostatic patch in contact with the tissue of the plurality of first subjects compared to a plurality of second subjects treated by delivering a first contrast device.

[0267] Clause 18: The method of Clause 17, further comprising achieving approximately 100% hemostasis within 8 minutes by delivering the first hemostatic patch to the first plurality of subjects.

[0268] Clause 19: The method of Clause 17, further comprising achieving approximately 88% hemostasis in 3 minutes or less by delivering the first hemostatic patch to the first plurality of subjects.

[0269] Clause 20: The method of Clause 19, further comprising achieving approximately 88% hemostasis within 30 seconds by delivering the first hemostatic patch to the first plurality of subjects.

[0270] Clause 21: The method of clause 17, further comprising: increasing the degree of hemostatic control in 3 minutes or less by positioning the first hemostatic patch in contact with the tissue of the plurality of first subjects compared to the plurality of second subjects treated by delivering a first contrast device.

[0271] Clause 22: The method of any one of clauses 16 to 21, wherein the bleeding site is located in one of the following locations: liver, pancreas, spleen, stomach, gastrointestinal tract, kidney, bladder, reproductive organs, lung, mediastinum, breast, lymph node, thymus, muscle, fat, heart, blood vessel, iliac artery, carotid artery, vena cava or brain.

[0272] Item 23: A method for treating bleeding in a subject during surgery, the method comprising: delivering a first hemostatic patch into contact with tissue at a bleeding site of an organ of a corresponding subject among a plurality of first subjects, the first hemostatic patch comprising three-dimensionally interconnected interstitial spaces, the three-dimensionally interconnected interstitial spaces comprising a plurality of reactive polymer particles, the reactive polymer particles comprising: a nucleophilic polymer carrying a reactive nucleophilic group; and an electrophilic polymer carrying at least three reactive electrophilic groups, the at least three reactive electrophilic groups being capable of reacting with the nucleophilic polymer and amine groups in tissue and blood; and restoring hemostasis to the organ within at least three minutes.

[0273] Clause 24: The method of clause 23, further comprising: achieving hemostasis within about 10 seconds.

[0274] Clause 25: The method of clause 23, further comprising: reducing the time to hemostatic control of active bleeding from the bleeding site of the organ by delivering the first hemostatic patch to the plurality of first subjects as compared to a plurality of second subjects treated by delivering a second contrast device.

[0275] Clause 26: The method of Clause 25, further comprising: achieving increased hemostatic efficacy against active bleeding from a bleeding site of an organ by delivering the first hemostatic patch to the plurality of first subjects compared to the plurality of second subjects treated by delivering the second contrast device.

[0276] Clause 27: The method of clause 23, further comprising: reducing the time to hemostatic control of active bleeding from the bleeding site of the organ by delivering the first hemostatic patch to the plurality of first subjects as compared to a plurality of third subjects treated by delivering a third contrast device.

[0277] Clause 28: The method of Clause 27, further comprising: achieving increased hemostatic efficacy against active bleeding from a bleeding site of an organ by delivering the first hemostatic patch to the plurality of first subjects as compared to the plurality of third subjects treated by delivering the third comparison device.

[0278] Clause 29: The method according to any one of clauses 23 to 28, further comprising: positioning the first hemostatic patch in contact with tissue at the bleeding site of the organ; and applying pressure to the hemostatic patch while in contact with the tissue at the bleeding site of the organ.

[0279] Clause 30: The method of Clause 29, further comprising achieving approximately 100% hemostasis within approximately 30 seconds by delivering the first hemostatic patch to the plurality of first subjects.

[0280] Item 31: A method for treating bleeding in a subject during surgery, the method comprising: delivering a first hemostatic patch to a site of bleeding in or around an organ of a corresponding subject among a plurality of first subjects, the first hemostatic patch comprising: a nucleophilic polymer carrying a reactive nucleophilic group; and an electrophilic polymer carrying at least three reactive electrophilic groups, the at least three reactive electrophilic groups being capable of reacting with the nucleophilic polymer and amine groups in tissue and blood; and achieving hemostasis of the organ within approximately one minute.

[0281] Clause 32: The method of clause 31, further comprising: achieving hemostasis within one minute for at least 94% of actively bleeding sites.

[0282] Clause 33: The method of clause 32, further comprising: increasing hemostatic control of active bleeding from the bleeding site of the organ by delivering the first hemostatic patch to the plurality of first subjects as compared to a plurality of second subjects treated by delivering a fourth contrast device.

[0283] Clause 34: The method of clause 32, further comprising: increasing hemostatic control of active bleeding from the bleeding site of the organ by delivering the first hemostatic patch to the plurality of first subjects as compared to a plurality of second subjects treated by delivering a fifth contrasting hemostatic device.

[0284] Clause 35: The method according to any one of clauses 31 to 34, further comprising: positioning the first hemostatic patch in contact with tissue at the bleeding site of the organ; and applying pressure to the hemostatic patch for approximately 30 seconds while in contact with the tissue at the bleeding site of the organ.

[0285] Clause 36: The method of Clause 35, wherein the first hemostatic device is further configured to adhere to the organ until at least a portion of the first hemostatic patch biodegrades within approximately 6 weeks.

[0286] Item 37: A device for treating surgical bleeding, the device comprising a biocompatible, flexible hemostatic patch, the biocompatible, flexible hemostatic patch comprising: a nucleophilic polymer carrying a reactive nucleophilic group; and an electrophilic polymer carrying at least three reactive electrophilic groups, the at least three reactive electrophilic groups being capable of reacting with the nucleophilic polymer and amine groups in tissue and blood, the hemostatic patch being configured to be delivered to an organ of a subject and, after the hemostatic patch is positioned in contact with tissue at a bleeding site of the organ, restore hemostasis to the organ within approximately three minutes or less.

[0287] Item 38: The device of Item 37, wherein the electrophilic polymer is selected from the group consisting of polyoxazoline, polyethylene glycol, polyvinyl pyrrolidone, polyurethane, and combinations thereof.

[0288] Clause 39: The device of clause 37 or 38, wherein the electrophilic polymer is a polyoxazoline.

[0289] Clause 40: The device of any one of clauses 37 to 39, wherein the reactive electrophilic group is selected from the group consisting of carboxylates, sulfonates, phosphonates, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrophenylthio esters, acyl halide groups, anhydrides, ketones, aldehydes, isocyanates, thioisocyanates, isocyano groups, epoxides, activated hydroxyl groups, olefins, glycidyl ethers, carboxyl groups, succinimidyl esters, sulfosuccinimidyl esters, maleimido groups, vinylsulfonyl groups, imidoesters, acetoacetates, haloacetals, o-pyridyl disulfides, dihydroxyphenyl derivatives, vinyl groups, acrylates, acrylamides, iodoacetamides, and combinations thereof.

[0290] Clause 41: The device of any one of clauses 37 to 39, wherein the hemostatic device is further configured to achieve hemostasis within approximately three minutes in at least 65.5% of subjects after positioning the hemostatic device near or around the bleeding site of the organ of the respective subject.

[0291] Clause 42: The device of any one of clauses 37 to 41, wherein the hemostatic device is further configured to achieve hemostasis within approximately three minutes in at least 84.6% of subjects after positioning the hemostatic device near or around the bleeding site of the organ of the respective subject.

[0292] Clause 43: The device of any one of clauses 37 to 42, wherein the hemostatic device is further configured to achieve hemostasis within approximately one minute in at least 81.4% of subjects after positioning the hemostatic device near or around the bleeding site of the organ of the respective subject.

[0293] Clause 44: The device of any one of clauses 37 to 43, wherein the hemostatic device is further configured to achieve hemostasis within approximately 30 seconds in at least 65.9% of subjects after positioning the hemostatic device near or around the bleeding site of the organ of the respective subject.

[0294] Clause 45: The device of any one of clauses 37 to 44, wherein the bleeding site is located in one of the following locations: liver, pancreas, spleen, stomach, gastrointestinal tract, kidney, bladder, reproductive organs, lung, mediastinum, breast, lymph node, thymus, muscle, fat, heart, blood vessel, iliac artery, carotid artery, vena cava or brain.

[0295] Clause 46: The device of any one of Clauses 37 to 45, wherein the hemostatic device is further configured to adhere to the organ until at least a portion of the hemostatic device biodegrades within approximately 6 weeks.

[0296] Clause 47: The device of any one of Clauses 37 to 46, wherein the hemostatic device is further configured to degrade after hemostasis to the organ is restored.

[0297] Item 48: A biocompatible, flexible hemostatic device for treating surgical bleeding, the hemostatic device comprising: a water-resistant, adhesive fibrous carrier structure comprising: three-dimensionally interconnected interstitial spaces, the three-dimensionally interconnected interstitial spaces containing: a plurality of reactive polymer particles, the reactive polymer particles comprising an electrophilic polymer; and fibers, the fibers comprising a nucleophilic polymer carrying reactive nucleophilic groups; and wherein the hemostatic device is capable of being delivered to an organ of a subject and restoring hemostasis to the organ in approximately three minutes or less by positioning the hemostatic device near or around a bleeding site on the organ.

[0298] Clause 49: The device of Clause 48, wherein the hemostatic device further comprises a blue colorant.

[0299] Clause 50: The device of clause 48 or 49, wherein the hemostatic device is further configured to achieve hemostasis within approximately three minutes in at least 84.6% of subjects after positioning the hemostatic device near or around the bleeding site of the organ of the respective subject.

[0300] Clause 51: The device of clause 48, wherein the hemostatic device is further configured to achieve hemostasis within approximately one minute in at least 81.4% of subjects after positioning the hemostatic device near or around the bleeding site of the organ of the respective subject.

[0301] Clause 52: The device of clause 48, wherein the hemostatic device is further configured to achieve hemostasis within approximately 30 seconds in at least 65.9% of subjects after positioning the hemostatic device near or around the bleeding site of the organ of the respective subject.

[0302] Clause 53: The device of clause 48, wherein the bleeding site is located in one of the following locations: liver, pancreas, spleen, stomach, gastrointestinal tract, kidney, bladder, reproductive organs, lung, mediastinum, breast, lymph node, thymus, muscle, fat, heart, blood vessel, iliac artery, carotid artery, vena cava or brain.

[0303] Clause 54: A device according to any one of clauses 48 to 53, wherein the hemostatic device is configured to restore hemostasis to the organ of a subject by adhering the hemostatic device into contact with tissue at the bleeding site of the organ, the subject presenting a bleeding severity equal to or less than 3 at the bleeding site of the organ, as determined by the Surface Bleeding Severity Scale (SBSS).

[0304] Clause 55: The device of clause 48, wherein the electrophilic polymer comprises at least three reactive electrophilic groups capable of reacting with amine groups in the nucleophilic polymer and tissues of the organ and blood.

[0305] Item 56: The device of Item 55, the reactive polymer particles comprising a diameter in a range from about 0.5 μm to about 100 μm and present in an amount of at least 3% by weight of the fibrous support structure.

[0306] Clause 57: The device of clause 48, wherein the fiber carrier structure is a felt structure, a woven structure, or a knitted structure.

[0307] Item 58: The device of Item 48, wherein the electrophilic polymer is selected from the group consisting of polyoxazoline, polyethylene glycol, polyvinyl pyrrolidone, polyurethane, and combinations thereof.

[0308] Clause 59: The device of clause 58, wherein the electrophilic polymer is a polyoxazoline.

[0309] Item 60: The device of Item 55, wherein the reactive electrophilic group is selected from the group consisting of carboxylates, sulfonates, phosphonates, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrophenylthio esters, acyl halide groups, anhydrides, ketones, aldehydes, isocyanates, thioisocyanates, isocyano groups, epoxides, activated hydroxyl groups, olefins, glycidyl ethers, carboxyl groups, succinimidyl esters, sulfosuccinimidyl esters, vinyl sulfonyl groups, imidoesters, acetoacetates, haloacetals, o-pyridyl disulfides, dihydroxyphenyl derivatives, vinyl groups, acrylates, acrylamides, iodoacetamides, and combinations thereof.

[0310] Clause 61: The device of Clause 48, comprising a molar ratio of electrophilic polymer to nucleophilic polymer ranging from about 1.0:0.10 to about 1.0:0.40.

[0311] The hemostatic device 200 and related methods of use disclosed herein have demonstrated high rates of significant hemostasis in patients with bleeding during minimally invasive surgery. The specific configuration, choice of materials, and the sizes and shapes of the various components may vary as needed to meet the specific design specifications or constraints of a system or method constructed according to the principles of the disclosed technology. Such variations are intended to be encompassed within the scope of the disclosed technology. Therefore, the embodiments disclosed herein are to be considered in all respects as illustrative and not restrictive. Therefore, it will be apparent from the foregoing that, while particular forms of the disclosure have been shown and described, various modifications may be made without departing from the spirit and scope of the invention, and all variations that come within the meaning and range of equivalents thereof are intended to be encompassed therein.

Claims

1. A method for treating bleeding in a subject during surgery, the method comprising: Positioning a hemostatic patch in contact with tissue at a bleeding site of a respective subject of a plurality of first subjects, the hemostatic patch comprising: carrier structure, and a reactive electrophilic group capable of reacting with amine groups in tissue and blood; and Hemostasis is restored to the tissue within at least three minutes.

2. The method according to claim 1, wherein The hemostatic patch further comprises: Three-dimensionally interconnected interstitial spaces, the three-dimensionally interconnected interstitial spaces comprising a plurality of reactive polymer particles, the reactive polymer particles comprising: an electrophilic polymer carrying the reactive electrophilic group, and A nucleophilic crosslinker contains a reactive nucleophilic group capable of reacting with the reactive electrophilic group of the electrophilic polymer under formation of a covalent bond.

3. The method according to claim 1, further comprising: After positioning the hemostatic patch in contact with the tissue at the bleeding site of the respective subjects, hemostasis was achieved within approximately three minutes in at least 84.6% of the subjects.

4. The method according to claim 1, further comprising: After positioning the hemostatic patch in contact with the tissue at the bleeding site of the respective subjects, hemostasis was achieved within approximately one minute in at least 81.4% of the subjects.

5. The method according to claim 1, further comprising: After positioning the hemostatic patch in contact with the tissue at the bleeding site of the respective subjects, hemostasis was achieved within approximately 30 seconds in at least 65.9% of the subjects.

6. The method according to claim 1, wherein: The bleeding site is located in one of the following locations: liver, pancreas, spleen, stomach, gastrointestinal tract, kidney, bladder, reproductive organs, lung, mediastinum, breast, lymph node, thymus, muscle, fat, heart, blood vessel, iliac artery, carotid artery, vena cava or brain; and at least one of the following is present: The hemostatic patch is configured to completely degrade in approximately six weeks; The hemostatic patch is configured to degrade after restoring hemostasis to the tissue; and The hemostatic patch also includes a blue colorant.

7. The method according to claim 1, further comprising: Hemostasis is restored to the tissue, the tissue exhibiting a bleeding severity of equal to or less than 5 at the bleeding site of the tissue, the bleeding severity being determined by a surface bleeding severity scale (SBSS).

8. The method of claim 2, wherein the electrophilic polymer comprises at least three reactive electrophilic groups capable of reacting with the nucleophilic cross-linking agent and amine groups in the tissue and blood.

9. The method according to claim 8, wherein At least one of the following exists: The electrophilic polymer is selected from polyoxazoline, polyethylene glycol, polyvinyl pyrrolidone, polyurethane and combinations thereof; and The reactive electrophilic group is selected from the group consisting of carboxylates, sulfonates, phosphonates, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrophenylthio esters, acyl halide groups, anhydrides, ketones, aldehydes, isocyanates, thioisocyanates, isocyano groups, epoxides, activated hydroxyl groups, olefins, glycidyl ethers, carboxyl groups, succinimidyl esters, sulfosuccinimidyl esters, maleimido groups, vinylsulfonyl groups, imidoesters, acetoacetates, haloacetals, o-pyridyl disulfides, dihydroxyphenyl derivatives, vinyl groups, acrylates, acrylamides, iodoacetamides, and combinations thereof.

10. The method according to claim 9, wherein: The electrophilic polymer is a polyoxazoline.

11. The method according to claim 8, wherein The hemostatic patch comprises a molar ratio of electrophilic polymer to nucleophilic polymer ranging from about 1.0:0.10 to about 1.0:0.

40.

12. A method for treating bleeding in a subject during surgery, the method comprising: Positioning a first hemostatic patch in contact with tissue at a bleeding site of an organ of a respective subject of a plurality of first subjects, the first hemostatic patch comprising: carrier structure, and a reactive electrophilic group capable of reacting with amine groups in tissue and blood; Restoring hemostasis to the organ within at least three minutes, and The time for hemostatic control of active bleeding from the bleeding site of the organ is reduced by positioning the first hemostatic patch in contact with the tissue of the first plurality of subjects as compared to a second plurality of subjects treated by delivery of a first contrasting device.

13. The method according to claim 12, further comprising: Approximately 100% hemostasis is achieved within 8 minutes by delivering the first hemostatic patch to the first plurality of subjects.

14. The method according to claim 12, further comprising: Approximately 88% hemostasis is achieved in 3 minutes or less by delivering the first hemostatic patch to the first plurality of subjects.

15. The method according to claim 14, further comprising: Approximately 88% hemostasis is achieved within 30 seconds by delivering the first hemostatic patch to the first plurality of subjects.

16. The method according to claim 12, further comprising: The degree of hemostatic control is increased in 3 minutes or less by positioning the first hemostatic patch in contact with the tissue of the first plurality of subjects as compared to the second plurality of subjects treated by delivery of a first comparison device.

17. The method according to claim 12, wherein: The bleeding site is located in one of the following locations: liver, pancreas, spleen, stomach, gastrointestinal tract, kidney, bladder, reproductive organs, lung, mediastinum, breast, lymph node, thymus, muscle, fat, heart, blood vessel, iliac artery, carotid artery, vena cava or brain.

18. A device for treating surgical bleeding, the device comprising a biocompatible, flexible hemostatic patch, the biocompatible, flexible hemostatic patch comprising: a nucleophilic polymer carrying a reactive nucleophilic group, and an electrophilic polymer carrying at least three reactive electrophilic groups capable of reacting with amine groups in the nucleophilic polymer and tissue and blood; The hemostatic patch is configured to be delivered to an organ of a subject and to restore hemostasis to the organ in approximately three minutes or less after the hemostatic patch is positioned in contact with tissue at a bleeding site of the organ.

19. The device according to claim 18, wherein At least one of the following exists: The electrophilic polymer is selected from polyoxazoline, polyethylene glycol, polyvinyl pyrrolidone, polyurethane and combinations thereof; the reactive electrophilic group is selected from the group consisting of carboxylates, sulfonates, phosphonates, pentafluorophenyl esters, p-nitrophenyl esters, p-nitrophenylthio esters, acyl halide groups, anhydrides, ketones, aldehydes, isocyanates, thioisocyanates, isocyano groups, epoxides, activated hydroxyl groups, olefins, glycidyl ethers, carboxyl groups, succinimidyl esters, sulfosuccinimidyl esters, maleimido groups, vinylsulfonyl groups, imidoesters, acetoacetates, haloacetals, orthopyridyl disulfides, dihydroxyphenyl derivatives, vinyl groups, acrylates, acrylamides, iodoacetamides, and combinations thereof; and The bleeding site is located in one of the following locations: liver, pancreas, spleen, stomach, gastrointestinal tract, kidney, bladder, reproductive organs, lung, mediastinum, breast, lymph node, thymus, muscle, fat, heart, blood vessel, iliac artery, carotid artery, vena cava or brain.

20. The apparatus according to claim 18, wherein The electrophilic polymer is a polyoxazoline.

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