HEMOSTATIC DRESSING AND ITS PRODUCTION CONTAINING CROSS-LINKED BIOADHESIVE CHITOSAN MATRIX WITH A CONTROLLED PORE STRUCTURE AND PROVIDING RAPID BLOOD ABSORPTION.
Patent Information
- Authority / Receiving Office
- TR · TR
- Patent Type
- Applications
- Current Assignee / Owner
- TURGA BİYOTEKNOLOJİ ANONİM ŞİRKETİ
- Filing Date
- 2026-05-20
- Publication Date
- 2026-06-22
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Abstract
Description
1 TARIFF CROSS-LINKED BIOADHESIVE WITH CONTROLLED PORE STRUCTURE CONTAINING CHITOSAN MATRIX AND PROVIDING RAPID BLOOD ABSORPTION. HEMOSTATIC DRESSING AND ITS PRODUCTION 5 Technological Field: The invention describes a hemostatic agent based on covalently cross-linked chitosan with high porosity. It is related to the dressing. The dressing in question is a three-dimensional cross-linked polymer matrix 10 and thanks to its interconnected open macroporous structure, it reacts quickly when it comes into contact with blood. It promotes clot formation by facilitating fluid absorption. The invention also includes... The topic also includes the production method of hemostatic dressings. State of the Art: 15 One of the most critical problems in traumatic injuries is controlling bleeding. The inability to receive blood. Severe blood loss leads to circulatory failure, resulting in impaired perfusion. to deterioration and the development of hypoxia in all organs and tissues, especially the brain This is the cause. If the bleeding is not stopped in time, hemorrhagic shock develops quickly; this occurs in 20 days. Metabolic acidosis, hypothermia, and coagulopathy accompany the condition, and achieving hemostasis gradually becomes more difficult. It becomes more difficult. In particular, 50% of major artery injuries occur on the battlefield, while in civilian clinical settings... It has been reported to cause death in 31% of cases1. Battlefield injuries; high-energy shrapnel and bullet impact, limited mobility 25 Due to reasons such as a lack of experienced healthcare personnel and equipment, civilian facilities It differs significantly from injuries². Military data shows that limb bleeding is related to This shows that deaths account for more than half of all preventable deaths. Especially in areas where tourniquets cannot be applied, such as the neck, armpits, and groin. Bleeding is one of the primary causes of this condition. In both civilian and military traumas, 30 1 Khan, MA and M. Mujahid (2019). "A review on recent advances in chitosan based composite for hemostatic dressings." International journal of biological macromolecules 124: 138-147 2 Champion, HR, RF Bellamy, CP Roberts and A. Leppaniemi (2003). "A Profile of Combat Injury." Journal of Trauma and Acute Care Surgery 54(5): S13-S19. 2 A significant proportion of deaths due to bleeding occur within the first few hours after injury. This occurs.3. Therefore, prompt intervention in bleeding is crucial in the early stages. to bring the situation under control and transport the patient to an appropriate health center as soon as possible. It is of vital importance. In cases that reach the hospital, the majority of deaths occur within the first hour. It occurs within 4. Uncontrolled bleeding continuing in a hospital setting; surgery 5 prolonged duration, delayed wound healing, infection, coagulopathy, and multiple It can lead to serious complications such as organ failure5. Trauma patients It is reported that approximately 25% of patients develop coagulopathy before reaching the emergency department.6 Therefore, stopping the bleeding within the first hour following the injury, It plays a critical role in preventing coagulopathy and related mortality.7 10 In the current state of the technique, hemostatic dressings are used for traumatic injuries, surgery, etc. It is widely used for bleeding control in interventions and emergency situations. Based on their mechanisms of action, these agents can be classified as mechanical, chemical, physical, and physiological. They are classified. Due to their ease of practical application, chemical agents, especially 15 It is more frequently preferred in battlefield and emergency situations8. Uncontrolled in the management of bleeding, supporting the intravascular coagulation cascade or By providing an extravascular surface, both intravenous and intravenous drugs accelerate clot formation. Topical agents have been developed. In particular, externally applied hemostatic dressings, used in war. 20 in injuries and bleeding in the groin and axillary regions where tourniquets cannot be applied They are used effectively as topical hemostatic agents. They are classified. Topical active hemostats contain high concentrations of fibrinogen and coagulation factors. fibrin-based adhesives (TachoSil, PGA-felt, Fibrin Pad) and thrombin-based 25 3 Stephens, CT, S. Gumbert and J. B. Holcomb (2016). "Trauma-associated bleeding: management of massive transfusion." Current Opinion in Anesthesiology 29(2): 250-255. 4 Martin, M., J. Oh, H. Currier, N. Tai, A. Beekley, M. Eckert and J. Holcomb (2009). "An analysis of in-hospital deaths at a modern combat support hospital." Journal of Trauma and Acute Care Surgery 66(4): S51-S61. Howe, N. and B. Cherpelis (2013). "Obtaining rapid and effective hemostasis: Part I. Update and review of topical hemostatic agents." Journal of the American Academy of Dermatology 69(5): 659. e651-659. e617 6 Khoshmohabat, H., S. Paydar, H. M. Kazemi and B. Dalfardi (2016). "Overview of agents used for emergency hemostasis." Trauma monthly 21(1). 7 Gruen, R. L., K. Brohi, M. Schreiber, Z. J. Balogh, V. Pitt, M. Narayan and R. V. Maier (2012). "Haemorrhage control in severely injured patients." The Lancet 380(9847): 1099-1108. 8 Malik, A., FU Rehman, KU Shah, SS Naz and S. Qaisar (2021). "Hemostatic strategies for uncontrolled bleeding: A comprehensive update." Journal of Biomedical Materials Research Part B: Applied Biomaterials 109(10): 1465-1477. 3 These products (Surgiflo, Floseal) are used in clinical practice as topical treatments. In contrast, Mechanical hemostats; oxidized regenerated cellulose (ORC) derivatives (Surgicel, Surgicel) Fibrillar, Nu-Knit, Reoxcel, Oxicel) rapidly absorb water from blood plasma. gelatin-based products that trigger clotting (Gelfoam, Avitene Ultrafoam, EndoAvitene, Avitene UltraWrap, Helitene, Helistat) and collagen-based agents (TachoSil®) 5 It includes. External hemostatic dressings are used in war zones where surgical intervention is not possible. These bandages were developed to quickly control severe bleeding. especially in anatomical areas such as the axilla and groin where tourniquets are ineffective, external 10 They are preferred in bleeding disorders. According to their mechanisms of action, these products include: factor thickeners (zeolite), procoagulants (kaolin) and mucoadhesive agents (chitin / chitosan) They are classified as follows. These agents, which are available in granular, powder, or bandage form, platelets, clotting factors, and red blood cells localized to the wound area. By increasing its concentration, it supports hemostasis. Zeolite-based products QuikClot granular 15 QuikClot Combat offers kaolin-based products in powder form and under the name Advanced Clothing Sponge (ACS). Gauze is marketed in the following forms: Combat Gauze XL, Trauma Pad, and Interventional. However, current hemostatic products used in the known state of the art It has several limitations. For example, QuikClot produces 20 oz as a result of an exothermic reaction. It can cause tissue damage and, due to its low biodegradability, can be a foreign body. It can cause a reaction. HemCon dressings have antimicrobial properties. Although it shows some effectiveness, it is not sufficiently effective in deep, narrow, or irregular wounds. Montmorillonite-containing hemostats carry a risk of vascular thrombosis. Combat Gauze, Although widely used on the battlefield, it is also used in coagulopathic conditions. 25 It has been reported that its effectiveness is reduced. Gelatin-based sponges are generally used for minor hemorrhages. It is suitable for this purpose but is limited in cases of severe bleeding. While natural polysaccharides such as chitosan, cellulose and their derivatives exhibit a hemostatic effect, In addition to its biocompatible, antibacterial, and antifungal properties, its extracellular matrix is 30 Due to its ability to mimic (ECM) radiation, it is frequently used as a hemostatic dressing. It is used. Oxidized regenerated cellulose has an intrinsic hemostatic effect. 4 Although not directly related, it absorbs blood and other fluids, forming a physical barrier. In this way, it supports hemostasis. However, by lowering the pH of the environment, it has an antimicrobial effect. This can also lead to the oxidation of hemoglobin. The environment becomes acidic. The presence of these substances disrupts cell integrity, leading to cell breakdown. This situation is caused by the environment. It can increase inflammation in the tissue, negatively affecting the wound healing process. Also, these 5 The acidic structure of oxidized regenerated cellulose, along with other procoagulant agents such as thrombin. It also limits their combined use. Commercial oxidized regenerated cellulose-based products. Products include Surgicel® (US2015147558A1), TraumaStem® (US2015147558A1) and ActCel® (US2012315305A1) is included. These include Surgicel®, in particular. The main cellulose-based hemostatic agents commonly used in liver and spleen surgery are 10. Surgicel® is one of the agents used in the in vitro Lee–White clotting time test and in vivo tests. Animal models were used to compare different hemostatic agents. The results obtained... The results show bleeding control, especially in high-pressure and active arterial bleeding. Studies have shown that it exhibits lower effectiveness compared to other agents. (Sondeen et al., 2003). 15 In current techniques, chitosan-based biopolymers are preferred due to their hemostatic properties. These are commercial chitosan-based products such as HemCon® and Celox®. (US20230270914A1) and TraumaStat® are included. Patent number US 7,371,403, It describes a chitosan hemostatic bandage and HemCon hemostatic bandage 20 This product is used by the US military. This product proved beneficial in the Gulf War. It has received negative reactions. However, in cases of arterial bleeding, non-professionals should not be consulted. Due to interventions, it is often difficult to pinpoint the location of the bleeding. HemCon The dressing may detach from the wound surface after a certain period of time, and this situation This can lead to a resumption of bleeding (US 8,668,924 B2). Rigid / wafer 25 Due to its similar structure, it is difficult to apply to deep, narrow, or small wounds9. TraumaStat combines mesoporous silicone, chitosan, and polyethylene materials. It is a hemostatic material. Its composite structure is ideal in terms of biodegradability. It is not. TraumaStat is a gauze containing chitosan, silicon dioxide, and polyethylene. 30 It is reported that this composition is fully biodegradable, particularly due to the presence of polyethylene. 9 Littlejohn, L., Bennett, B.L., & Drew, B. (2015). Application of current hemorrhage control techniques for backcountry care: part two, hemostatic dressings and other adjuncts. Wilderness & environmental medicine, 26(2), 246-254 This can be considered a limitation in terms of the hemostat target. Severe groin pain. In studies conducted on injury models10, survival was particularly high in puncture models. The success rate was reported as 50% for TraumaStat and 88% for Combat Gauze. Additionally, post- Treatment-related uncontrolled blood loss is higher in the TraumaStat group. This indicates that... 5 There may be performance limitations, especially in certain types of high-risk injuries. It shows. Patent aortic no. US2009 / 0186851A1, WO / 2009 / 130485, PCT / GB2009 / 001065 Celox, a hemostatic material for bleeding, consists of granular chitosan, a hemostatic powder. It describes a hemostatic material. It exhibits a good hemostasis effect. However, Celox 10 The granulation of hemostasis is milder. In practical applications, especially in the injured person When used to save oneself, it's difficult to use and easy to reach the bleeding point. Furthermore, these hemostatic products, based solely on chitosan, do not provide hemostasis other than that. to obtain anti-inflammatory, antibacterial and tissue repair related functions It works, but its effect is limited. It's small, deep, and the bleeding point cannot be directly seen. 15 In a penetrating wound model, Celox-A was found to be as effective as standard gauze. It has been reported. Therefore, it may not show significant superiority in every wound type.11 Granule Removing Celox from the wound can pose surgical problems. (Littlejohn et al. 2015). Patent texts for the effective use of Celox-based products. (US20230270914A1) describes the application of constant pressure. This situation requires the user to use the product at 20:00. This makes it dependent on the application. Although Celox can form stable clots, some In these cases, it is associated with tissue damage. Hemostats with a porous sponge structure provide fluid absorption. Cross-linked Bonded polymer networks offer mechanical strength and stability. However, 25 Current solutions are unable to adequately control pore size and distribution, rapidly It is unable to optimize absorption and hemostasis performance and microstructure. They are unable to effectively utilize the relationship between performance and other factors. Arnaud, F., Teranishi, K., Okada, T., Parreño-Sacdalan, D., Hupalo, D., McNamee, G., ... & McCarron, R. (2011). comparison of Combat Gauze and TraumaStat in two severe groin injury models. Journal of Surgical Research, 169(1), 92-98. 11 Littlejohn, L.F., Devlin, J.J., Kircher, SS, Lueken, R., Melia, MR, & Johnson, AS (2011). Comparison of Celox‐A, ChitoFlex, WoundStat, and combat gauze hemostatic agents versus standard gauze dressing in control of hemorrhage in a swine Model of penetrating trauma. Academic Emergency Medicine, 18(4), 340-350. 6 For example, patent number CN111617310B describes chitosan, sodium alginate, and fucoidan sulfate. Hemostatic sponge obtained by using the weight ratio 1:(1-6):(1-6) This explains its preparation method and application. Cross-linking of chitosan and alginate. The sponge produced using the bonding strategy has good swelling and water absorption properties, and It can quickly absorb blood from the wound, causing blood cells to thicken and 5 This triggers a hemostatic cascade reaction. Polyvinyl alcohol cross-linked chitosan matrices in patent number KR101971652B1 It has been defined. The present invention describes polyvinyl alcohol with stability towards the human body and It consists of chitosan, which has excellent biodegradability and biocompatibility. 10 According to the current invention, the polymer matrix reacts with water-containing body fluids such as blood. Because it can expand spontaneously by more than four times its original size, it provides safety and its use as a hemostatic material with biocompatibility properties is expected. Patents numbered CN107501579A and CN104474575A concern covalent cross-linking. chitosan hemostatic materials produced through this method and its preparation method This explains why these patents covalently link cross-linked chitosan hemostatic material is used. It is obtained by cross-linking. In patent number CN107501579A, cross-linking is described. as a component, 1,4-butanediol diglycidyl ether, and in patent number CN104474575A, 20 Polyethylene glycol diglycidyl ether is used. Patent number WO2023225752A1 focuses on a double-network polymer matrix. The first mesh, physically, provides bioadhesion, biocompatibility, and hemostatic properties. It is a cross-linked chitosan (or alginate) network. The second network has mechanical properties and 25 covalently cross-linked polyacrylamide or PEG, which enhance durability. It is a synthetic polymer bonded together. These two networks come together to adhere to wet biological surfaces. It forms an interlocking matrix that maintains its flexibility while adhering strongly to the adhesive. This The material can absorb interface fluids such as blood, mucus, lymph, or cerebrospinal fluid. It is designed as a porous bioadhesive hemostatic. By absorbing these fluids, it can absorb 30... By removing the barrier material, it increases the effective contact area and reduces congestion at the interface; This improves adhesion on wet and bleeding surfaces. Double mesh structure. 7 It provides mechanical strength and energy distribution to the material; this also affects physiological movements. or increases resistance to rupture during fluid flow. Patent number US 8,668,924 B2 describes a biopolymeric structure primarily containing chitosan, and In addition, hydrophilic polymers or polyacrylic polymers (or 5 of these) (combinations) are used to create the material in this patent, in the form of a porous sponge. It is prepared and then compressed to improve its mechanical and hemostatic performance. The structure, a substance that adheres to the bleeding area, accelerating clot formation and strengthening the clot It is a biomaterial system. Patent number US8741335B2 describes a process primarily involving hydrophilic polymer foam, specifically... Hemostatic agent in granular / particle form derived from chitosan and its production method. This is explained in this patent. The hemostatic agent is primarily based on hydrophilic polymer. It consists of particles, and the preferred structure is a system containing chitosan. The particles, 15 biocompatible materials, primarily chitosan, but also alginate, polyacrylate, and polyamines. It can be produced from polymers or combinations thereof. The structure comes into contact with blood. a positively charged substance that, when applied, acts adhesively and rapidly binds to red blood cells and platelets. It has a surface. Patent number US 9,364,578 B2 concerns the preparation of chitosan-based nonwoven fiber structures and 20 Coating with triprotic and solvent acids exhibits antimicrobial and biofilm-disrupting properties. It protects the hemostatic wound dressing compositions to which it is added. Patent number US 2005 / 0203058 A1 describes volatile (monoprotic) and volatile α and β-chitosan. Salted with non-triprotic (organic) acids, then lyophilized and dried, and mixed with water at 25%. preserving the formation of an insoluble but controllably swollen hemostatic structure. It is included. Patent number US2023 / 0270914A1 concerns chitosan and chitosan salts with bioadhesive polymers. High adhesion and fast 30 thanks to the combination of (carbomer, polyacrylic acid, etc.) Protecting hemostatic systems in coating or granular form that provide hemostasis It is receiving. 8 However, new studies show that most materials have poor safety and It cannot proceed to the clinical stage because of its biocompatibility. Furthermore, it is a chemical... Modified biomaterials also face safety and biocompatibility issues. may have. Some of these biological materials may be cytotoxic, while others 5 It can cause hemolysis. Some materials are either not biodegradable or... The degradation products are toxic, which hinders biosafety and approval for clinical trials. One of the main challenges in bleeding treatment is the use of hemostatic agents. This is due to the material's inability to provide sufficient adhesion to the wound surface. Blood flow is 10 In cases where the levels are high, premature platelet plugs and fibrin clots form mechanically. They can easily separate due to the forces, and this affects the sustainability of hemostasis. It can damage it. In this context, the main problem is the sufficient adhesion ability of the hemostatic material. It is the absence of a visible clot and the detachment of the partially formed clot from the wound area. Most hemostatic products on the market are only for superficial wounds. It is appropriate; pressure must be applied to this type of wound, otherwise clotting will occur. There is a risk of these factors entering the circulatory system. Many hemostatic agents It is presented in powder form. Because the powder is difficult to use, its application is cumbersome. It can be in various forms. Also, the powder can be used during nasal or oral surgery, on gums or the back, etc. 20 It may be difficult to apply to various parts of the body. An ideal hemostatic material has the ability to rapidly absorb blood and It must have excellent biocompatibility, be easily degraded in vivo, and the wound... It should not have a negative effect on healing, the adhesion should be good, and healing should be within 25 days. It should also speed up the process. Furthermore, it must have high quality and stability, and It must be safe to use.12 For some specific tissues, mechanical compatibility is required. Adjustable inflation rate and adhesion requirements are also essential. A good hemostatic material... In addition to being high-strength and biodegradable, it is also advanced. It should have tissue compatibility and advanced wound dressing properties. 30 12 Qin, XH, K. Labuda, J. Chen, V. Hruschka, A. Khadem, R. Liska, H. Redl and P. Slezak (2015). "Development of Synthetics Platelet†Activating Hydrogel Matrices to Induce Local Hemostasis." Advanced Functional Materials 25(42): 6606-6617. 9 Today, hemostatic dressings are used in scientific research and clinical applications. It is a commonly used hemostatic preparation formulation. This hemostatic Dressings have swelling and water-absorbing properties, absorbing blood from the wound area. It causes blood cells to concentrate, thus triggering a hemostatic cascade reaction. 5 It initiates different bleeding disorders that have good biocompatibility and biodegradability properties. a hemostatic agent more suitable for their conditions and capable of performing the hemostatic function The development of the dressing eliminates the limitations of existing hemostatic products. By removing it, it can be applied in different bleeding scenarios, rapid blood absorption, increased A hemostatic 10 that exhibits clotting activity and strong bioadhesion properties It can facilitate the provision of the dressing. The aim of this invention is to improve existing hemostatic materials, especially chitosan hemostatics. New, highly efficient, multifunctional chitosan emergency bleeding solution to address material shortages. The goal is to prepare a hemostatic agent. It differs from existing chitosan-based hemostatic products by 15. Thus, this invention utilizes cross-linked, high-structured compounds rather than granular or flat-surfaced structures. It has a porous and three-dimensional network architecture, and allows for rapid absorption of blood. It provides mechanical stabilization of the clot that forms together. Description of the invention: 20 The present invention, which aims to overcome the shortcomings of the previous technique, uses carrier structure fibers. three-dimensional chitosan integrated within, cross-linked by covalent bonds. It has a highly porous and interconnected macroporous architecture consisting of a network of pores. It aims to develop a hemostatic material. 25 The hemostatic material described in this invention, when applied to the bleeding site, both Rapid and effective hemostasis through the combined action of both physical and biochemical mechanisms. This material is covalently integrated into the load-bearing structure. a three-dimensional chitosan network of macroporous particles cross-linked and interconnected by bonds 30 It contains [this structure]. Thanks to this structure, it acts via capillary action immediately after contact with blood. The blood is drawn into the material rapidly. Following the transfer of blood into the material, erythrocytes, platelets, and plasma are formed. Proteins penetrate into the porous structure. The interconnectedness of the pores allows blood to pass through. This allows the components to not only remain on the surface but also to be distributed throughout the volume of the material. It recognizes [this]. During this process, an electrostatic relationship occurs between the cationic structure of chitosan and blood cells. Interactions occur, accelerating the clotting process. At the same time, platelets... Activation and fibrin formation are supported. One of the most important technical implications of the invention is that the clot formed occurs only on the surface. not only does it remain, but it also penetrates into the three-dimensional macroporous network of the material, forming this structure 10 It is the physical retention within the pore. The fibrin network and cellular components By adhering to its walls and cross-linked polymer network, it creates a three-dimensional mechanical structure. It creates a lock. Thanks to this mechanical lock, the clot that forms is protected from external forces and blood. The clot does not dislodge under the influence of blood flow, maintaining its integrity even in high-pressure bleeding. This protects against and significantly reduces the risk of rebleeding. 15 Furthermore, the chitosan network, cross-linked by covalent bonds, maintains the structural integrity of the material. By protecting it, it prevents it from dissolving upon contact with blood and contributes to the stabilization of the clot. It provides. Thanks to its controlled pore size and interconnected pore structure, the material, It enables the directed transport of blood and its local concentration. This 20 This situation accelerates the coagulation process while simultaneously improving the internal cohesion of the material. It increases fluid management effectively, and blood absorption is rapid. This prevents excessive fluid accumulation and provides an optimal environment for clot formation. As a result of this multiple action mechanism, unlike the current technique, only 25 faster, compared to hemostatic systems based on chemical or biological effects Stable and more reliable hemostasis is achieved. The key properties of this hemostatic material are as follows: 1) In cases of bleeding caused by trauma or surgery due to local or systemic reasons, directly 30 applicable; 11 2) The hemostatic agent applied to the bleeding area is rapidly absorbed and acts quickly and It provides strong tissue adhesion; 3) Capillary action directs and rapidly transports blood to the depth of the wound. It contains microchannels that provide 4) A hemostat that comes into contact with blood exhibits a swelling or expansion response; 5 5) It shows significantly faster bleeding control than standard care; 6) It ensures rapid and strong blood clotting and mechanical stabilization of the clot; 7) Thanks to its structural properties, it can be locked not only by chemical action but also by mechanical locking. It provides hemostasis through its mechanism; 8) 10 cross-linked three-dimensional chitosan network integrated into the carrier structure has; 9) It has a highly porous and interconnected macroporous architecture; 10) Achieving effective fluid management with controlled pore size and strong internal structure. It has cohesive properties; 11) By providing oxygen permeability thanks to its porous structure, it promotes wound healing. 15 supports; 12) It is biocompatible, causes minimal irritation to tissue, and reduces the inflammatory response. It is limited; 13) Its solubility is limited under strong blood flow; 14) depending on the pressure created by the bleeding, under low pressure or without applying pressure 20 It can even provide effective hemostasis; 15) It can be easily removed from the wound bed; 16) It is applied easily and quickly in a single step after being removed from the packaging; 17) They can be prepared in different shapes and sizes to adapt to various wound types. Explaining the Figures: The invention will be described by referring to the attached figures, so that the features of the invention can be explained. It will be understood and appreciated more clearly, but the purpose of this invention is this obvious It is not about limiting it with regulations. On the contrary, the invention is defined by the accompanying claims. all alternatives, modifications, and options that could be included within the defined area The aim is to cover their equivalences. The details shown are only for the present invention. 12 It is shown to illustrate the preferred arrangements and both the methods shaping, as well as the most useful and conceptual features of the invention's rules and principles It should be understood that these drawings are presented to provide an easily understandable definition. In these drawings; Figure 1. A highly porous and interconnected 5-dimensional chitosan network. The invention concerns the production of a macroporous hemostatic material. It is the method. Figure 2 shows the mechanical locking behavior of the hemostatic material. It is the appearance. Figure 2A is a cross-sectional view showing the contact of blood with the hemostatic material. 10 Figure 2B Macro-linked structures of erythrocytes, platelets, and plasma proteins. This is a BB cross-sectional view showing its penetration into the pores. Figure 2C shows the result of the interaction between the chitosan network and blood components. This is a CC section view showing the initiation of the coagulation process. Figure 2D shows the formation of fibrin fibers and their adhesion to pore walls. This is a DD cross-sectional view. Figure 2E shows fibrin fibers coiled around pore walls and carrier fibers. This is an EE cross-sectional view showing the formation of a mechanical lock. Figure 2F Mechanically stabilized blood in hemostatic material. This is a FF cross-sectional view showing the clot. 20 Figure 3 shows the graph of coagulation values that vary over time. Figure 4. Scanning after contact of the hemostatic material subject to the invention with blood. This is an electron microscope image. Figures that will help to understand this invention are shown in the attached image, number 25. They are numbered and their names are given below. Explanation of References: 10. Mixing bowl 30 11. Mixer 12. Chitosan solution 13 13. Covalent crosslinking agent 14. Chitosan and covalent crosslinking agent solution 15. Crosslinking catalyst 16. Hemostatic material solution 17. Carrier matrix fibers 5 18. Hemostatic material dispersion 19. Lyophilized hemostatic material 20. Pressing plates 21. Final product (Hemostatic material) 100. Hemostatic material 10 101. 3D cross-linked chitosan network 102. Carrier fibers 103. Interconnected macropores 104. Capillary pathways 105. Pore walls 15 106. Blood 107. Erythrocyte 108. Platelets 109. Plasma protein 110. Fibrin fibers 20 111. Stabilized blood clot S1. Chitosan solution is obtained by mixing chitosan in a solvent acid. preparation S2. Adding covalent crosslinking agent solution drop by drop to chitosan solution. 25 drops added S3. Crosslinker to chitosan and covalent crosslinking agent solution. addition of catalyst solution S4. Addition of carrier matrix fibers to the hemostatic material solution. S5. Freezing of hemostatic material dispersion. S6. Drying / lyophilizing of frozen dispersion 30 S7. Pressing of macroporous hemostatic material S8. Obtaining the final hemostatic material. 14 Detailed Description of the Invention: The terminology used here is intended solely to describe specific applications. and does not limit the scope of the invention. The number 5 used here... The term "and / or" refers to any of the items listed as related. It includes one and all combinations thereof. Also, the singular "one" used here, "one" The terms "number" and "specified" are used in their plural forms unless the context explicitly indicates otherwise. It is designed to include singular forms such as those mentioned above. Furthermore, the terms used in this specification... The terms "includes" and / or "contains" refer to the specified features, steps, processes, 10 It indicates the presence of elements and / or components, but one or more other features, steps, processes, elements, components and / or groups thereof It will be understood that this does not exclude its existence or addition. Unless otherwise noted, all terms used herein (including technical and scientific terms) are copyrighted under Article 15. in the sense that a person with general knowledge in the field to which this invention belongs would generally understand it They have the same meaning. Furthermore, as defined in commonly used dictionaries... The terms will have a meaning consistent with the context of the relevant field and this explanation. it should be interpreted as idealized unless otherwise explicitly defined here. or it will be understood that it will not be interpreted in an overly formal sense. 20 The description of the invention will reveal a series of techniques and steps involved. These are: Each of them provides benefits individually, and at the same time, one or more of them can be used together. In some cases, all of the other techniques described may be used in combination. Accordingly, To ensure clarity, each step in the disclosure of the invention should be presented in 25 steps if possible. By doing this, unnecessary repetition of all combinations will be avoided. Together, the specification and claims, such combinations fully constitute an invention and claims. It should be read with the understanding that it falls within its scope. This paper discusses a new hemostatic dressing and its production technique. The following 30 The statement outlines several specific requirements to ensure a full understanding of the current invention. Details have been provided. However, even without these details, the present invention... Its applicability will be clearly understood by experts in the field. The present invention describes three cross-linked fibers integrated into carrier structure fibers (102). a highly porous and interconnected macro 5-dimensional chitosan network (101) It is a hemostatic material with a porous (103) architecture (100). The invention is further detailed below through concrete examples along with laboratory tests. It is explained as follows. These examples are for illustrative purposes only and the invention It should be understood that this is not intended to limit its scope. Furthermore, experts in this field number 10. by, various modifications to the invention within the scope of the teachings of the present invention. It should also be noted that modifications may be made. A highly porous and interconnected macro composed of a three-dimensional chitosan network (101). The production process of a hemostatic material (100) with a porous (103) architecture Figure-15 It is given in 1. As shown in Figure 1, the present invention is nonwoven carrier structure fibers (102) consisting of a cross-linked three-dimensional chitosan network (101) integrated into it, having a highly porous and interconnected macroporous (103) architecture, 2-7 mm 20 It is a hemostatic material of high height (100). A hemostatic material (100) described above is a hemostatic material product. obtained by integrating and cross-linking into nonwoven carrier fiber (102). porous dressings, porous fibers, porous sponges or porous 25 Bandages are a hemostatic material that is formed. The method of preparing the hemostatic material (100) product is as follows: Hemostatic material, carrier matrix fibers (17), chitosan, covalent cross-linking 30 It includes the agent (13), solvent acid and crosslinking catalyst (15). 16 Chitosan, more than 70%, preferably in the 80-95% range and even more preferably in the 85-91% range. It may have a degree of deacetylation. Typically, in the composition of the present invention The molecular weight of the chitosan used is less than approximately 2,000,000; more typically approximately in the range of 1,000,000-100,000 and more typically around 100,000-300,000 It is within the range of 5%. Chitosan in a 1% acetic acid solution has a concentration lower than 200 cps. It has viscosity. The composition of the present invention includes a solvent acid. The solvent acid dissolves the chitosan solution. It refers to the acid used to prepare it. Solvents include acid, hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, and propionic acid. acid, butyric acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, benzoic acid It may contain acids or a combination of two or more of these. First, the chitosan is dissolved in the acid in the mixing bowl (10) at approximately 150-500 rpm 15 in the range of, preferably, approximately 200-350 rpm, or preferably approximately 200-250 Chitosan solution (12) is prepared by mixing with mixer (11) in rpm range (S1 (step). Chitosan is dissolved in acid for approximately 1-7 hours, preferably around 2-5 hours. Chitosan solution (12) mixed at intervals or preferably at intervals of about 2-3 hours It is prepared. Chitosan is dissolved in acid at a temperature range of approximately 25-60 ℃, preferably around [approximately 0.55-60 ℃]. 25-50 ℃ temperature range or preferably around 25-35 ℃ Chitosan solution (12) is prepared by mixing. The pH of the chitosan solution (12) is generally between approximately 3.5 and 8.0, preferably It is approximately between 3.5 and 6.0, or preferably between 4.5 and 5.5. 17 The chitosan content of the chitosan solution (12) is approximately 0.01% to 10% w / w by weight. within the range of approximately 0.01% to 7% w / w, and also 0.05% to 5%. It could be in the w / w range or approximately 3% w / w. The solvent acid content of the chitosan solution (12) is approximately 0.01% to 5% w / w 5% by weight. within the range of approximately 0.01% to 3% w / w, and also 0.05% to 2%. It can be in the w / w range or approximately 1% w / w. Solution of covalent crosslinking agent (13) is added drop by drop to chitosan solution (12) is added (S2 step). Crosslinking agent (13) succinic acid anhydride, oxalic acid 10 anhydride, malonic acid anhydride, azelaic acid anhydride, glutaric acid anhydride, adipic acid anhydrides of di- or tri-carboxylic acids such as citric acid anhydride and isocitric acid anhydride anhydrides or glycolic acid anhydride, glyoxylic acid anhydride, lactic acid anhydride, anhydrides of hydroxy acids, such as acrylic acid anhydride, or two or more of these. It may include a combination of more than 15. The covalent crosslinking agent (13) content of the chitosan solution (12) is approximately by weight. The w / w content should be between 0.01% and 5%, preferably around 0.01% to 3%. It can also be in the range of 0.05% to 2% w / w, or approximately 1% w / w. Chitosan solution (12) and covalent crosslinking agent (13) solution approximately 150-500 in the rpm range, preferably around 200-350 rpm, or preferably around 200- Chitosan and covalent crosslinking agent solution mixed at 250 rpm (14) It is prepared. Chitosan solution (12) and covalent crosslinking agent (13) solution approximately 1-7 hours between, preferably approximately 2-5 hours, or preferably approximately 2-3 hours chitosan and covalent crosslinking agent solution mixed in between (14) It is prepared. Chitosan solution (12) and covalent crosslinking agent (13) solution at approximately 25-60 ℃ in the temperature range, preferably around 25-50 ℃, or preferably around 18 Chitosan and covalent crosslinking agent mixed at a temperature range of 25-35 ℃. solution (14) is prepared. The pH value of the chitosan and covalent crosslinking agent solution (14) is generally approximately between 4.5 and 8.0, preferably between 5.0 and 7.4, or preferably 5 It is approximately between 5.5 and 6.0. Crosslinker to chitosan and covalent crosslinking agent solution (14) The solution of catalyst (15) is added drop by drop to the hemostatic material solution (16) is prepared (step S3). Crosslinking catalyst (15) iron (III) chloride, iron (II) 10 chloride, copper (II) sulfate, copper (I) sulfate, copper (I) chloride, calcium chloride, calcium acetate, zinc chloride, zinc selenite, sodium selenite, sodium chloride, manganese acetate, manganese chloride, magnesium citrate, magnesium glycinate, magnesium malate, It may contain magnesium chloride or a combination of two or more of these. Crosslinking catalyst (15) content of hemostatic material solution (16) by weight approximately 0.005% to 3% w / w, preferably approximately 0.005% to 2% w / w It can also be in the range of 0.005% to 1% w / w, or approximately 0.5% w / w. Hemostatic material solution (16) is applied at approximately 150-500 rpm, preferably around 20 Mixing at a speed between 200-350 rpm, or preferably around 200-250 rpm. It is prepared. Hemostatic material solution (16) should be applied over approximately 1-7 hours, preferably around 2-5 hours. It is prepared by stirring at intervals of 25 hours, or preferably around 2-3 hours. Hemostatic material solution (16) should be at a temperature range of approximately 25-80 ℃, preferably approximately 25-70 ℃ temperature range or preferably approximately 25-45 ℃ It is prepared by mixing within this range. 19 The pH value of the hemostatic material solution (16) is usually between 5.5 and 8.0 in the range of, preferably, approximately 5.5 to 7.4 or, preferably, approximately 5.5 to 6.0 It is within the range. By adding carrier matrix fibers (17) to the hemostatic material solution (16) 5 Hemostatic material dispersion (18) is prepared (step S4). Carrier matrix fibers (17) cotton, viscose, polyester, polypropylene, polyethylene (spunbond, meltblown, hydrojet, (prickling, SMS) fibers or a combination of two or more thereof or These nanostructures may include a combination of two or more of these. The carrier matrix fiber (17) content of the hemostatic material dispersion (18) by weight approximately 0.1% to 20% w / w, preferably approximately 0.1% to 10% w / w It can be in the range of 0.2% to 2% w / w, or approximately 1% w / w. The hemostatic material dispersion (18) undergoes a freezing step (step S5). 15 The freezing process preferably involves reacting the dispersion of the hemostatic material (18) with acid. an inert metal coated with titanium, chromium, tungsten, vanadium, nickel, or platinum that does not give off by cooling in the mold and raising the dispersion temperature from room temperature to freezing point This is accomplished by gradually lowering the temperature to a final temperature below this. Preferably this The freezing process is carried out on a plate freezer. Plate freezer 20 before contact with the surface of the hemostatic material dispersion (18) and the mold The temperature is close to room temperature. The gradual freezing process of the hemostatic material... its structure, the high porosity of the cross-linked chitosan network matrix (101), macro porous architecture, cohesive properties, capillary effects, absorption It affects its properties, adhesion properties, and mechanical properties. 25 Hemostatic material dispersion (18) takes approximately 5-24 hours, preferably approximately Gradual freezing over a period of 5-12 hours, or preferably around 6-10 hours. It is subjected to the process. 20 Hemostatic material dispersion (18) in the temperature range of approximately -10 to -80 ℃, preferably at a temperature range of approximately -25 to -60 ℃ or preferably approximately -20 to -40 ℃ It undergoes a gradual freezing process within a temperature range. Frozen hemostatic material dispersion is dried to obtain hemostatic material. 5 (S6 step). The drying process involves the sublimation of ice, resulting in the formation of a liquid phase. It must be done without damaging the structural integrity. Therefore, drying The preferred methods for this are freeze-drying or lyophilization. The drying process of the frozen hemostatic material dispersion takes 10 minutes in the lyophilizer. approximately 12-72 hours, preferably approximately 18-36 hours, or preferably Lyophilized hemostatic material (19) was obtained by making the process in approximately 18-24 hours. It is done. The drying process for frozen hemostatic material dispersion is approximately -40 to -80 ℃ 15 in the temperature range, preferably around -40 to -80 ℃, or preferably Lyophilized hemostatic produced at a temperature range of approximately -45 to -60 ℃ material (19) is obtained. The drying process of the frozen hemostatic material dispersion is approximately 0.1 to 20 Pa. in the vacuum range, preferably approximately 0.1 to 10 Pa, or preferably Lyophilized hemostatic material produced in a vacuum range of approximately 0.1 to 5 Pa. (19) is obtained. The preferred drying method in the preparation of hemostatic material is freezing. While drying is involved, other drying techniques can also be used for preparation. Suitable methods are known in the field and include foaming, particle staining method, Sol-Gel. This method may include chemical foaming. The final step in preparing the hemostatic material is pressing. The pressing process takes 30 minutes. It must be done without damaging macro-pores and structural integrity. Hemostatic 21 The material is pressed using steel, chrome, nickel, platinum, or Teflon-coated inert heat. The pressing is done between the plate (20) (step S7). The pressing process for the macroporous hemostatic material takes approximately 5-100 seconds. within a range, preferably approximately 5-50 seconds, or preferably approximately 5-20 seconds. The final product (21) is obtained by making it in the interval. The pressing process of the macroporous hemostatic material is carried out at a temperature of approximately 40 to 130 ℃. in the range, preferably at a temperature of approximately 50 to 100 ℃, or preferably around 70 The final product (21) is obtained by making it in the temperature range of 90 ℃. 10 The pressing process for macroporous hemostatic material is carried out at approximately 10 to 200 bar pressure. in the range, preferably at a pressure range of approximately 20 to 150 bar, or preferably approximately 20 The final product (21) is obtained by making it in the pressure range of 50 bar (S8 step). Hemostatic material (100) if necessary or desired, known techniques in the field It can be sterilized using [method]. The hemostatic material (100) that is the subject of the present invention, when applied to the bleeding area, both Rapid and effective hemostasis through the combined action of both physical and biochemical mechanisms. 20 It provides three macroporous (103) cross-linked and interconnected by covalent bonds. Thanks to a three-dimensional chitosan network (101), capillary action immediately after contact with blood (106) By means of the effect, blood (106) is drawn into the material rapidly. When hemostatic material (100) comes into contact with blood (106), it exerts a strong force on the tissue surface. It seals by adhering to the skin and by causing swelling or expansion in response to blood flow. 25 After the blood (106) is transported into the material, erythrocytes (107) and platelets (108) and plasma proteins (109) penetrate into the porous structure. The pores (103) Thanks to their interconnectedness, blood components do not remain only on the surface, but also on the same In time, it distributes homogeneously throughout the entire volume of the material. During this process, 30 Electrostatic interactions occur between the cationic structure of chitosan and blood cells, and 22 The clotting process is accelerated. At the same time, platelet (108) activation is supported and Fibrin formation is stimulated. One of the most important technical implications of the invention is that the resulting clot is only on the surface. not remaining, on the contrary, into the three-dimensional macroporous network of the material (101, 103) 5 It is the physical retention of this structure by progressing. Fibrin fibers (110) and cellular components, pore walls (105) and cross-linked polymer network (101) By gripping, it creates a three-dimensional mechanical locking mechanism. This mechanical locking mechanism... Thanks to this, the clot does not dislodge under the influence of external forces and blood flow; high Even in cases of pressurized bleeding, clot integrity is preserved and the risk of rebleeding is significant. It decreases to a certain extent. In addition, the covalently cross-linked chitosan network (101) is structural of the material. It preserves its integrity and prevents the clot from dissolving when it comes into contact with blood (106). It contributes to its stabilization. Controlled pore size and interconnected pores 15 Thanks to its architecture (103), the material flows through the capillary pathways (104) of the blood (106). It enables its directed transport and local concentration. This accelerates the coagulation process while also breaking down the internal structure of the material. It increases cohesion. Thus, fluid management is effectively ensured, and the blood (106) is rapidly Absorption prevents excessive fluid accumulation and creates an optimal environment for clot formation. is created. As a result of this multiple mechanism of action, a stabilized blood clot (111) is obtained. by using hemostatic systems that rely solely on chemical or biological effects Compared to others, a faster, more stable and more reliable hemostasis is achieved. 25 Laboratory Tests Pro-coagulant capability of hemostatic material (100) Blood coagulation index (BCI) test This was determined using... A whole blood sample taken from a human was placed in a citrate tube for 5 minutes and 30 seconds. It was placed in an incubator at 37 °C throughout. A 50 µL blood sample was taken for an experiment. It was placed in a tube and 10 mg of hemostatic material was added to it. At 37 °C, 1, 2, 23 It was incubated for 3, 4, and 5 minutes. 10 mL of distilled water was added and gently rinsed. The mixture was shaken. Then, measurements were taken at 540 nm using a UV-Vis spectrophotometer. As a negative control group, 50 μL of anticoagulated blood was mixed in 10 mL of deionized water. BCI value was calculated according to the following equation. % BCI=[(In-Io) / (Ir-Io)]x100 Here, In is the absorbance of the sample, Ir is the absorbance of the negative control, and Io is the absorbance of the deionized water. It is absorbance. Blood clotting (BCI) levels measure the amount of unclogged free hemoglobin. This reflects and the lower it is, the less effective the clotting effect of the blood-stopping material will be. This shows how good it is. In hemostatic material, the BCI is 4.98% at 1 minute. The BCI value was determined to be 0.40% at 5 minutes. Low BCI values indicate rapid clotting. This indicates that it started and stabilized quickly. Also, a low BCI of 15. These values indicate the strong adhesion of blood cells to the material. is doing. Clot formation percentages support the BCI findings. In hemostatic material 1. and High and consistent values between 95.02% and 99.60% during the 5-minute interval indicate a strong 20-minute trend. This shows that a fibrin network has formed. These results indicate that the hemostatic material is both fast and effective. It has been shown to have a highly efficient clotting mechanism. (Figures 3A-3B). High adhesion capacity with blood, clot stability in hemostatic materials, and 25% adhesion to tissue. This is a critical factor that directly affects adhesion performance. In the present invention, Upon examining the digital photographs from the BCI study (not shown in the figures), The hemostatic material not only causes rapid clotting but also has a pronounced effect. It appears that erythrocytes exhibit bioadhesion capacity from the very first minute. By adhering to the surface and forming a localized and compact structure, the material's blood components 30 This shows that it interacts strongly with the upper phase (water phase), which remains clear even in the first minute. The presence of free hemoglobin in the environment, and the clot being hemostatic, indicates that no free hemoglobin is present. 24 This suggests that it formed integrated into the surface of the material. Further on... The clot does not shift within minutes and remains attached to the surface, the fibrin network to the surface This indicates that it exhibits adhesion and is mechanically stable. This situation, The hemostatic material adheres to the bleeding site, forming an effective barrier. This indicates its potential. 5 Hemolysis Test Hemolysis occurs when red blood cells (RBCs) lose their membrane integrity. It causes hemoglobin (Hb) to leak into the blood plasma. In vitro hemolysis test, 10 To understand the interaction of materials with RBCs, blood compatibility is important. It is a fundamental method that enables evaluation. Hemolysis rate, on the other hand, is a blood compatibility test. This is the most important parameter. Hemolysis rate for biocompatible materials GB / T16886.4- According to the 2003 standard, it should be below 5%. Blood in hemostats Compatibility assessment is crucial and includes evaluating the risk of thrombosis, immune responses, and 15 It affects blood-related complications. The rate of hemolysis of the hemostatic material varies depending on the hemocytes incubated with the samples. Absorbance was measured using their absorbances. Whole blood sample at a 9:1 ratio: whole blood:3.8% It was anticoagulated with sodium citrate. Then 20 ml of normal saline was administered. Diluted. 5 mg hemostatic material sample in 1 mL of normal saline at 37 °C. It was incubated for 2 hours. Then it was added to a hemostatic material suspension. 100 μL of diluted blood is added to the suspension and incubated in a shaking incubator at 37 °C for 1 hour. It was further incubated. Then, the supernatant was centrifuged at 3000 rpm for 10 minutes. The absorbance of the supernatant was measured as 25 at 540 nm using a UV-vis spectrophotometer. It has been read. The hemolysis rate was calculated from the following equation. %Hemolysis= [(ODsample-ODnegative) / ODpositive-ODnegative)]x100 When hemolysis results are evaluated within the framework of international standards, hemostatic 30 The material was determined to have a hemolysis rate of 1.40%. GB / T16886.4-2003 According to the standard, it is seen to be in the non-hemolytic class (<2%). This situation, The material caused minimal damage to the erythrocyte membrane and was compatible with blood. This shows that it exhibits a profile. As a result, the hemostatic material has a low profile. Maintaining biocompatibility with the level of hemolysis, along with high hemostatic efficacy. This shows that it offers a safe blood-material interaction. Blood absorption test Hematopoietic material samples of mg were immersed in blood samples for 1 minute. Their weights were measured and their absorption capacities were determined. In hemostatic materials. High blood absorption leads to increased local factor concentration and increased clotting. It enables acceleration. The current invention has an absorption value of 2303%. High absorption means that blood is rapidly drawn to the surface of the material, preventing clotting. This shows that the factors are concentrated locally. Therefore, in the present invention... The observed low BCI and high clotting percentage, along with high absorption capacity. It can be explained in a consistent manner. 15 In vitro erythrocyte aggregation test Whole blood samples are centrifuged at 3000 rpm for 15 minutes to separate blood cells. Platelet-rich plasma (PRP) and RBCs were obtained by this process. The separated cells were 20 It was washed three times with PBS solution. 5 mg hemostatic sponge in a shaking incubator. It was incubated with 100 μL of RBCs and PRP for 30 minutes at 37 °C. After incubation... Then, apply PBS twice to remove any blood cells that haven't adhered to the sample surface. It was gently washed with the solution. Then, it was collected with RBCs and platelets. The samples were fixed with 2.5% glutaraldehyde for 2 hours and then in a 25°C solution for 10 minutes. a series of ethanol solutions (50%, 60%, 70%, 80%, 90%, 100%) are used gradually They were dehydrated. Finally, the dehydrated samples were characterized by SEM.
Claims
26 REQUESTS 1- The invention is a hemostatic material (100), the characteristic of which is; a three-dimensional cross-linked chitosan network (101), Carrier fibers (102) integrated into the chitosan network (101), 5 interconnected macropores (103), Capillary pathways that enable fluid passage between the macropores (103) (104) and pore walls (105) are included. 2- The hemostatic material mentioned in Claim 1 is (100), and its characteristic is that it is a 10 with chitosan. is obtained by cross-linking of the covalent cross-linking agent (13) and word The subject is three-dimensional cross in which the carrier fibers (102) are positioned in an integrated manner. It is characterized by having a linked chitosan network (101). 3- The hemostatic material mentioned in Claim 1 is (100), and its characteristic is; porous dressing, 15 It is characterized by being in the form of porous fiber, porous sponge or porous bandage. It is done. 4- The hemostatic material mentioned in Claim 1 is (100), and its characteristic is that the chitosan in question More than 70%, preferably in the 80-95% range, even more preferably in the 85-91% range 20 It is characterized by having a certain degree of deacetylation. 5- The hemostatic material mentioned in Claim 1 is (100), and its characteristic is that the chitosan in question molecular weight less than approximately 2,000,000, preferably around 1,000,000-100,000 25 characterized by being in the range, more preferably around 100,000-300,000. It is done. 6- The hemostatic material mentioned in Claim 1 is (100), and its characteristic is that the chitosan in question It is characterized by having a viscosity of less than 200 cps in a 1% acetic acid solution. It is done. 30 27 7- The hemostatic material mentioned in Claim 1 is (100), and its characteristic is; the said covalent crosslinking agent (13), succinic acid anhydride, oxalic acid anhydride, malonic acid anhydride, azelaic acid anhydride, glutaric acid anhydride, adipic acid anhydride, citric acid anhydride, isocitric acid anhydride, glycolic acid anhydride, glyoxylic acid anhydride, lactic acid anhydride, acrylic acid anhydride, or a combination of two or more of these 5 It is characterized by its inclusion. 8- The hemostatic material mentioned in Claim 1 is (100), and its characteristic is; cross-linking. three-dimensional cross-linked chitosan network (101) formed in the presence of catalyst (15) It is characterized by having. 10 9- The hemostatic material mentioned in claim 8 is (100), and its characteristic is; the cross in question binder catalyst (15), iron (III) chloride, iron (II) chloride, copper (II) sulfate, copper (I) sulfate, copper (I) chloride, calcium chloride, calcium acetate, zinc chloride, zinc selenite, sodium selenite, sodium chloride, manganese acetate, manganese chloride, magnesium citrate, 15 magnesium glycinate, magnesium malate, magnesium chloride, or two or more of these It is characterized by containing a combination of many of the above. 10- The hemostatic material mentioned in Claim 1 is (100), and its characteristic is; the carrier in question. fibers (102), cotton, viscose, polyester, polypropylene, polyethylene fibers or 20 It is characterized by containing a combination of two or more of these. 11- A method of producing a hemostatic material (100), its characteristic is; Chitosan solution (12) by mixing chitosan in a solvent acid preparation, 25 by adding covalent crosslinking agent (13) to chitosan solution (12) Preparation of chitosan and covalent crosslinking agent solution (14), crosslinking agent solution to chitosan and covalent crosslinking agent (14) by adding catalyst (15) to the hemostatic material solution (16) preparation, 30 addition of carrier matrix fibers (17) to hemostatic material solution (16) by preparing the dispersion of hemostatic material (18), 28 Freezing of the dispersion of hemostatic material (18), Dried and lyophilized dispersion of frozen hemostatic material Obtaining hemostatic material (19), between pressing plates (20) of lyophilized hemostatic material (19) The process involves pressing to obtain the final product (21). 5 12- The production method mentioned in Claim 11 is characterized by the chitosan solution (12), Chitosan is dissolved in the solvent acid at approximately 150-500 rpm, preferably around 200- Mixing at around 350 rpm, more preferably at around 200-250 rpm. It is characterized. 10 13- The production method referred to in Claim 11 or Claim 12, and its characteristic is chitosan. the solution (12) of chitosan in solvent acid for approximately 1-7 hours, preferably by mixing every 2-5 hours, more preferably every 2-3 hours. It is a characterization. 15 14- The production method mentioned in Claim 11 is characterized by the chitosan solution (12), Chitosan is dissolved in solvent acid at a temperature range of approximately 25-60 ℃, preferably around In the temperature range of 25-50 ℃, more preferably around 25-35 ℃. It is characterized by being mixed. 20 15- The production method mentioned in Claim 11 is characterized by the pH of the chitosan solution (12). its value is approximately between 3.5 and 8.0, preferably between approximately 3.5 and 6.0, more It is preferably characterized by being in the range of approximately 4.5 to 5.
5. 16- The production method mentioned in Claim 11 is characterized by the chitosan solution (12) Chitosan content should be approximately 0.01% to 10% by weight, preferably approximately 0.01%. characterized by being in the range of 7%, or more preferably around 0.05% to 5%. It is done. 17- The production method mentioned in Claim 11, characterized by the fact that the solvent acid is hydrochloric acid. acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, butyric acid, 29 monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, benzoic acid, or any of these It is characterized by containing a combination of two or more of these. 18- The production method mentioned in Claim 11 is characterized by covalent cross-linking. 5 characterized by the drop-by-drop addition of the agent (13) to the chitosan solution (12). It is done. 19- The production method mentioned in Claim 11, characterized by; chitosan and covalent cross-linking. the binding agent solution (14) is at approximately 150-500 rpm, preferably around 200- Mixing at around 350 rpm, preferably at around 200-250 rpm. 10 It is characterized by its preparation. 20- The production method mentioned in Claim 11, characterized by its composition: chitosan and covalent cross-linking. The pH of the binding agent solution (14) should be approximately between 4.5 and 8.0, preferably approximately between 5.0 and 7.4, more preferably between 5.5 and 6.0, and 15 It is the characterization of the situation. 21- The production method mentioned in Claim 11, characterized by the use of a cross-linking catalyst. (15) by adding the chitosan and covalent crosslinking agent solution (14) drop by drop. It is characterized. 20 22- The production method mentioned in Claim 11, its characteristic is; hemostatic material. the solution (16) at approximately 150-500 rpm, preferably approximately 200-350 rpm by mixing within this range, more preferably around 200-250 rpm. It is characterized. 25 23- The production method mentioned in Claim 11, its characteristic is; hemostatic material. The pH of the solution (16) should be approximately between 5.5 and 8.0, preferably between approximately 5.5 and It is characterized by being in the 7.4 range, more preferably around the 5.5 to 6.0 range. It is done. 30 24- The production method mentioned in Claim 11, its characteristic is; hemostatic material. The dispersion (18) of the carrier matrix fiber (17) content is approximately 0.1% by weight to In the range of 20%, preferably around 0.1% to 10%, even more preferably around 0.2% It is characterized by being in the range of 2%. 25- The production method mentioned in Claim 11, its characteristic is; hemostatic material. dispersion (18) in approximately 5-24 hours, preferably approximately 5-12 hours subjected to a phased freezing process, preferably over a period of approximately 6-10 hours. It is characterized by being affected by seizures. 26- The manufacturing method referred to in Claim 11 or Claim 25, characterized by its hemostatic properties. material dispersion (18) in a temperature range of approximately -10 to -80 ℃, preferably approximately in the temperature range of -25 to -60 ℃, more preferably approximately -20 to -40 ℃. It is characterized by undergoing a phased freezing process over a certain period. 27- The production method mentioned in Claim 11, characterized by the freezing process, dispersion of hemostatic material (18), titanium, chromium, which do not react with acid, by cooling it in an inert metal mold coated with tungsten, vanadium, nickel, or platinum. It is characterized by its realization. 28- The production method mentioned in Claim 11 is characterized by the freezing process on a plate. It is characterized by the fact that it takes place on the freezer. 29- The production method mentioned in Claim 11 is characterized by; frozen hemostatic The drying process of the material dispersion takes approximately 12-72 hours in the lyophilizer. between, preferably, approximately 18-36 hours, or even more preferably, approximately 18-24 hours It is characterized by being carried out within a certain range. 30- The production method referred to in Claim 11 or Claim 29, characterized by being frozen. The drying process of the hemostatic material dispersion is approximately at a temperature of -40 to -80 ℃ for 30 minutes. carried out within this range, preferably at a temperature range of approximately -45 to -60 ℃. It is the characterization of the situation. 31 31- The production method referred to in Claim 11 or Claim 29, characterized by being frozen. The drying process of the hemostatic material dispersion is carried out under a vacuum of approximately 0.1 to 20 Pa. in the range, preferably a vacuum range of approximately 0.1 to 10 Pa, more preferably approximately 0.1 It is characterized by being performed in a vacuum range of 5 Pa. 32- The production method mentioned in Claim 11 is characterized by; lyophilized hemostatic two pressings of inert hot steel, chrome, nickel, platinum or Teflon coated material (19). It is characterized by being pressed between plates (20). 33- The production method referred to in Claim 11 or Claim 32, characterized by: pressing 10 The process takes approximately 5-100 seconds, preferably approximately 5-50 seconds. more preferably characterized by being performed within approximately 5-20 seconds. It is done. 34- The manufacturing method referred to in Claim 11 or Claim 32, characterized by pressing 15 The process should take place at a temperature range of approximately 40 to 130 ℃, preferably around 50 to 100 ℃. in the temperature range, more preferably around 70 to 90 ℃. It is characterized by its realization. 35- The production method referred to in Claim 11 or Claim 32, characterized by: pressing 20 the process should be carried out at a pressure range of approximately 10 to 200 bar, preferably approximately 20 to 150 bar. in the pressure range, more preferably around 20 to 50 bar. It is characterized by its realization. 30