Multifunctional calcium-phosphorus-based bone wound hemostatic and preparation method thereof

Abstract

The invention relates to a biomedical material, in particular to a multifunctional calcium-phosphorus-based bone wound hemostatic which mainly comprises medical high-purity tricalcium phosphate ceramic particles, monocalcium phosphate powder, disodium dihydrogen pyrophosphate, sodium hydroxide, distilled water and a retarding material, and a first semi-solid and a second semi-solid are prepared from the materials. After mixing, the calcium-phosphorus-based ceramic particles, distilled water and monocalcium phosphate powder form a self-curing reaction for stopping bleeding of bone wounds. In order to adapt to different clinical application scenes, the hemostatic can be designed into two dosage forms, namely a plastic type hemostatic and an injection type hemostatic. The hemostatic provided by the invention has excellent chemical stability and biological safety, strong hemostatic effect, controllable degradation rate, good operability and action convenience, and also has the functions of promoting tissue regeneration, resisting infection and the like.

Description

Technical Field

[0001] The present invention relates to biomedical materials, and particularly to a multifunctional calcium phosphate-based bone wound hemostatic agent and a preparation method thereof, which can achieve hemostasis of bone tissue wounds while accompanying other therapeutic functions and are commonly used in the medical and veterinary fields. Background Art

[0002] Bone wound hemostasis faces many challenges, which mainly stem from the particularity of bone tissue and its complex anatomical structure, specifically manifested in:

[0003] 1. Difficulty in controlling wound bleeding: Due to the abundant blood supply in bone tissue, there are numerous and tiny bleeding points, and traditional mechanical hemostasis or electrocoagulation means are difficult to effectively seal all bleeding points.

[0004] 2. Difficulty in compressing hard bone: Because the bone surface has high hardness and is not easily deformed, mechanical hemostasis (such as gauze compression) is difficult to stably apply on the bone surface, affecting the hemostasis effect.

[0005] 3. Difficulty in controlling bleeding from the medullary cavity: The blood vessels in the medullary cavity are densely distributed. Especially during operations such as bone shaft surgery or joint incision that expose the bone marrow, bleeding is likely to occur. Traditional compression or local electrocoagulation means have limited control over bleeding from the medullary cavity.

[0006] 4. Poor adhesion of chemical hemostatic agents: Chemical hemostatic agents are difficult to stably adhere to the bone surface, are easy to fall off and difficult to form a lasting hemostatic barrier. In addition, some chemical hemostatic agents may inhibit bone healing and are not suitable for bone wounds that require rapid healing.

[0007] 5. Limited surgical field of view in deep operations: In deep operations such as hip joint and spine surgeries, due to anatomical location restrictions, the accuracy and efficiency of hemostasis operations are affected.

[0008] 6. Increased difficulty in special diseases: In cases such as osteoporosis or neoplastic bone destruction, the bone is fragile and the bleeding volume is large, and at the same time, the healing ability is poor, increasing the difficulty of hemostasis and postoperative recovery.

[0009] 7. Difficulty in balancing hemostasis and healing: Some chemical hemostatic agents or electrocoagulation hemostasis methods may affect the activity of bone cells, thereby hindering bone healing. The balance between hemostasis and bone healing is particularly important.

[0010] 8. Minimally invasive surgery restricts hemostasis means: Due to the narrow channel in minimally invasive surgery, traditional hemostasis equipment is difficult to use, restricting the selection and efficiency of hemostasis tools.

[0011] Existing bone wound hemostatic products are diverse, mainly including:

[0012] 1. Bone wax is a traditional mechanical hemostatic material that stops bleeding by physically blocking bone canaliculi. Patent CN1172725C discloses a medical sterile bone wax, which improves the hemostatic effect. However, bone wax may hinder bone tissue regeneration and is not suitable for rapidly healing sites. In addition, inflammatory reactions may occur, prolonging the recovery time.

[0013] 2. Gelatin sponge can absorb blood and expand to form a barrier, suitable for large-area oozing wounds. Patent CN116747344B improves the hemostatic performance, but it is prone to cause compression effects, especially in areas such as the spine.

[0014] 3. Oxidized cellulose has strong adhesion and can quickly form a hemostatic barrier. Patent CN105561379B optimizes its structure, but its acidic environment may affect bone cell proliferation.

[0015] 4. Collagen sponge can promote platelet aggregation and activate coagulation factors to stop bleeding quickly. Patent CN105169461B enhances its biological activity, but its hemostatic effect on large blood vessels is limited.

[0016] 5. Hemostatic powders and granules are usually made of calcium phosphate or hydroxyapatite, with both hemostatic and bone-healing effects. Patent CN111729125B improves the hemostatic performance, but the granules are easily washed away by blood and it is difficult to form a stable barrier in large wounds or high-bleeding areas.

[0017] 6. Fibrin glue mimics the human blood coagulation mechanism and forms a gel to stop bleeding at the wound surface, with good biocompatibility. Patent CN114073788B improves the safety and effect, but it is expensive and its effect on large-area bleeding is limited.

[0018] 7. Polymer hemostatic patches are made of absorbable polymers and form a barrier to achieve hemostasis. Patent CN110483767B improves the hemostatic persistence, but the adhesion on irregular bone surfaces is insufficient and may cause a slight foreign body reaction.

[0019] 8. The new minimally invasive hemostatic materials include injectable hemostatic agents or filling materials, which are suitable for minimally invasive surgeries and have high hemostatic efficiency. However, their cost is relatively high, and their effect in large wounds or severe bleeding is limited. In addition, some materials may have risks of contamination and infection.

[0020] The above products have their respective advantages and limitations. Future research and development directions should pay more attention to the balance between hemostatic effect and bone healing, as well as the convenience of application. Summary of the Invention

[0021] To solve the above technical problems, the present invention provides a multifunctional calcium phosphate-based bone wound hemostatic agent and a preparation method thereof, aiming to address the deficiencies in the prior art, having excellent hemostatic and degradation properties, and being able to promote bone healing at the same time. The tricalcium phosphate bioceramic particles and the calcium dihydrogen phosphate powder form a rapid self-curing reaction through an aqueous medium, achieving excellent chemical stability, good operability, strong hemostatic effect, and controllable degradation rate.

[0022] A multifunctional calcium phosphate-based bone wound hemostatic agent, the main components of which include medical high-purity tricalcium phosphate ceramic particles, calcium dihydrogen phosphate powder, disodium dihydrogen pyrophosphate, sodium hydroxide, distilled water, and a setting retarder, and the first semi-solid and the second semi-solid are prepared using the aforementioned materials. After mixing, the calcium phosphate-based ceramic particles, distilled water, and calcium dihydrogen phosphate powder form a self-curing reaction for bone wound hemostasis. To adapt to different clinical application scenarios, the hemostatic agent is designed into two dosage forms: a plastic form and an injectable form.

[0023] A preparation method of a multifunctional calcium phosphate-based bone wound hemostatic agent includes the following steps:

[0024] S1. Preparation of the materials for the hemostatic agent: including ceramic particles, calcium dihydrogen phosphate, sodium hydroxide, disodium dihydrogen pyrophosphate, water, and a setting retarder;

[0025] The ceramic particles provide calcium ions and a reaction interface for the self-curing reaction of the hemostatic agent. Medical tricalcium phosphate powder with a purity ≥ 95% is used. Ceramics are formed by slip casting and high-temperature sintering, and the crushed particles are screened to obtain the required particle size, usually 10 - 200 μm, and then dried for standby;

[0026] The calcium dihydrogen phosphate is prepared by using commercial or self-made calcium dihydrogen phosphate powder and calibrating the purity for standby;

[0027] The water used is medical-grade purified water or distilled water;

[0028] The disodium dihydrogen pyrophosphate and the sodium hydroxide are soluble materials, and after calibrating the purity, they are formulated into corresponding concentration solutions;

[0029] The setting retarder includes calcium sulfate powder and citric acid solution, and the dosage is determined according to the required setting time;

[0030] Furthermore, when calcium sulfate dissolves in water, it releases calcium ions, which may undergo a competitive reaction with other reactants (such as phosphate groups) in the system, affecting the crystal growth rate of calcium phosphate, thereby indirectly delaying the setting. Adding calcium sulfate promotes the formation of the dicalcium phosphate phase and simultaneously inhibits the rapid formation of hydroxyapatite, regulating the setting time.

[0031] Furthermore, the carboxyl groups of citric acid can form stable complexes with calcium ions, reducing the calcium ion concentration and slowing down the formation of calcium phosphate crystals. The weak acidity of citric acid can lower the pH value of the hemostatic agent, affecting the rate of calcium phosphate precipitation. It can also inhibit the further growth of crystals by adsorbing on the surface of calcium phosphate crystals, thereby prolonging the coagulation time.

[0032] S2. Preparation of the first semi-solid: Using ceramic particles (50 - 80 wt%), sodium hydroxide (0.1 - 1 wt%), disodium dihydrogen pyrophosphate (1 - 5 wt%) and distilled water (10 - 30 wt%), according to the designed quantitative ratio, stir and mix to form the flowable first semi-solid.

[0033] S3. Preparation of the second semi-solid: Using calcium dihydrogen phosphate (20 - 80 wt%), calcium sulfate (10 - 40 wt%) and distilled water (10 - 40 wt%), according to the designed quantitative ratio, stir and mix to form the flowable second semi-solid.

[0034] S4. Filling and sealed packaging: Load the first semi-solid and the second semi-solid into the first loading tube and the second loading tube of the integrated dual-tube injector respectively, cover and seal, and package in the dark.

[0035] S5. Mixing and curing: During use, remove the packaging and cap, and push out part or all of the first semi-solid and the second semi-solid from the loading tube by pushing, and stir and mix the hemostatic agent for bone wound hemostasis.

[0036] During the preparation and use of the hemostatic agent, active ingredients can be appropriately added in powder or liquid form according to the functional and application requirements to optimize its performance and application effect.

[0037] Furthermore, to enhance the hemostatic effect, calcium ions (Ca 2 +) and platelet-activating factor (PAF) and other active ingredients can be added to the hemostatic agent to promote the coagulation reaction.

[0038] Furthermore, to enhance the ability of blood vessel and tissue regeneration, growth factors such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) can be added to the hemostatic agent to promote tissue repair.

[0039] Furthermore, to regulate the degradation rate and osteogenic performance, materials containing magnesium (Mg 2 +) and zinc (Zn 2 +) ions can be added to the hemostatic agent to optimize the biological behavior of the material.

[0040] Furthermore, to endow the hemostatic agent with antibacterial and bacteriostatic functions, copper (Cu2 (+) and gallium (Ga 3 (+)-plasma materials, and antibiotics such as gentamicin and vancomycin can also be added to enhance the anti-infection ability.

[0041] In addition, to reduce the dosage of the retarder and improve the biological activity of the hemostatic agent, the characteristics that the smaller the particle size of the ceramic particles and the larger the specific surface area are utilized. By precisely controlling the particle size and dosage of the ceramic particles, the curing reaction rate can be effectively accelerated, thereby achieving precise control of the curing time.

[0042] The objective of the present invention is to develop a multifunctional calcium phosphate-based bone wound hemostatic agent of brushite to achieve efficient hemostasis for different bone wounds. Its mechanism of action includes:

[0043] 1) Immediate hemostatic barrier effect: The hemostatic agent can quickly penetrate into bone tissue in a semi-solid state, block the bleeding points of capillaries and small blood vessels, and quickly form an immediate hemostatic barrier within seconds.

[0044] 2) Durable hemostatic barrier effect: The hemostatic agent can form a solidified durable hemostatic barrier within dozens of seconds to several minutes during use, firmly and stably block the bleeding points of the bone wound, and can prevent the collapse of the hemostatic barrier caused by blood or liquid, preventing secondary bleeding. This barrier can last for several days to several months and can be degraded and absorbed and disappear.

[0045] 3) Calcium ion coagulation-promoting hemostatic effect: The hemostatic agent is rich in calcium ions and plays a key role in the coagulation cascade reaction:

[0046] a) Activate coagulation factors to accelerate fibrin generation and quickly form a blood clot to seal the wound surface.

[0047] b) Promote platelet aggregation and activation, enhance adhesion to form an initial thrombus.

[0048] c) Participate in the construction of the fibrin network structure, capture platelets and red blood cells to stabilize the blood clot.

[0049] d) Stimulate vascular smooth muscle contraction to reduce bleeding and gain time for the coagulation process.

[0050] e) Promote the proliferation and migration of vascular endothelial cells, accelerate angiogenesis and wound healing.

[0051] Another objective of the present invention is to make full use of the excellent biocompatibility of the calcium phosphate-based material, which can be gradually degraded and absorbed in the body without obvious foreign body reaction. At the same time, the degradation products can regulate the microenvironment pH value and release calcium ions and phosphate ions, which is helpful for blood vessel and bone tissue regeneration. Therefore, the present invention uses a completely inorganic material as the raw material of the hemostatic agent.

[0052] Another object of the present invention is that through the osteoconduction and induction of the calcium phosphate-based inorganic material, the hemostatic agent provides a scaffold for blood vessel and bone tissue regeneration, significantly promoting the healing of bone wounds.

[0053] Another object of the present invention is that the hemostatic agent mainly consists of ceramic particles, thereby optimizing the curing performance, reducing or avoiding the formation of microparticles after curing, and reducing the risk of inflammatory reactions and tissue and organ damage.

[0054] Another object of the present invention is that the hemostatic agent can not only effectively bond comminuted small bone fragments and fracture ends, promoting bone healing, but also treat deep bleeding and bone tissue defects through a minimally invasive channel, expanding its scope of application.

[0055] Another object of the present invention is that by adjusting the composition formula and raw material properties of the hemostatic agent, its curing time can be flexibly adjusted to meet the requirements of different diseases, treatment sites, and treatment methods, improving clinical adaptability.

[0056] Another object of the present invention is that by adopting the loading method of a dual-tube injector, the first semi-solid and the second semi-solid are respectively loaded into different loading tubes, avoiding the curing reaction caused by their contact, so that it can be stored for a long time.

[0057] Another object of the present invention is that according to the usage method, the hemostatic agent is divided into two types: plastic type and injection type. The plastic type hemostatic agent extrudes the first and second semi-solids, and after manual or mechanical stirring, it is directly applied to the bone wound under pressure to achieve the hemostatic effect; the injection type hemostatic agent is uniformly mixed by the spiral structure in the dual-tube injection tube when the first and second semi-solids are extruded, and then directly injected into the treatment site for hemostasis, and can also be used for pressure application.

[0058] Another object of the present invention is that the part of the hemostatic agent that has not been extruded from the loading tube can maintain its original state, and the dosage can be flexibly adjusted according to the size of the wound, supporting repeated use, so that the treatment is faster, simpler, and more accurate.

[0059] Compared with the prior art, the present invention has the following advantages: The present invention provides a multi-purpose calcium phosphate-based bone wound hemostatic agent with both hemostatic and other treatment functions, breaking through the limitation of the traditional single hemostatic function;

[0060] Achieving rapid, efficient, and stable hemostatic efficacy through a hemostatic barrier and procoagulant effect;

[0061] In terms of biosafety and functional adaptation, it has excellent biocompatibility and degradation performance, no obvious foreign body reaction, and the released ions optimize the microenvironment, promoting blood vessel and tissue regeneration;

[0062] The present invention is not limited to hemostasis, but can also be used as a filling material for bone defect repair, assisting wound healing, and achieving an integrated treatment of "hemostasis-repair-regeneration";

[0063] The present invention adopts a dual - syringe design to achieve precise operation and multiple uses, enhancing clinical practicability;

[0064] The optimization of materials and formulations enables its performance to be regulated according to different clinical needs, with a wide range of applications. It achieves a balance in material research and development, hemostatic performance, and biorepair ability, having significant clinical application value and commercialization prospects. Brief Description of the Drawings

[0065] Figure 1 is the preparation flow chart of the multifunctional calcium - phosphate - based bone wound hemostatic agent of the present invention;

[0066] Figure 2 is the schematic diagram of the injection - type loading form and usage method of the hemostatic agent of the present invention. Detailed Embodiments

[0067] As Figure 1 shown, a preparation method of a multifunctional calcium - phosphate - based bone wound hemostatic agent includes the following steps:

[0068] S1. Preparation of materials for the hemostatic agent: including ceramic particles, calcium dihydrogen phosphate, sodium hydroxide, disodium dihydrogen pyrophosphate, water, and a setting retarder;

[0069] The ceramic particles provide calcium ions and a reaction interface for the self - curing reaction of the hemostatic agent. Medical tricalcium phosphate powder with a purity of ≥95% is used, formed into ceramics through slip casting and high - temperature sintering, and the crushed particles are screened to obtain the required particle size, usually 10 - 200 μm, and then dried for standby;

[0070] The calcium dihydrogen phosphate uses commercial or self - made calcium dihydrogen phosphate powder, and is calibrated for purity and then reserved;

[0071] The water uses medical - grade purified water or distilled water;

[0072] The disodium dihydrogen pyrophosphate and the sodium hydroxide are soluble materials, which are prepared into solutions with corresponding concentrations after purity calibration;

[0073] The setting retarder includes calcium sulfate powder and citric acid solution, and the dosage is determined according to the required setting time;

[0074] S2. Preparation of the first semi - solid: Using ceramic particles (50 - 80 wt%), sodium hydroxide (0.1 - 1 wt%), disodium dihydrogen pyrophosphate (1 - 5 wt%), and distilled water (10 - 30 wt%), according to the designed quantitative ratio, stirring and mixing to form the fluid first semi - solid;

[0075] S3. Preparation of the second semi-solid: Using calcium dihydrogen phosphate (20 - 80 wt%), calcium sulfate (10 - 40 wt%) and distilled water (10 - 40 wt%), according to the designed quantitative ratio, stir and mix to form the flowable second semi-solid;

[0076] S4. Filling and sealing packaging: Load the first semi-solid and the second semi-solid into the first loading tube and the second loading tube of the integrated dual-tube injector respectively, cover and seal, and package in the dark;

[0077] S5. Blending, mixing and curing: During use, remove the packaging and cap in S4, push out part or all of the first semi-solid and the second semi-solid from the loading tube by pushing, and form a hemostatic agent through stirring and mixing for bone wound hemostasis.

[0078] When calcium sulfate dissolves in water, it releases calcium ions, which can undergo a competitive reaction with other reactants in the system, affecting the crystal growth rate of calcium phosphate, thereby indirectly delaying coagulation; adding calcium sulfate promotes the formation of the dicalcium phosphate phase and at the same time inhibits the rapid formation of hydroxyapatite, regulating the curing time.

[0079] The carboxyl group of citric acid can form a stable complex with calcium ions, reducing the calcium ion concentration and slowing down the formation of calcium phosphate crystals; the weak acidity of citric acid can reduce the pH value of the hemostatic agent, affecting the calcium phosphate precipitation rate; it can also inhibit the further growth of crystals by adsorbing on the surface of calcium phosphate crystals, thereby prolonging the coagulation time.

[0080] To enhance the hemostatic effect, active ingredients can be added to the hemostatic agent to promote the coagulation reaction. The active ingredients include calcium ions (Ca 2 +) and platelet activating factor (PAF).

[0081] To enhance the ability of blood vessel and tissue regeneration, regeneration-promoting factors can be added to the hemostatic agent to promote regeneration and repair. The regeneration-promoting factors include bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF).

[0082] To regulate the degradation rate and osteogenic performance, materials containing magnesium (Mg 2 +) and zinc (Zn 2 +) ions can be added to the hemostatic agent to optimize the biological behavior of the material.

[0083] To endow the hemostatic agent with antibacterial and bacteriostatic functions, ionic materials or antibiotics can be added to the hemostatic agent to enhance the anti-infection ability. The ionic materials include copper (Cu 2 +) and gallium (Ga 3 +), and the antibiotics include gentamicin and vancomycin.

[0084] The hemostatic agent of the present invention is divided into two types, plastic type and injection type, according to the usage mode:

[0085] The plastic hemostatic agent extrudes the first semi-solid and the second semi-solid, and after manual or mechanical stirring, it is directly applied to the bone wound surface under pressure to achieve the hemostatic effect. This type has a short storage time;

[0086] The injection hemostatic agent is extruded through a double tube, and is uniformly mixed when the first and second semi-solids are extruded. It can be directly mixed and injected into the treatment site for hemostasis, or can be used for pressure application, such as Figure 2 shown. This type of product greatly improves the convenience of use and the accuracy of treatment; specifically, the present invention adopts a double-tube syringe design, with two injection lumen, which respectively accommodate pastes of different components, namely the first semi-solid and the second semi-solid. When in use, the two components are uniformly mixed and extruded through the spiral structure in the injection tube, and the unextruded part remains in its original state, which is convenient for multiple uses;

[0087] The double-tube syringe adopted by the present invention can be realized by using an existing 14ML manual dental AB glue cylinder + small base mixing tube.

[0088] Case 1 of use

[0089] The patient is a 52-year-old female who needs to undergo posterior internal fixation and fusion surgery due to lumbar spondylolisthesis. To improve the success rate of the surgery, the surgeon decided to take autologous bone from both iliac bones and mix it with tricalcium phosphate bioceramic particles for bone grafting. In order to preserve the overall shape of the iliac bone, an iliac crest longitudinal splitting technique was adopted, and the outer part was taken for bone grafting, forming a bone wound surface of more than 10 cm 2 which led to rapid bleeding and a large amount of blood loss. During the operation, a plastic calcium phosphate-based bone wound hemostatic agent was applied under pressure, and the bleeding stopped completely after 1 minute. After the operation, the patient did not have a hematoma or wound bleeding, nor did inflammation or rejection occur, and the wound achieved primary healing. Two months after the operation, the imaging showed that new bone had formed in the bone donor area, and the material density had decreased significantly, indicating that the plastic hemostatic agent not only has a good hemostatic effect on bone wounds, but also can promote bone repair and degradation and absorption.

[0090] Case 2 of use

[0091] The patient is a 76-year-old male who needs open reduction and internal fixation due to comminuted intertrochanteric fracture of the right femur with severe osteoporosis. Due to a large number of fracture fragments and significant bleeding at the wound surface, reduction and fixation during the operation were difficult. An injectable calcium phosphate-based bone wound hemostatic agent was injected into the fracture gap and applied under pressure to the bleeding bone wound surface. After 10 minutes, the bleeding was completely controlled, and the operation proceeded smoothly. No hematoma or wound oozing was observed after the operation, nor were there any inflammatory or rejection reactions, and the wound healed by first intention. Three months after the operation, X-ray films showed fracture healing, a significant reduction in the amount of material, and a significant increase in bone mass. The patient can already walk with a cane and has regained the ability to take care of himself. This shows that the injectable hemostatic agent has significant efficacy and a significant osteogenic effect.

[0092] Case of use three

[0093] The patient is a 12-year-old male who needs to undergo fenestration and debridement for chronic osteomyelitis of the left tibia. During the operation, it was found that the affected bone was hard and bleeding was obvious, seriously affecting the operation. Traditional hemostatic agents are not conducive to the treatment of chronic osteomyelitis. The hemostatic agent added with 1% gentamicin was used during the operation to effectively control the bleeding of the bone wound surface and ensure the smooth completion of the operation. No wound exudation or sinus tract formation was observed after the operation. Imaging follow-up after six months showed that the osteomyelitis was completely controlled, the material was basically degraded, and new bone was formed at the same time, indicating that the hemostatic agent has good anti-infection and bone healing-promoting effects.

[0094] In summary, the present invention has biocompatibility and degradability

[0095] The hemostatic agent uses a calcium phosphate-based material, has excellent biocompatibility, gradually degrades and is absorbed in the body, does not cause foreign body reactions, and its degradation products regulate the local pH value, optimize the microenvironment of blood coagulation and tissue healing, and at the same time promote the regeneration of blood vessels and bone tissue.

[0096] The present invention has osteoconductivity and osteoinductivity

[0097] The hemostatic agent has both hemostatic and repair functions. The ceramic particles provide a growth scaffold for bone tissue, support the formation of new bone and the ingrowth of blood vessels. The calcium and phosphate ions released during the degradation process further promote angiogenesis and bone tissue regeneration, and contribute to the healing of bone wounds.

[0098] The present invention has material optimization and formulation regulation

[0099] By optimizing the calcium-phosphorus ratio, the particle size of ceramic particles, adding bioactive components and adjusting the curing time, the performance of the hemostatic agent is comprehensively improved to meet different clinical needs.

[0100] The present invention has a dual-syringe system

[0101] The present invention adopts a double-tube loading design, which respectively accommodates pastes with different components, namely the first semi-solid and the second semi-solid. During use, the two components are evenly mixed through the spiral structure in the injection tube and then extruded, and solidify within a controllable time. The unextruded part remains in its original state, facilitating multiple uses. This design makes the operation of the hemostatic agent simple, fast and accurate, and the dosage can be flexibly adjusted according to the size of the wound surface.

[0102] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing a multifunctional calcium-phosphorus-based bone wound hemostatic agent, characterized in that: The following steps are involved: S1. Preparation of materials for the hemostatic agent: including ceramic particles, calcium dihydrogen phosphate, sodium hydroxide, disodium dihydrogen pyrophosphate, water and a retarder; The ceramic particles provide calcium ions and reaction interfaces for the self-curing reaction of the hemostatic agent. The medical tricalcium phosphate powder with a purity of ≥95% is used to form ceramics through grouting and high-temperature sintering. The crushed particles are screened to obtain the required particle size, usually 10-200 μm, and dried for use. The monocalcium phosphate is commercial or homemade monocalcium phosphate powder, which is calibrated for purity and ready for use; The water is medical grade purified water or distilled water; The disodium dihydrogen pyrophosphate and the sodium hydroxide are soluble materials, which are prepared into solutions of corresponding concentrations after purity calibration; The retarder includes calcium sulfate powder and citric acid solution, and the dosage is determined according to the required curing time; S2, preparation of the first semi-solid: ceramic particles (50-80wt%), sodium hydroxide (0.1-1wt%), disodium dihydrogen pyrophosphate (1-5wt%) and distilled water (10-30wt%) are used, and the mixture is mixed according to the designed quantitative ratio to form the first semi-solid with fluidity; S3, preparation of the second semi-solid: using calcium dihydrogen phosphate (20-80wt%), calcium sulfate (10-40wt%) and distilled water (10-40wt%), according to the designed quantitative ratio, stirring and mixing to form the second semi-solid with fluidity; S4, filling and sealing packaging: respectively loading the first semi-solid and the second semi-solid into the first loading tube and the second loading tube of the integrated double-tube injector, covering and plugging, and sealing and packaging in a light-proof manner; S5, blending and solidification: during use, the packaging and cover in S4 are removed, and the first semisolid and the second semisolid are partially or completely pushed out of the corresponding loading tube by push injection, and stirred and mixed to form a hemostatic agent for use in bone wound hemostasis.

2. The method for preparing a multifunctional calcium-phosphorus-based bone hemostatic agent according to claim 1, characterized in that: In order to enhance the hemostatic effect, active ingredients can be added to the hemostatic agent to promote the coagulation reaction. The active ingredients include calcium ions (Ca 2 +) and platelet activating factor (PAF).

3. The method for preparing a multifunctional calcium-phosphorus-based bone hemostatic agent according to claim 1, characterized in that: In order to enhance the regeneration capacity of blood vessels and tissues, pro-regeneration factors can be added to promote regeneration and repair. The pro-regeneration factors include bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF).

4. The method for preparing a multifunctional calcium-phosphorus-based bone hemostatic agent according to claim 1, characterized in that: In order to regulate the degradation rate and osteogenic properties of hemostatic agents, magnesium (Mg 2 +) and zinc (Zn 2 +) ions to optimize the biological behavior of the material.

5. The method for preparing a multifunctional calcium-phosphorus-based bone hemostatic agent according to claim 1, characterized in that: In order to give the hemostatic agent antibacterial and antibacterial functions, ionic materials or antibiotics can be added to enhance the anti-infection ability. The ionic materials include copper (Cu 2 +) and gallium (Ga 3 +), the antibiotics include gentamicin and vancomycin.

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