CN112138205A - Bone hemostatic material - Google Patents

Bone hemostatic material Download PDF

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Publication number
CN112138205A
CN112138205A CN201910558727.4A CN201910558727A CN112138205A CN 112138205 A CN112138205 A CN 112138205A CN 201910558727 A CN201910558727 A CN 201910558727A CN 112138205 A CN112138205 A CN 112138205A
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parts
bone
hemostatic material
acetate
bone hemostatic
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徐宝艳
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Shaanxi Bio Regenerative Medicine Co ltd
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Guangdong Bo Yu Regenerative Medicine Co ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • A61L24/0042Materials resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0084Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • A61L24/0015Medicaments; Biocides
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08Polysaccharides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02Inorganic materials
    • A61L27/12Phosphorus-containing materials, e.g. apatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/20Polysaccharides
    • AHUMAN NECESSITIES
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    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112Phosphorus-containing compounds, e.g. phosphates, phosphonates
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    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23Carbohydrates
    • A61L2300/232Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412Tissue-regenerating or healing or proliferative agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45Mixtures of two or more drugs, e.g. synergistic mixtures
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/04Materials for stopping bleeding
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/02Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Abstract

The invention provides a bone hemostatic material, which comprises calcium phosphate, carboxymethyl chitosan and vitamin E acetate. The bone hemostatic material provided by the invention has good adhesion performance and strong hemostatic performance, can obviously promote bone wound repair, can be degraded and absorbed in vivo, and has no immunogenicity and high safety.

Description

Bone hemostatic material
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a bone hemostatic material.
Background
The bleeding is treated in a certain way, so that the outward flowing of blood is quickly stopped, namely the hemostasis process, and the hemostasis process mainly comprises three processes of vasoconstriction, platelet thrombosis and blood coagulation. Hemostasis is an important step of medical treatment, the tissue and organ injury and operation of a patient need to be fully stopped, and rapid hemostasis is needed when sudden trauma occurs in daily life, so that the rapid and effective hemostasis is particularly important to realize in severe war environments and wound emergency treatment in complex emergencies; the hemostasis effect varies from person to person, and is fast, slow and related to blood platelets, under normal conditions, bleeding caused by small blood vessel injury can stop within a few minutes, the phenomenon is called physiological hemostasis, which is one of important protection mechanisms of the organism and is the result of interaction of various factors and mechanisms. The hemostatic function of normal human body can only act on slow and small amount of bleeding, but the action effect is not obvious to various large-scale accidents and hidden bleeding phenomena of rupture of artery bleeding, viscera and the like in surgical operation, and an effective hemostatic material is urgently needed.
Generally, in the case where the blood of a human body is normally coagulated by itself, general tissue wounds can be self-repaired, and epidermal bleeding or venous bleeding can be self-coagulated. However, arterial bleeding, major venous bleeding, severe tissue trauma, or most surgical procedures do not allow the blood to self-coagulate and achieve self-protection in time, and if measures are not taken in time, serious bleeding can occur, and excessive blood loss can be life-threatening. Especially, under various conditions such as battlefields, field sudden accidents, earthquake natural disasters, surgical operations and the like, the use of the quick and effective hemostatic material is particularly important.
Intraoperative wound bleeding is a common surgical problem and can cause blood transfusion and related complications, the operation time is prolonged due to excessive intraoperative bleeding, serious complications such as hemorrhagic shock occur, and even death of a patient is caused. Intraoperative hemorrhage not only causes difficulty for doctors, but also brings undesirable loss to patients. Therefore, the development of hemostatic materials is always one of the major concerns in the fields of clinical medicine, biomaterials, and medical devices.
The bleeding of the cancellous wound surface in the orthopedic operation is not only stopped or the complete hemostasis is difficult, which is a troublesome problem often encountered by craniocerebral surgery, orthopedics and orthopedic surgeons. Cancellous bone is loose in structure and rich in blood circulation, and the wound surface is mostly caused by sharp instrument cutting and violent striking, the bleeding is mostly oozing blood, different from bleeding of other tissues, the self hemostasis by vasoconstriction is difficult, and the complete hemostasis is also difficult to be realized by conventional methods such as electric coagulation, clamping, hemostatic gauze and collagen sponge filling in the operation.
At present, the cancellous bone wound surface hemostasis is carried out on the bone wax which is commonly used clinically, the main components of the cancellous bone wound surface hemostasis are beeswax, sesame oil and the like, the biocompatibility is poor, the cancellous bone wound surface hemostasis is difficult to degrade and absorb by organisms, residues are locally and greatly hindered to bone healing, and the formation of original callus is not facilitated, so that bone non-healing is caused.
Patent CN109675094A discloses an absorbable bone wax with hemostatic function, whose raw material is composed of solid matter and water, the solid matter includes cross-linked hyaluronic acid, calcium phosphate and soluble starch, the weight of the water is 20% -100% of the weight of the solid matter; the weight ratio of the solid is as follows: cross-linked hyaluronic acid: calcium phosphate: the soluble starch is (20-70): (20-50): (0-10). Aiming at the defects of poor biocompatibility, nondegradable property and influence on bone healing of the traditional bone wax, the bone wax can be naturally degraded in vivo without causing related complications of residues in a later period while keeping the good hemostatic effect of the traditional bone wax. However, the system has general adhesiveness on the bone wound surface, and the preparation process is relatively complex, so that the system is inconvenient for clinical use.
Therefore, in the field of medical technology, in order to satisfy clinical convenience, improvement of the performance of the existing bone hemostatic material is still required.
Disclosure of Invention
In view of the above, the present invention aims to provide a bone hemostatic material which has good adhesion and strong hemostatic property and can promote bone wound repair and be degradable and absorbable, and a preparation method thereof.
Therefore, the invention provides the following technical scheme.
In a first aspect, the present invention provides a bone hemostatic material, wherein the bone hemostatic material comprises calcium phosphate, carboxymethyl chitosan, and vitamin E acetate.
In a preferred embodiment, the calcium phosphate is present in an amount of 2 to 40 parts by weight.
In a more preferred embodiment, the weight fraction of the calcium phosphate may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40.
In a preferred embodiment, the carboxymethyl chitosan is present in an amount of 10 to 40 parts by weight.
In a more preferred embodiment, the part by weight of the carboxymethyl chitosan may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40.
In a preferred embodiment, the vitamin E acetate is present in an amount of 10 to 60 parts by weight.
In a more preferred embodiment, the vitamin E acetate may be present in 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 parts by weight.
In a second aspect, the invention provides a bone hemostatic material, wherein the bone hemostatic material comprises, by weight, 2-40 parts of calcium phosphate, 10-40 parts of carboxymethyl chitosan, and 10-60 parts of vitamin E acetate.
In a preferred embodiment, the weight fraction of the calcium phosphate may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.
In a preferred embodiment, the carboxymethyl chitosan may be present in an amount of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 parts by weight.
In a preferred embodiment, the vitamin E acetate may be present in 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 parts by weight.
In a third aspect, the present invention provides a bone hemostatic material, wherein the bone hemostatic material comprises, by weight, 10 parts of calcium phosphate, 30 parts of carboxymethyl chitosan, and 50 parts of vitamin E acetate.
In a fourth aspect, the present invention provides a method for preparing a bone hemostatic material, wherein the method comprises the following steps:
1) uniformly mixing 2-40 parts of calcium phosphate and 10-40 parts of carboxymethyl chitosan;
2) heating 10-60 parts of vitamin E acetate at 30-50 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
In a preferred embodiment, the carboxymethyl chitosan has a particle size of 50 to 200 μm.
In a fifth aspect, there is provided a bone hemostatic product comprising a bone hemostatic material according to the present invention.
In a sixth aspect, a pharmaceutical composition is provided comprising a safe and effective amount of a bone hemostatic material according to the present invention.
In addition, the invention also provides the application of the bone hemostatic material in preparing bone hemostatic products or pharmaceutical compositions.
In the present invention, the particle size of the carboxymethyl chitosan is controlled within the range of 50 to 200 μm. The excessive particle size of the carboxymethyl chitosan can cause uneven mixing of the bone-forming hemostatic material, and the use effect is influenced; the small particle size of carboxymethyl chitosan can cause raw material waste and high cost.
In the present invention, a safe and effective amount refers to an amount of a combination of agents sufficient to significantly induce a positive benefit, preferably a positive hemostatic benefit, including the benefits disclosed herein, either individually or in combination, but low enough to avoid serious side effects, i.e., to provide a reasonable benefit to risk ratio, within the scope of sound judgment of the skilled artisan.
Compared with the prior art, the invention has the beneficial effects that:
the calcium phosphate used in the invention has the similarity of chemical components and crystal structures with inorganic minerals of natural bone tissues, has good biocompatibility and high biological activity, is easy to be accepted by organisms, and can be combined with host bone tissues in a bone nature to form a new bone organism, thereby promoting the repair of damaged parts; the bone repair promoting effect of the over-high content of the calcium phosphate tends to be gentle, and the bone repair effect is not obvious any more; too low a calcium phosphate content is relatively ineffective in bone repair.
The carboxymethyl chitosan used in the invention belongs to absorbable polymer materials, can effectively adsorb redundant water in blood, inhibit the fluidity of the blood, simultaneously can excite a physiological hemostasis mechanism, and plays roles in physical hemostasis and physiological hemostasis, and the addition of the carboxymethyl chitosan can effectively improve the hemostasis performance of the bone hemostasis material. The adhesion of the bone hemostatic material is affected by the excessive content of the carboxymethyl chitosan, so that the adhesion of the bone hemostatic material is reduced; too low a content of carboxymethyl chitosan may decrease hemostatic effect.
The carboxymethyl chitosan and vitamin E acetate system used in the invention can enhance the adhesion of the bone hemostatic material, and is convenient for clinical use; the adhesive performance of the bone hemostatic material is improved to be in a stable trend when the content of the carboxymethyl chitosan and the vitamin E acetate is too high, and the increase of the content is avoided; the effect of improving the adhesive property is weak if the content of carboxymethyl chitosan and vitamin E acetate is too low.
The bone hemostatic material with specific components has better adhesion performance, better hemostatic performance, better bone wound repair performance, difficult shedding, no immunogenicity and high safety by adjusting the proportion of the calcium phosphate, the carboxymethyl chitosan and the vitamin E acetate.
On the other hand, the bone hemostatic material of the invention has simple components and low cost.
On the other hand, the bone hemostatic material of the invention has simple preparation process and is convenient for large-scale production.
Drawings
FIG. 1 is a diagram illustrating the effect of drawing materials after 112 weeks in an experimental bone wound repair;
FIG. 2 is a diagram showing the effect of the comparative example 112 weeks after drawing materials in the bone wound repair experiment;
FIG. 3 is a graph showing the effect of a white control group in a bone wound repair experiment after taking materials for 12 weeks;
FIG. 4 is a graph of the effect of Mirco-CT at 112 weeks in a bone wound repair experiment;
FIG. 5 is a graph of the effect of Mirco-CT at comparative example 112 weeks in a bone wound repair experiment;
FIG. 6 is a graph of the effect of Mirco-CT on the white control group at 12 weeks in the bone wound repair experiment.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that these specific embodiments and examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.
Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.
The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.
Example 1
This example provides a bone hemostatic material comprising, in parts by weight, 2 parts calcium phosphate, 10 parts carboxymethyl chitosan, and 10 parts vitamin E acetate.
The bone hemostatic material of this example was prepared as follows:
1) uniformly mixing 2 parts of calcium phosphate and 10 parts of carboxymethyl chitosan;
2) heating 10 parts of vitamin E acetate at 30 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Example 2
This example provides a bone hemostatic material comprising, in parts by weight, 40 parts calcium phosphate, 40 parts carboxymethyl chitosan, and 60 parts vitamin E acetate.
The bone hemostatic material of this example was prepared as follows:
1) uniformly mixing 40 parts of calcium phosphate and 40 parts of carboxymethyl chitosan;
2) heating 60 parts of vitamin E acetate at 50 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Example 3
This example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium phosphate, 30 parts carboxymethyl chitosan, and 50 parts vitamin E acetate.
The bone hemostatic material of this example was prepared as follows:
1) uniformly mixing 10 parts of calcium phosphate and 30 parts of carboxymethyl chitosan;
2) heating 50 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 1
To further illustrate the beneficial effects of the present invention, comparative example 1 is provided, which is different from example 3 in that: calcium phosphate was replaced by calcium hydrogen phosphate.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium hydrogen phosphate, 30 parts carboxymethyl chitosan, and 50 parts vitamin E acetate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) uniformly mixing 10 parts of calcium hydrophosphate and 30 parts of carboxymethyl chitosan;
2) heating 50 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 2
To further illustrate the beneficial effects of the present invention, comparative example 2 is provided, which comparative example 2 differs from example 3 in that: calcium phosphate was replaced by calcium chloride.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium chloride, 30 parts carboxymethyl chitosan, and 50 parts vitamin E acetate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) uniformly mixing 10 parts of calcium chloride and 30 parts of carboxymethyl chitosan;
2) heating 50 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 3
To further illustrate the beneficial effects of the present invention, comparative example 3 is provided, which comparative example 3 differs from example 3 in that: carboxymethyl chitosan is replaced by chitosan.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium phosphate, 30 parts chitosan, and 50 parts vitamin E acetate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) uniformly mixing 10 parts of calcium phosphate and 30 parts of chitosan;
2) heating 50 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 4
To further illustrate the beneficial effects of the present invention, comparative example 4 is provided, which comparative example 4 differs from example 3 in that: carboxymethyl chitosan is replaced by chitosan acetate.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium phosphate, 30 parts chitosan acetate, and 50 parts vitamin E acetate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) uniformly mixing 10 parts of calcium phosphate and 30 parts of chitosan acetate;
2) heating 50 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 5
To further illustrate the beneficial effects of the present invention, comparative example 5 is provided, which comparative example 5 differs from example 3 in that: replacing carboxymethyl chitosan with sodium carboxymethyl cellulose.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium phosphate, 30 parts sodium carboxymethylcellulose, and 50 parts vitamin E acetate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) uniformly mixing 10 parts of calcium phosphate and 30 parts of sodium carboxymethylcellulose;
2) heating 50 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 6
To further illustrate the beneficial effects of the present invention, comparative example 6 is provided, which comparative example 6 differs from example 3 in that: the vitamin E acetate is replaced by triethyl citrate.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium phosphate, 30 parts carboxymethyl chitosan, and 50 parts triethyl citrate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) uniformly mixing 10 parts of calcium phosphate and 30 parts of carboxymethyl chitosan;
2) heating 50 parts of triethyl citrate at 40 ℃, adding the mixture obtained in the step 1) into heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 7
To further illustrate the beneficial effects of the present invention, comparative example 7 is provided, which comparative example 7 differs from example 3 in that: the weight part of the calcium phosphate is adjusted to 1 part.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 1 part calcium phosphate, 30 parts carboxymethyl chitosan, and 50 parts vitamin E acetate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) 1 part of calcium phosphate and 30 parts of carboxymethyl chitosan are uniformly mixed;
2) heating 50 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 8
To further illustrate the beneficial effects of the present invention, comparative example 8 is provided, which comparative example 8 differs from example 3 in that: the weight portion of carboxymethyl chitosan is adjusted to 9 portions.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium phosphate, 9 parts carboxymethyl chitosan, and 50 parts vitamin E acetate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) uniformly mixing 10 parts of calcium phosphate and 9 parts of carboxymethyl chitosan;
2) heating 50 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 9
To further illustrate the beneficial effects of the present invention, comparative example 9 is provided, which comparative example 9 differs from example 3 in that: the weight portion of the vitamin E acetate is adjusted to 9 portions.
This comparative example provides a bone hemostatic material comprising, in parts by weight, 10 parts calcium phosphate, 30 parts carboxymethyl chitosan, and 9 parts vitamin E acetate.
The preparation method of the bone hemostatic material of the comparative example is as follows:
1) uniformly mixing 10 parts of calcium phosphate and 30 parts of carboxymethyl chitosan;
2) heating 9 parts of vitamin E acetate at 40 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
Comparative example 10
To further illustrate the beneficial effects of the present invention, an absorbable bone wax with hemostatic function is provided, which is prepared by the method of patent CN 109675094A.
Effect verification:
adhesion test:
twenty-six cortical bone rings having a width of 10mm were prepared from bovine femurs, the samples prepared in examples 1 to 3 and comparative examples 1 to 10 were uniformly applied to the surface (area S) of one cortical bone ring, and the other cortical bone ring was brought into contact with the surface of the cortical bone ring thus treated, and pressure was applied to 78N at a rate of 1mm/min for 1 min. Then connecting the two sides of the cortical bone ring with a stretching clamp of a multifunctional mechanical testing machine, pulling the two cortical bone rings apart at the speed of 1mm/min until the bonded part is broken, recording the maximum tensile force F when the bonded part is broken, and calculating the bonding strength (MPa) as F/S. The results of the experiment are shown in table 1.
Hemostasis test:
56 New Zealand rabbits are used as experimental animals and are evenly divided into 14 groups, skin, soft tissues and periosteum are sequentially cut along the midline of the skull of the New Zealand rabbits by a dermatome, and bone defects with the diameter of 5mm and the depth of about 3mm are respectively drilled at the positions 1cm away from the orbit and 1cm away from the ear on the sagittal line. The samples prepared in examples 1 to 3 and comparative examples 1 to 10 were implanted into skull defects of new zealand rabbits, respectively, without using the sample as a blank, the injury site was covered with periosteum covering material by using a piece of sterile gauze of known weight M1, the bleeding at the defect site was observed after 10min, the gauze was removed and weighed as M2, and the bleeding weight (M3) was calculated, wherein M3 is M2-M1. The results of the experiment are shown in table 1.
Bone wound repair experiment:
56 New Zealand rabbits are used as experimental animals and are evenly divided into 14 groups, skin, soft tissues and periosteum are sequentially cut along the midline of the skull of the New Zealand rabbits by a dermatome, and bone defects with the diameter of 5mm and the depth of about 3mm are respectively drilled at the positions 1cm away from the orbit and 1cm away from the ear on the sagittal line. Samples prepared in examples 1 to 3 and comparative examples 1 to 10 were implanted into skull defects of New Zealand rabbits, respectively, without using the sample for a blank control, taking the sample for 12 weeks, and observing the BV/TV (bone volume fraction) results. The results of the experiment are shown in table 1.
TABLE 1
Figure BDA0002107629800000091
Figure BDA0002107629800000101
Likewise, to further illustrate the beneficial effects of the present invention, the following comparative examples are provided:
comparative example 7.1 is provided, which is distinguished from example 3 by the following: the weight portion of the calcium phosphate is 41 portions; the osteogenic hemostatic material prepared by the preparation method is tested according to the test methods of an adhesion experiment, a hemostasis experiment and a bone wound repair experiment. Experimental verification results of the bone hemostatic material prepared in comparative example 7.1 were observed. The results were similar to those in comparative example 7 described above.
Likewise, to further illustrate the beneficial effects of the present invention, the following comparative examples are provided:
comparative example 8.1 is provided, which comparative example 8.1 differs from example 3 in that: the weight portion of the carboxymethyl chitosan is 41 portions;
the osteogenic hemostatic material prepared by the preparation method is tested according to the test methods of an adhesion experiment, a hemostasis experiment and a bone wound repair experiment. Experimental verification results of the bone hemostatic material prepared in comparative example 8.1 were observed. The results were similar to those in comparative example 8 described above.
Likewise, to further illustrate the beneficial effects of the present invention, the following comparative examples are provided:
comparative example 9.1 is provided, which is distinguished from example 3 by the following: the weight portion of the vitamin E acetate is 61 portions.
The osteogenic hemostatic material prepared by the preparation method is tested according to the test methods of an adhesion experiment, a hemostasis experiment and a bone wound repair experiment. Experimental verification results of the bone hemostatic material prepared in comparative example 9.1 were observed. The results were similar to those in comparative example 9 described above.
From the above results, it can be seen that:
the bonding strength of the bone hemostatic material is about 0.17MPa, and the bonding strength of the bone hemostatic material can be improved to about 0.20MPa by further screening the reagent components and the dosage of each reagent component in the bone hemostatic material. Compared with the comparative example, the bone hemostatic material has higher bonding strength and better adhesion performance, and can more effectively prevent the bone material from falling off.
The weight of the exudation blood of the bone hemostatic material is about 0.05g, and the weight of the exudation blood of the bone hemostatic material can be reduced to about 0.01g by further screening the reagent components and the dosage of each reagent component in the bone hemostatic material. Compared with a comparative example, the bone hemostatic material has less exudation blood volume and better hemostatic performance, and can more effectively realize short-term hemostatic effect.
The bone volume fraction of the bone hemostatic material is about 35%, and the bone volume fraction of the bone hemostatic material can be increased to about 45% by further screening the reagent components and the dosage of each reagent component in the bone hemostatic material. Compared with a comparative example, the bone hemostatic material has a larger bone body integral number and a better bone wound repair effect, and can remarkably promote the bone wound repair.
Fig. 1 and 4 are an effect diagram and a Mirco-CT effect diagram after drawing materials for 112 weeks in an example of a bone wound repair experiment, respectively, fig. 2 and 5 are an effect diagram and a Mirco-CT effect diagram after drawing materials for 112 weeks in a comparative example of the bone wound repair experiment, respectively, and fig. 3 and 6 are an effect diagram and a Mirco-CT effect diagram after drawing materials for 12 weeks in a white control group in the bone wound repair experiment, respectively. As can be seen from FIGS. 1-6, after 112 weeks of the example, the bone hemostatic material has been partially degraded, the boundary between the normal bone tissue and the bone hemostatic material is clear, and fibrous tissue grows into the bone defect; after 112 weeks of the comparative example, an annular light-transmitting band exists between the normal bone tissue and the bone hemostatic material, and bone defects are visible; after 12 weeks in the blank control group, the bone defect part was obvious and the bone defect was not completely healed.
It is to be understood that the invention disclosed is not limited to the particular methodology, protocols, and materials described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
Those skilled in the art will also recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (10)

1. A bone hemostatic material, wherein the bone hemostatic material comprises calcium phosphate, carboxymethyl chitosan, and vitamin E acetate.
2. The bone hemostatic material according to claim 1, wherein the calcium phosphate is present in an amount of 2 to 40 parts by weight.
3. The bone hemostatic material of claim 1, wherein the carboxymethyl chitosan is present in an amount of 10 to 40 parts by weight.
4. The bone hemostatic material of claim 1, wherein the vitamin E acetate is 10-60 parts by weight.
5. The bone hemostatic material comprises, by weight, 2-40 parts of calcium phosphate, 10-40 parts of carboxymethyl chitosan and 10-60 parts of vitamin E acetate.
6. The bone hemostatic material comprises, by weight, 10 parts of calcium phosphate, 30 parts of carboxymethyl chitosan and 50 parts of vitamin E acetate.
7. A method for preparing a bone hemostatic material, wherein the method comprises the following steps:
1) uniformly mixing 2-40 parts of calcium phosphate and 10-40 parts of carboxymethyl chitosan;
2) heating 10-60 parts of vitamin E acetate at 30-50 ℃, adding the mixture obtained in the step 1) into the heated vitamin E acetate, and uniformly mixing to obtain a wax/paste material;
3) and cooling the wax/paste material at room temperature, solidifying and molding, packaging and sterilizing to obtain the bone hemostatic material.
8. The bone hemostatic material of any one of claims 1-6, wherein the carboxymethyl chitosan has a particle size of 50-200 μ ι η.
9. A bone hemostatic product, wherein the bone hemostatic product comprises the bone hemostatic material of any one of claims 1-6.
10. Use of the bone hemostatic material of any one of claims 1-6 in the preparation of a bone hemostatic product or pharmaceutical composition.
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CN1856283A (en) * 2003-09-23 2006-11-01 奥斯治疗有限公司 Bioabsorbable putty-like hemostatic implants
CN102579162A (en) * 2003-09-23 2012-07-18 奥索康公司 Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects
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