CN119033991A - Absorbable bone hemostatic material and preparation method thereof - Google Patents
Absorbable bone hemostatic material and preparation method thereof Download PDFInfo
- Publication number
- CN119033991A CN119033991A CN202411188289.4A CN202411188289A CN119033991A CN 119033991 A CN119033991 A CN 119033991A CN 202411188289 A CN202411188289 A CN 202411188289A CN 119033991 A CN119033991 A CN 119033991A
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- China
- Prior art keywords
- absorbable bone
- hemostatic material
- bone hemostatic
- active ester
- folic acid
- Prior art date
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- 239000000463 material Substances 0.000 title claims abstract description 98
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 92
- 230000002439 hemostatic effect Effects 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 56
- 230000033558 biomineral tissue development Effects 0.000 claims abstract description 29
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229960000304 folic acid Drugs 0.000 claims abstract description 28
- 235000019152 folic acid Nutrition 0.000 claims abstract description 28
- 239000011724 folic acid Substances 0.000 claims abstract description 28
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229920001983 poloxamer Polymers 0.000 claims abstract description 19
- 229960000502 poloxamer Drugs 0.000 claims abstract description 19
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 13
- 239000002562 thickening agent Substances 0.000 claims abstract description 13
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000004698 Polyethylene Substances 0.000 claims abstract description 12
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 229920000573 polyethylene Polymers 0.000 claims abstract description 12
- 229960004343 alendronic acid Drugs 0.000 claims abstract description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 14
- 230000009435 amidation Effects 0.000 claims description 12
- 238000007112 amidation reaction Methods 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 239000012530 fluid Substances 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 8
- 239000008055 phosphate buffer solution Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 claims description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229940005550 sodium alginate Drugs 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 3
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 3
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- ADYWUAMYLMRHRL-UHFFFAOYSA-N ethyl n-(2-aminoethyl)carbamate Chemical compound CCOC(=O)NCCN ADYWUAMYLMRHRL-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- RLRHPCKWSXWKBG-UHFFFAOYSA-N n-(2-azaniumylethyl)carbamate Chemical compound NCCNC(O)=O RLRHPCKWSXWKBG-UHFFFAOYSA-N 0.000 claims description 2
- 229940062527 alendronate Drugs 0.000 claims 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 abstract description 5
- 229910001424 calcium ion Inorganic materials 0.000 abstract description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 230000007547 defect Effects 0.000 description 12
- 230000000740 bleeding effect Effects 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000002156 mixing Methods 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
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- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
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- 230000011164 ossification Effects 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
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- 206010028980 Neoplasm Diseases 0.000 description 3
- 241000283977 Oryctolagus Species 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 230000008468 bone growth Effects 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 2
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- 208000006735 Periostitis Diseases 0.000 description 1
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- 238000010521 absorption reaction Methods 0.000 description 1
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- 239000003124 biologic agent Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
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- 239000008280 blood Substances 0.000 description 1
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- 230000017531 blood circulation Effects 0.000 description 1
- 230000010478 bone regeneration Effects 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
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- TZJALUIVHRYQQB-XLRXWWTNSA-N icariin Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-XLRXWWTNSA-N 0.000 description 1
- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 150000002632 lipids Chemical class 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/216—Biologically 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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- A—HUMAN NECESSITIES
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- A61L—METHODS 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A—HUMAN NECESSITIES
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- A—HUMAN NECESSITIES
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- A61L—METHODS 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Veterinary Medicine (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种可吸收骨止血材料及其制备方法，所述材料包括生物矿化材料、泊洛沙姆、钙盐、增稠剂，所述所述生物矿化材料由酰胺化叶酸与接枝阿仑膦酸的活性酯‑聚乙二醇‑活性酯反应得到。本发明的可吸收骨止血材料中生物矿化材料的分子链有亲水段和亲油段，和泊洛沙姆特性相同，可以确保和泊洛沙姆具有良好的相容性，与增稠剂配伍能够增强可吸收骨止血材料的的粘稠度以增强材料的止血性能；此外可吸收骨止血材料在植入人体后，生物矿化材料会吸附钙盐中释放的钙离子，吸附的钙离子又会逐步吸附磷酸根离子，从而形成矿化层，可以用于骨组织自修复的需求。
The invention discloses an absorbable bone hemostatic material and a preparation method thereof, wherein the material comprises a biomineralization material, a poloxamer, a calcium salt, and a thickener, wherein the biomineralization material is obtained by reacting amidated folic acid with an active ester-polyethylene glycol-active ester of grafted alendronic acid. The molecular chain of the biomineralization material in the absorbable bone hemostatic material of the present invention has a hydrophilic segment and a lipophilic segment, which is the same as the poloxamer property, and can ensure good compatibility with the poloxamer, and can enhance the viscosity of the absorbable bone hemostatic material with the thickener to enhance the hemostatic performance of the material; in addition, after the absorbable bone hemostatic material is implanted in the human body, the biomineralization material will absorb the calcium ions released in the calcium salt, and the adsorbed calcium ions will gradually adsorb phosphate ions, thereby forming a mineralized layer, which can be used for the needs of bone tissue self-repair.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to an absorbable bone hemostatic material and a preparation method thereof.
Background
In the operation process of departments such as clinical orthopaedics, neurosurgery, thoracic surgery and the like, bone destruction is often involved, so that cancellous bone bleeding is caused, and especially in osteoporosis patients, the bleeding is more serious because the blood sinuses of the osteoporosis patients are more open, and the conventional gauze, sponge filling and the like often cannot effectively stop bleeding. The bone wound hemostatic product widely used in clinic at present is bone wax which has the advantages of rapid hemostasis and good plasticity, but the main component of the bone wax contains a large amount of lipid which cannot be absorbed by human body, so that foreign body granuloma and the like are easily caused to patients, and the bone wax retained in the body also easily induces the infection of the patients and blocks bone regeneration. The ideal bone wound hemostatic material needs to meet the following requirements of 1, arbitrary molding, filling of various bone wounds, 2, good bone adhesiveness, resistance to blood flow impact, 3, complete absorbability, high biosafety, 4, bone formation by matching of absorption rate, and 5, promotion of bone tissue healing.
Researchers have made some progress in research work on absorbable bone hemostatic materials with artificial polymeric materials, biological agents, and the like. For example, CN111714687A discloses an absorbable bone hemostatic material composed of poloxamer and cellulose derivatives, comprising 10-45 parts of poloxamer and 15-70 parts of cellulose derivatives. The absorbable bone hemostatic material disclosed in the patent can be absorbed in vivo, and does not influence bone healing of bone wound surfaces. However, this material only plays a role in physical tamponade hemostasis, and has no effect of promoting bone healing. CN115887741a discloses an absorbable bone wax containing hydrogel/healing gum/anti-collapsibility gum and a preparation method thereof, wherein the hydrogel is crosslinked by gelatin and carrageenan, and the healing gum mainly comprises beta-tricalcium phosphate, sodium alginate, acetic acid and the like. The absorbable bone wax disclosed by the patent has a certain hemostatic effect and can be absorbed by a human body, however, the bone injury surface of the material has poor adhesiveness and quick degradation. CN115645594a discloses an absorbable bone wax, which comprises a mixed matrix material composed of caprolactone-glycolide copolymer, propiolactone-glycolide copolymer, hydroxyapatite and other components, and antibiotic, water-soluble cellulose and icariine are added. The absorbable bone wax disclosed in the patent has the bone hemostasis effect and can promote bone repair, however, the material has strong granular feel and poor operation hand feeling.
Although a great deal of research work on absorbable bone wound hemostatic materials is currently carried out, the practical problems of poor adhesion, no potential for promoting bone wound healing, poor operation hand feeling and the like still exist. Thus, to further meet clinical needs, there remains a need for further improvements in absorbable bone hemostatic material properties.
Disclosure of Invention
The invention aims to provide an absorbable bone hemostatic material which has good hemostatic performance, can be completely absorbed, does not obstruct osteogenesis and has certain osteogenesis promoting capacity.
In order to achieve the above object, the present invention provides an absorbable bone hemostatic material comprising a biomineralization material, poloxamer, calcium salt, and a thickener;
The biomineralization material is obtained by reacting amidated folic acid with active ester-polyethylene glycol-active ester of grafted alendronic acid.
Further, the preparation method of the biomineralization material comprises the steps of,
Dissolving folic acid in dimethyl sulfoxide, adding a catalyst and an amidation reagent solution, and reacting to obtain amidated folic acid;
respectively dissolving alendronic acid and active ester-polyethylene glycol-active ester in a phosphate buffer solution, mixing for reaction, and then adding amidated folic acid into the mixed solution for continuous reaction to obtain the biomineralization material.
In the present invention, the concentration of the phosphate buffer solution is not strictly limited, and a person skilled in the art can routinely select the phosphate buffer solution, and the preferable concentration range is 0.01 to 0.1mol/L.
Further, the molar ratio of folic acid, catalyst and amidation agent is 1:1-3:1-3;
the catalyst comprises N, N' -carbonyl diimidazole;
The amidation reagent solution is obtained by dissolving an amidation reagent in methylene dichloride, wherein the amidation reagent comprises at least one of N- (2-aminoethyl) carbamic acid tert-butyl ester, N- (2-aminoethyl) carbamic acid and N- (2-aminoethyl) carbamic acid ethyl ester;
the volume ratio of the dimethyl sulfoxide solution of folic acid to the amidation reagent solution is 10-30:1.
Further, the initial concentration of alendronic acid and active ester-polyethylene glycol-active ester in the mixed solution is 0.2-0.3mol/L;
the ratio of the amidated folic acid to the mixed solution is 1-1.5g/L.
Further, when folic acid is dissolved in dimethyl sulfoxide, alkaline substances are added to help dissolution.
Further, the mass ratio of the biomineralization material to the poloxamer to the thickening agent to the calcium salt is 15-25:50-70:10-15:1-5.
Further, the molecular weight of the poloxamer is 2000-3000.
Further, the calcium salt includes at least one of calcium chloride, calcium carbonate, and calcium phosphate.
Further, the thickener comprises at least one of sodium carboxymethylcellulose, sodium alginate and sodium hyaluronate.
The invention also provides a preparation method of the absorbable bone hemostatic material, which comprises the following steps,
Reacting amidated folic acid with active ester-polyethylene glycol-active ester of grafted alendronic acid to prepare biomineralization material;
Mixing the biomineralization material, poloxamer, calcium salt and thickener at 70-95deg.C to obtain fluid, cooling the fluid, and solidifying to obtain absorbable bone hemostatic material.
Compared with the prior art, the invention has the following beneficial effects:
(1) The molecular chain of the biomineralization material has a hydrophilic segment and a lipophilic segment, has the same characteristics as poloxamer, can ensure good compatibility with poloxamer, and can enhance the viscosity of the absorbable bone hemostatic material by being matched with a thickening agent so as to enhance the hemostatic performance of the material.
(2) After the absorbable bone hemostatic material is implanted into a human body, calcium salt can release a large amount of calcium ions to be combined with a biomineralization material, so that phosphate ions are gradually absorbed, a mineralization layer is gradually formed, and the absorbable bone hemostatic material can be used for the self-repairing requirement of bone tissues. When the bone grafting area is a tumor area, the material is coated on the surface of the lesion area after tumor resection, and due to the mineralization of the biological material, when new tumor cells appear in the tumor resection area, a mineralization layer can be formed on the surface of the tumor cells to prevent the transmission of nutrient substances, thereby playing a role in potentially inhibiting the growth of tumors.
(3) After the absorbable bone hemostatic material is implanted into a human body, calcium salt directly releases a large amount of calcium ions to be combined with a thickening agent to generate certain crosslinking effect, so that the hemostatic blocking effect is enhanced.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows an external appearance map of the absorbable bone hemostatic material prepared in example 1;
FIG. 2 shows a photograph of bleeding at a rabbit femoral condyle defect;
FIG. 3 shows a photograph of the absorbable bone hemostatic material of example 1 after hemostasis of a rabbit femoral condyle defect;
FIG. 4 shows a photograph of hematoxylin-eosin stained sections of the absorbable bone hemostatic material prepared in example 1 taken 4 weeks after implantation in a rabbit femoral condyle defect;
fig. 5 shows hematoxylin-eosin stained section pictures of the material taken 4 weeks after implantation of the conventional bone wax of comparative example 1 into the femoral condyle defect of a rabbit.
Detailed Description
The endpoints of the ranges and any values disclosed in the present invention are not limited to the precise range or value, and the range or value should be understood to include values close to the range or value. For numerical ranges, one or more new numerical ranges may be obtained in combination with each other between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point values, and are to be considered as specifically disclosed in the present invention.
The following description of specific embodiments of the present invention and the accompanying drawings will provide a clear and complete description of the technical solutions of embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
A preparation method of absorbable bone hemostatic material comprises the following steps:
S1, folic acid (0.88 g,2 mmol) is dissolved in 20mL of dry dimethyl sulfoxide, 0.8g of re-steamed triethanolamine is added to help dissolution during dissolution, then N, N' -carbonyldiimidazole (0.65 g,4 mmol) is added, stirring is carried out at 25 ℃ for 1h, 1mL of 4mol/L methylene dichloride solution of N- (aminoethyl) carbamic acid tert-butyl ester is added dropwise, stirring is carried out at 25 ℃ for overnight, and then the amidated folic acid is obtained through ethyl acetate recrystallization;
S2, respectively dissolving alendronic acid (34.1 mg,0.105 mol) and active ester-polyethylene glycol-active ester (molecular weight 600,0.1 mol) in 20mL of 0.02mol/L phosphate buffer solution, then mixing and stirring for 5 hours under the condition of 25 ℃ and nitrogen to obtain a mixed solution, then adding 53mg of amidated folic acid into the mixed solution, continuing stirring and reacting for 5 hours under the condition of 25 ℃ and nitrogen, stopping, dialyzing with water for three days (the molecular weight cut-off is 1000 Da), and finally freeze-drying to obtain the biomineralization material;
S3, mixing the biomineralization material, poloxamer with molecular weight of 2500, sodium carboxymethylcellulose and calcium nitrate according to a mass ratio of 18:63:15:4, transferring to a vacuum environment with a temperature of 95 ℃, stirring to obtain uniform fluid, pouring the fluid into a mould, cooling and molding, and taking out to obtain the absorbable bone hemostatic material.
Example 2
A preparation method of absorbable bone hemostatic material comprises the following steps:
S1, folic acid (0.88 g,2 mmol) is dissolved in 20mL of dry dimethyl sulfoxide, 0.8g of re-steamed triethanolamine is added to help dissolution during dissolution, then N, N' -carbonyldiimidazole (0.65 g,4 mmol) is added, stirring is carried out at 25 ℃ for 1h, 1mL of 4mol/L methylene dichloride solution of N- (aminoethyl) carbamic acid tert-butyl ester is added dropwise, stirring is carried out at 25 ℃ for overnight, and then the amidated folic acid is obtained through ethyl acetate recrystallization;
S2, respectively dissolving alendronic acid (34.1 mg,0.105 mol) and active ester-polyethylene glycol-active ester (molecular weight 600,0.1 mol) in 20mL of 0.05mol/L phosphate buffer solution, then mixing and stirring for 5 hours under the condition of 25 ℃ and nitrogen to obtain a mixed solution, then adding 53mg of amidated folic acid into the mixed solution, continuing stirring and reacting for 5 hours under the condition of 25 ℃ and nitrogen, stopping, dialyzing with water for three days (the molecular weight cut-off is 1000 Da), and finally freeze-drying to obtain the biomineralization material;
S3, mixing the biomineralization material, poloxamer with molecular weight of 2500, sodium alginate and calcium chloride according to a mass ratio of 20:65:10:5, transferring to a vacuum environment with a temperature of 95 ℃, stirring to obtain uniform fluid, pouring the fluid into a mould, cooling and molding, and taking out to obtain the absorbable bone hemostatic material.
Example 3
A preparation method of absorbable bone hemostatic material comprises the following steps:
S1, folic acid (0.88 g,2 mmol) is dissolved in 20mL of dry dimethyl sulfoxide, 0.8g of re-steamed triethanolamine is added to help dissolution during dissolution, then N, N' -carbonyldiimidazole (0.65 g,4 mmol) is added, stirring is carried out at 25 ℃ for 1h, 1mL of 4mol/L methylene dichloride solution of N- (aminoethyl) carbamic acid tert-butyl ester is added dropwise, stirring is carried out at 25 ℃ for overnight, and then the amidated folic acid is obtained through ethyl acetate recrystallization;
S2, respectively dissolving alendronic acid (34.1 mg,0.105 mol) and active ester-polyethylene glycol-active ester (molecular weight 600,0.1 mol) in 20mL of 0.05mol/L phosphate buffer solution, then mixing and stirring for 5 hours under the condition of 25 ℃ and nitrogen to obtain a mixed solution, then adding 53mg of amidated folic acid into the mixed solution, continuing stirring and reacting for 5 hours under the condition of 25 ℃ and nitrogen, stopping, dialyzing with water for three days (the molecular weight cut-off is 1000 Da), and finally freeze-drying to obtain the biomineralization material;
S3, mixing the biomineralization material, poloxamer with molecular weight of 2500, sodium hyaluronate, calcium nitrate and calcium chloride according to a mass ratio of 25:60:13:1:1, transferring to a vacuum environment with a temperature of 95 ℃, stirring to obtain uniform fluid, pouring the fluid into a mould, cooling and molding, and taking out to obtain the absorbable bone hemostatic material.
Comparative example
The hemostatic material adopts traditional bone wax.
Test case
Fig. 1 is an external appearance diagram of the absorbable bone hemostatic material prepared in example 1 of the present invention, and it can be seen that the absorbable bone hemostatic material is solid at normal temperature.
A hemostatic test was performed by taking 10 New Zealand rabbits (1.5-2 kg) as experimental animals, anesthetizing with isoflurane, shaving Mao Beipi, cutting skin, soft tissue and periosteum along the long axis of femur on knee joint, and drilling bone defect with diameter of 5mm and depth of about 6mm at the lateral condyle of femur of New Zealand rabbit with a plum blossom drill. The sample prepared in FIG. 1 was implanted into a new Zealand-free femoral condyle defect, and bleeding was immediately observed at the defect.
The absorbable bone hemostatic material prepared in example 1 was implanted into a femoral defect of rabbit, and bleeding was observed. Before the rabbit femoral condyle defect is plugged by using the absorbable bone hemostatic material, the bleeding at the rabbit femoral condyle defect is shown in fig. 2, and the result after hemostasis by using the material of example 1 is shown in fig. 3. It can be seen that the bleeding at the pore of the femoral condyle before plugging is obvious, and the bleeding is stopped immediately after the absorbable bone hemostatic material is smeared, which indicates that the absorbable bone hemostatic material has excellent hemostatic capability. The bone hemostatic capacity of the absorbable bone hemostatic material is mainly beneficial to the good bone adhesiveness and the blocking property of Yu Boluo-mer, the viscosity of the absorbable bone hemostatic material is further improved by adding the thickening agent sodium carboxymethyl cellulose so as to enhance the hemostatic performance of the absorbable bone hemostatic material, and the molecular chain of the biomineralization material has the same characteristics as the poloxamer, so that the hemostatic performance of the material can be further enhanced, the endogenous coagulation is realized, and the hemostasis is finally realized.
The absorbable bone hemostatic material prepared in example 1 of the present invention and the conventional bone wax of comparative example 1 were implanted into a femoral defect, after 4 weeks, new zealand rabbits were sacrificed, their femur was harvested and decalcified, and hematoxylin-eosin staining was performed, and the results of hematoxylin-eosin staining slice pictures are shown in fig. 4 and 5, respectively. Compared with the traditional bone wax group, the bone defect area of the absorbable bone hemostatic material group is obviously reduced, a large amount of new bone is generated, the absorbable bone hemostatic material has good degradation performance and does not obstruct bone growth, and meanwhile, calcium salt adsorbed by the biomineralization material contained in the absorbable bone hemostatic material gradually releases a large amount of calcium ions, so that a mineralized layer is formed, and the regeneration of bone tissues is further promoted. While the conventional bone wax did not see new bone growth and tissue ingrowth, indicating that the conventional bone wax severely inhibited bone growth.
In conclusion, the absorbable bone hemostatic material prepared by the invention can effectively stop bleeding, and compared with the traditional hemostatic material bone wax, the absorbable bone hemostatic material has the advantages of being capable of being rapidly degraded, having certain bone formation promoting capacity, not obstructing new bone healing and the like.
It should be noted that the foregoing description is only a preferred embodiment of the present invention, and although the present invention has been described in detail with reference to the foregoing embodiments, it should be understood that modifications, equivalents, improvements and modifications to the technical solution described in the foregoing embodiments may occur to those skilled in the art, and all modifications, equivalents, and improvements are intended to be included within the spirit and principle of the present invention.
Claims (10)
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