WO2022199051A1 - 一种骨修复材料的制备方法 - Google Patents

一种骨修复材料的制备方法 Download PDF

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WO2022199051A1
WO2022199051A1 PCT/CN2021/130480 CN2021130480W WO2022199051A1 WO 2022199051 A1 WO2022199051 A1 WO 2022199051A1 CN 2021130480 W CN2021130480 W CN 2021130480W WO 2022199051 A1 WO2022199051 A1 WO 2022199051A1
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bone
bovine bone
bovine
collagen
particles
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PCT/CN2021/130480
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English (en)
French (fr)
Inventor
仇志烨
刘洋
李洪景
崔孟龙
宋天喜
朱艳泽
胡艳丽
李良才
朱金亮
何志敏
崔云
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潍坊奥精医学研究有限公司
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Publication of WO2022199051A1 publication Critical patent/WO2022199051A1/zh

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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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A61L27/3645—Connective tissue
    • A61L27/365—Bones
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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
    • A—HUMAN NECESSITIES
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    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking

Definitions

  • the invention relates to the field of bone damage repair, in particular to a preparation method of a bone repair material.
  • Bone injuries are often encountered in orthopedic treatment. There are many reasons for bone damage. Fractures caused by sports and accidents can cause bone damage. Bone damage may also be caused in the process of treating bone tumors and bone diseases. When bone injury occurs, it is necessary to fill the bone tissue defect with a bone repair material, which not only facilitates the fixation of the bone injury site, but also facilitates the regrowth of bone tissue.
  • bone injury repair has gone through different stages such as the use of autologous bone repair materials, the use of allogeneic bone repair materials, the use of xenogeneic bone repair materials, and the use of artificial synthetic materials.
  • Autologous bone repair material is a part of the patient's own bone tissue taken out to repair the defect.
  • the disadvantage of using autologous bone repair material is that the source is insufficient and it is easy to cause complications.
  • Allogeneic bone repair materials use the medically donated bone tissue of other individuals to repair bone defects.
  • the disadvantage of using allogeneic bone repair materials is that they are susceptible to virus infection.
  • the xenogeneic bone repair material is to use a part of bovine bone and pig bone to repair the bone defect.
  • the disadvantage of directly using the xenogeneic bone repair material is that it is easy to cause rejection.
  • Synthetic materials are made of synthetic or naturally occurring macromolecular compounds or inorganic substances into blocks for the repair of bone defects. Due to the advantages of a wide range of materials, no hidden danger of virus infection, and no rejection reaction, artificial synthetic materials have developed rapidly in recent years. However, the existing synthetic materials also have their shortcomings: 1) insufficient strength and toughness, and limited application range; 2) lack of growth factors in synthetic materials, and the speed of bone tissue regeneration and reconstruction is slow.
  • the purpose of the present invention is to provide a method for preparing a bone repair material with high strength and toughness, which has the effect of promoting bone tissue regeneration and reconstruction, in view of the above problems.
  • the present invention comprises the following steps: Step 1, take fresh bovine bones and cut them into small pieces for degreasing and de-antigen treatment to obtain bovine bone particles; Step 2, soak the bovine bone particles in step 1 in bone growth factor - Soak in the collagen mixture, take it out and freeze-dry it; Step 3, take the bovine bone particles in step 1, pulverize, calcine, and pulverize to obtain bovine bone meal; Step 4, take the bovine bone particles in step 1 and the bovine bone meal obtained in step 3 Collagen and nano-silver are mixed and put into a forming mold for freeze-drying to obtain a scaffold material; step 5, cross-linking and modification of the scaffold material obtained in step 4.
  • the step 1 includes: taking fresh beef bones and dividing them into particles of 10 ⁇ 10 ⁇ 10 mm, washing them with warm water and then soaking them in acetone solution for 12 hours, taking out and soaking in ether for 5 hours after the acetone volatilizes to achieve degreasing, degreasing and then placing in acetone.
  • De-antigen was achieved in hydrogen peroxide with a concentration of 8-10% hydrogen peroxide for 5 hours.
  • the bone growth factor in the step 2 is insulin-like growth factor-1, bone morphogenetic protein-2 or fibroblast growth factor-2.
  • the bovine bone meal is 80-120 mesh granules.
  • the collagen in the step 4 is type I collagen, type II collagen or type IM collagen.
  • the step 5 includes: soaking the scaffold material in step 4 with 0.3% glutaraldehyde solution for 5 hours, rinsing with deionized water for 3 times, soaking with 0.3% lysine solution for 3 hours, and rinsing with deionized water 3 times.
  • the beneficial effects of the present invention are as follows: as the skeleton of the bone repair material, the bovine bone granules play a role in increasing the strength, and at the same time, the bovine bone granules contain bone growth factors, which can be slowly released to promote bone growth.
  • Nano-silver is mixed in the production process. To achieve nano-scale metallic silver element, the bone repair material has a bactericidal effect.
  • Step 1 Take the fresh bovine bone and cut it into small pieces for defatting and antigen removing treatment to obtain bovine bone granules.
  • the step specifically includes: taking fresh beef bones and dividing them into 10 ⁇ 10 ⁇ 10 mm particles, washing them with warm water, then soaking them in acetone solution for 12 hours, taking them out and soaking them in ether for 5 hours after the acetone volatilizes to achieve degreasing, degreasing and then placing them in the De-antigen was achieved by keeping 8% hydrogen peroxide in hydrogen peroxide for 5 hours.
  • Step 2 Soak the bovine bone particles in step 1 in the bone growth factor-collagen mixture, take them out, and freeze-dry them; the bone growth factor in this embodiment is insulin-like growth factor-1.
  • Step 3 take the bovine bone particles in step 1, pulverize and calcine, and pulverize to obtain bovine bone meal; the bovine bone meal is 100 mesh particles.
  • Step 4 Take the bovine bone particles in step 1, the bovine bone powder obtained in step 3, mix with collagen and nano-silver, put them into a molding mold and freeze-dry to obtain a scaffold material; the collagen in this embodiment is type I collagen.
  • Step 5 cross-linking and modifying the scaffold material obtained in step 4.
  • This step specifically includes: soaking the scaffold material in step 4 with 0.3% glutaraldehyde solution for 5 hours, rinsing with deionized water for 3 times, soaking with 0.3% lysine solution for 3 hours, and rinsing with deionized water for 3 hours Second-rate.
  • Step 1 Take the fresh bovine bone and cut it into small pieces for defatting and antigen removing treatment to obtain bovine bone granules.
  • the step specifically includes: taking fresh beef bones and dividing them into 10 ⁇ 10 ⁇ 10 mm particles, washing them with warm water, then soaking them in acetone solution for 12 hours, taking them out and soaking them in ether for 5 hours after the acetone volatilizes to achieve degreasing, degreasing and then placing them in the De-antigen was achieved by keeping 9% hydrogen peroxide in hydrogen peroxide for 5 hours.
  • Step 2 Soak the bovine bone particles in step 1 in the bone growth factor-collagen mixture, take them out, and freeze-dry them; the bone growth factor in this embodiment is bone morphogenetic protein-2.
  • Step 3 take the bovine bone particles in step 1, pulverize and calcine, and pulverize to obtain bovine bone meal; the bovine bone meal is 120 mesh particles.
  • Step 4 Mix the bovine bone particles in step 1, the bovine bone powder obtained in step 3 with collagen and nano-silver, and put them into a molding mold to freeze-dry to obtain a scaffold material; the collagen in this embodiment is type II collagen.
  • Step 5 cross-linking and modifying the scaffold material obtained in step 4.
  • This step specifically includes: soaking the scaffold material in step 4 with 0.3% glutaraldehyde solution for 5 hours, rinsing with deionized water for 3 times, soaking with 0.3% lysine solution for 3 hours, and rinsing with deionized water for 3 hours Second-rate.
  • Step 1 Take the fresh bovine bone and cut it into small pieces for defatting and antigen removing treatment to obtain bovine bone granules.
  • the step specifically includes: taking fresh beef bones and dividing them into 10 ⁇ 10 ⁇ 10 mm particles, washing them with warm water, then soaking them in acetone solution for 12 hours, taking them out and soaking them in ether for 5 hours after the acetone volatilizes to achieve degreasing, degreasing and then placing them in the De-antigen was achieved in hydrogen peroxide with a concentration of 10% hydrogen oxide for 5 hours.
  • Step 2 Soak the bovine bone particles in step 1 in the bone growth factor-collagen mixture, take them out, and freeze-dry them; the bone growth factor in this embodiment is fibroblast growth factor-2.
  • Step 3 take the bovine bone particles in step 1, pulverize and calcine them, and pulverize to obtain bovine bone meal; the bovine bone meal is 80 mesh granules.
  • Step 4 Take the bovine bone particles in step 1, the bovine bone powder obtained in step 3, mix with collagen and nano-silver, put them into a molding mold and freeze-dry to obtain a scaffold material; the collagen in this embodiment is IM collagen.
  • Step 5 cross-linking and modifying the scaffold material obtained in step 4.
  • This step specifically includes: soaking the scaffold material in step 4 with 0.3% glutaraldehyde solution for 5 hours, rinsing with deionized water for 3 times, soaking with 0.3% lysine solution for 3 hours, and rinsing with deionized water for 3 hours Second-rate.

Abstract

本发明公开了一种骨修复材料的制备方法，包括如下步骤：步骤1、取新鲜牛骨分割后成小块进行脱脂、去抗原处理得到牛骨颗粒；步骤2、将步骤1中的牛骨颗粒浸泡到骨生长因子-胶原混合物中浸泡后取出后冻干；步骤3、取步骤1中的牛骨颗粒粉碎煅烧后粉碎得到牛骨粉；步骤4、取步骤1中的牛骨颗粒、步骤3中得到的牛骨粉跟胶原、纳米银混合后放入成型模具中冻干成型得到支架材料；步骤5、将步骤4中得到的支架材料交联改性。本发明以牛骨颗粒作为骨修复材料的骨架，起到增加强度的作用，牛骨粉跟胶原的混合物作为填充，再通过交联改性，具有较高的韧性，牛骨颗粒中可缓释骨生长因子，起到促进骨组织再生和重建的作用；填充物中的纳米银具有杀菌的作用。

Description

一种骨修复材料的制备方法 技术领域
本发明涉及骨损伤修复领域，具体的说涉及一种骨修复材料的制备方法。
 背景技术
骨科治疗中常常遇到骨损伤的问题。出现骨损伤的原因有很多，运动、事故等造成的骨折会造成骨损伤，治疗骨肿瘤、骨病等过程中也有可能造成骨损伤。当出现骨损伤时就需要在骨组织缺损的地方填充骨修复材料，这样不仅方便对出现骨损伤的部位进行固定，而且有利于骨组织的重新生长。
随着医疗水平的不断发展，骨损伤修复经历了采用自体骨修复材料、采用异体骨修复材料、采用异种骨修复材料、采用人工合成材料等不同阶段。
自体骨修复材料是从患者自身其他的骨组织上取下一部分用作缺损部位的修复，采用自体骨修复材料的缺点是来源不足、容易引起并发症。异体骨修复材料是利用医疗捐献的其他个体的骨组织用作骨缺损部位的修复，采用异体骨修复材料的缺点是容易感染病毒。异种骨修复材料是取用牛骨、猪骨的一部分用于骨缺损部位的修复，直接采用异种骨修复材料的缺点是容易引发排异反应。
人工合成材料是利用人工合成或天然存在的高分子化合物或无机物制作成块，用作骨缺损部分的修复。由于人工合成材料具有取材广泛、没有感染病毒的隐患、不易出现排异反应等优点，近年来得以快速发展。然而现有的人工合成材料的也有其不足之处：1）强度和韧性不够，应用范围受限；2）人工合成材料中缺少生长因子，骨组织再生和重建的速度较慢。
 技术问题
本发明的目的是针对以上问题提供一种强度和韧性较高并有促进骨组织再生和重建作用的骨修复材料的制备方法。
 技术解决方案
为达到上述目的，本发明包括如下步骤：步骤1、取新鲜牛骨分割后成小块进行脱脂、去抗原处理得到牛骨颗粒；步骤2、将步骤1中的牛骨颗粒浸泡到骨生长因子-胶原混合物中浸泡后取出后冻干；步骤3、取步骤1中的牛骨颗粒粉碎煅烧后粉碎得到牛骨粉；步骤4、取步骤1中的牛骨颗粒、步骤3中得到的牛骨粉跟胶原、纳米银混合后放入成型模具中冻干成型得到支架材料；步骤5、将步骤4中得到的支架材料交联改性。
所述步骤1包括：取新鲜牛骨分割成10×10×10mm的颗粒，温水洗净后放入丙酮液中浸泡12小时，取出待丙酮挥发后用乙醚浸泡5小时实现脱脂，脱脂后置于过氧化氢浓度为8-10％的双氧水中保持5小时实现去抗原。
所述步骤2中的骨生长因子为胰岛素样生长因子-1、骨形态发生蛋白-2或成纤维细胞生长因子-2。
所述步骤3中牛骨粉为80～120目的颗粒。
所述步骤4中的胶原为I 型胶原、II 型胶原或IM 型胶原。
所述步骤5包括：将步骤4中的支架材料用0.3%的戊二醛溶液浸泡5小时，用去离子水冲洗3次，用0.3%的赖氨酸溶液浸泡3小时，用去离子水冲洗3次。
 有益效果
综上所述，本发明的有益效果在于：牛骨颗粒作为骨修复材料的骨架，起到增加强度的作用，同时牛骨颗粒中含有骨生长因子，骨生长因子可缓慢释放，起到促进骨组织再生和重建的作用；牛骨粉跟胶原的混合物作为填充，再通过交联改性，使制作成的骨修复材料具有较高的韧性，制作过程中混合了纳米银，纳米银是将粒径做到纳米级的金属银单质，使骨修复材料具有杀菌的作用。
 本发明的最佳实施方式
实施例1。
步骤1、取新鲜牛骨分割后成小块进行脱脂、去抗原处理得到牛骨颗粒。该步骤具体包括：取新鲜牛骨分割成10×10×10mm的颗粒，温水洗净后放入丙酮液中浸泡12小时，取出待丙酮挥发后用乙醚浸泡5小时实现脱脂，脱脂后置于过氧化氢浓度为8％的双氧水中保持5小时实现去抗原。
步骤2、将步骤1中的牛骨颗粒浸泡到骨生长因子-胶原混合物中浸泡后取出后冻干；本实施例中的骨生长因子为胰岛素样生长因子-1。
步骤3、取步骤1中的牛骨颗粒粉碎煅烧后粉碎得到牛骨粉；牛骨粉为100目的颗粒。
步骤4、取步骤1中的牛骨颗粒、步骤3中得到的牛骨粉跟胶原、纳米银混合后放入成型模具中冻干成型得到支架材料；本实施例中的胶原为I 型胶原。
步骤5、将步骤4中得到的支架材料交联改性。该步骤具体包括：将步骤4中的支架材料用0.3%的戊二醛溶液浸泡5小时，用去离子水冲洗3次，用0.3%的赖氨酸溶液浸泡3小时，用去离子水冲洗3次。
 本发明的实施方式
实施例2。
步骤1、取新鲜牛骨分割后成小块进行脱脂、去抗原处理得到牛骨颗粒。该步骤具体包括：取新鲜牛骨分割成10×10×10mm的颗粒，温水洗净后放入丙酮液中浸泡12小时，取出待丙酮挥发后用乙醚浸泡5小时实现脱脂，脱脂后置于过氧化氢浓度为9％的双氧水中保持5小时实现去抗原。
步骤2、将步骤1中的牛骨颗粒浸泡到骨生长因子-胶原混合物中浸泡后取出后冻干；本实施例中的骨生长因子为骨形态发生蛋白-2。
步骤3、取步骤1中的牛骨颗粒粉碎煅烧后粉碎得到牛骨粉；牛骨粉为120目的颗粒。
步骤4、取步骤1中的牛骨颗粒、步骤3中得到的牛骨粉跟胶原、纳米银混合后放入成型模具中冻干成型得到支架材料；本实施例中的胶原为II 型胶原。
步骤5、将步骤4中得到的支架材料交联改性。该步骤具体包括：将步骤4中的支架材料用0.3%的戊二醛溶液浸泡5小时，用去离子水冲洗3次，用0.3%的赖氨酸溶液浸泡3小时，用去离子水冲洗3次。
实施例3。
步骤1、取新鲜牛骨分割后成小块进行脱脂、去抗原处理得到牛骨颗粒。该步骤具体包括：取新鲜牛骨分割成10×10×10mm的颗粒，温水洗净后放入丙酮液中浸泡12小时，取出待丙酮挥发后用乙醚浸泡5小时实现脱脂，脱脂后置于过氧化氢浓度为10％的双氧水中保持5小时实现去抗原。
步骤2、将步骤1中的牛骨颗粒浸泡到骨生长因子-胶原混合物中浸泡后取出后冻干；本实施例中的骨生长因子为成纤维细胞生长因子-2。
步骤3、取步骤1中的牛骨颗粒粉碎煅烧后粉碎得到牛骨粉；牛骨粉为80目的颗粒。
步骤4、取步骤1中的牛骨颗粒、步骤3中得到的牛骨粉跟胶原、纳米银混合后放入成型模具中冻干成型得到支架材料；本实施例中的胶原为IM 型胶原。
步骤5、将步骤4中得到的支架材料交联改性。该步骤具体包括：将步骤4中的支架材料用0.3%的戊二醛溶液浸泡5小时，用去离子水冲洗3次，用0.3%的赖氨酸溶液浸泡3小时，用去离子水冲洗3次。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和替换，这些改进和替换也应视为本发明的保护范围。

Claims (6)

  1. 一种骨修复材料的制备方法，其特征在于,该骨修复材料的制备方法包括如下步骤：
    步骤1、取新鲜牛骨分割后成小块进行脱脂、去抗原处理得到牛骨颗粒；
    步骤2、将步骤1中的牛骨颗粒浸泡到骨生长因子-胶原混合物中浸泡后取出后冻干；
    步骤3、取步骤1中的牛骨颗粒粉碎煅烧后粉碎得到牛骨粉；
    步骤4、取步骤1中的牛骨颗粒、步骤3中得到的牛骨粉跟胶原、纳米银混合后放入成型模具中冻干成型得到支架材料；
    步骤5、将步骤4中得到的支架材料交联改性。
  2. 根据权利要求1所述的骨修复材料的制备方法，其特征在于，所述步骤1包括：取新鲜牛骨分割成10×10×10mm的颗粒，温水洗净后放入丙酮液中浸泡12小时，取出待丙酮挥发后用乙醚浸泡5小时实现脱脂，脱脂后置于过氧化氢浓度为8-10％的双氧水中保持5小时实现去抗原。
  3. 根据权利要求1所述的骨修复材料的制备方法，其特征在于，所述步骤2中的骨生长因子为胰岛素样生长因子-1、骨形态发生蛋白-2或成纤维细胞生长因子-2。
  4. 根据权利要求1所述的骨修复材料的制备方法，其特征在于，所述步骤3中牛骨粉为80～120目的颗粒。
  5. 根据权利要求1所述的骨修复材料的制备方法，其特征在于，所述步骤4中的胶原为I 型胶原、II 型胶原或IM 型胶原。
  6. 根据权利要求1所述的骨修复材料的制备方法，其特征在于，所述步骤5包括：将步骤4中的支架材料用0.3%的戊二醛溶液浸泡5小时，用去离子水冲洗3次，用0.3%的赖氨酸溶液浸泡3小时，用去离子水冲洗3次。
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CN113546216B (zh) * 2021-07-14 2023-04-25 陕西巨子生物技术有限公司 胶原蛋白膜微裹骨粉复合材料及其制备方法
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