CN116262147A - Silk protein/biological ceramic composite material and preparation method and application thereof - Google Patents
Silk protein/biological ceramic composite material and preparation method and application thereof Download PDFInfo
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- CN116262147A CN116262147A CN202111539106.5A CN202111539106A CN116262147A CN 116262147 A CN116262147 A CN 116262147A CN 202111539106 A CN202111539106 A CN 202111539106A CN 116262147 A CN116262147 A CN 116262147A
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- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 35
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 239000000919 ceramic Substances 0.000 title abstract description 7
- 108010022355 Fibroins Proteins 0.000 claims abstract description 88
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- 239000000843 powder Substances 0.000 claims abstract description 53
- 239000007943 implant Substances 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 31
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- 238000004108 freeze drying Methods 0.000 claims abstract description 8
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- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 24
- 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 22
- 239000001506 calcium phosphate Substances 0.000 claims description 20
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 20
- 239000002245 particle Substances 0.000 claims description 19
- 235000011010 calcium phosphates Nutrition 0.000 claims description 18
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
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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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/10—Ceramics or glasses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
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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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/02—Inorganic materials
- A61L31/026—Ceramic or ceramic-like structures, e.g. glasses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
- A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Life Sciences & Earth Sciences (AREA)
- Oral & Maxillofacial Surgery (AREA)
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- Heart & Thoracic Surgery (AREA)
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Abstract
The invention discloses a silk fibroin/biological ceramic composite material, a preparation method and application thereof, wherein the method comprises the following steps: (1) Freeze-drying and grinding the silk protein solution to obtain silk protein freeze-dried powder; (2) Mixing the silk fibroin freeze-dried powder and the biological ceramic powder so as to obtain mixed powder; (3) And hot-pressing the mixed powder to obtain the silk fibroin/bioceramic composite material. The silk fibroin/bioceramic composite material prepared by the method has good mechanical properties, good biocompatibility and biological absorbability, and good bone conduction and bone induction capability, can be processed into bone implants such as bone nails and vertebral fillers, is used for replacing the currently used metal bone implants and degradable synthetic polymer bone implants, and avoids osteoporosis, possible secondary surgery, adverse immune reaction and the like caused by stress shielding after long-term implantation of the metal bone implants and the degradable synthetic polymer bone implants.
Description
Technical Field
The invention belongs to the technical field of implantable medical devices, and particularly relates to a silk fibroin/bioceramic composite material, and a preparation method and application thereof.
Background
Current orthopedic implant devices are based on metallic materials, such as stainless steel and titanium alloys. Although these materials have excellent mechanical properties, they have a number of clinical drawbacks such as osteoporosis due to stress shielding after long-term implantation, and possible secondary surgery. The research and development of bioabsorbable materials matched with the mechanical properties of natural bones can effectively solve the clinical difficulty. The related research on the biological absorbable orthopedic implant devices at present mainly comprises magnesium alloy, polylactic acid and copolymers thereof, biological ceramics, natural proteins and the like. The metal-based bioabsorbable materials represented by magnesium alloy have unsatisfactory effects in biocompatibility, osteoinductive property and the like, and the degradation of metal in vivo can cause great stress on kidneys. The synthetic polymer-based bioabsorbable materials represented by polylactic acid and its copolymers can overcome many disadvantages of the conventional implant materials, but the degradation products of the materials are acidic, which is unfavorable for new bone growth. Although the bioceramic materials represented by calcium phosphate have good biocompatibility and bone conductivity, the single bioceramic materials have low breaking strength and large brittleness, and are not suitable for bearing parts. And the degradation of the material is mainly physical dissolution, and the degradation rate is generally difficult to control.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. Therefore, the invention aims to provide a silk fibroin/bioceramic composite material, a preparation method and application thereof, and the silk fibroin/bioceramic composite material prepared by the method not only has good mechanical properties, but also has good biocompatibility, biological absorbability and good bone conduction and bone induction capability, and can be processed into bone implants such as bone nails, vertebral body fillers and the like to replace widely used metal bone implants and degradable synthetic polymer bone implants at present, so that osteoporosis, possible secondary surgery, adverse immune reaction and the like caused by stress shielding after long-term implantation of the metal bone implants and the degradable synthetic polymer bone implants are avoided.
In one aspect of the invention, a method of preparing a silk fibroin/bioceramic composite is provided. According to an embodiment of the invention, the method comprises:
(1) Freeze-drying and grinding the silk protein solution to obtain silk protein freeze-dried powder;
(2) Mixing the silk fibroin freeze-dried powder and the bioceramic powder so as to obtain mixed powder;
(3) And hot-pressing the mixed powder to obtain the silk fibroin/bioceramic composite material.
According to the method for preparing the silk fibroin/bioceramic composite material, the silk fibroin/bioceramic composite material prepared by the method has good biological performance (including biocompatibility, biodegradability, bioabsorbable property and the like), so that the silk fibroin/bioceramic composite material can be processed into bone implants such as bone nails, vertebral body fillers and the like to replace the metal bone implants and degradable synthetic polymer bone implants which are widely used at present, and osteoporosis, possible secondary surgery, adverse immune reaction and the like caused by stress shielding after long-term implantation of the metal bone implants and the degradable synthetic polymer bone implants are avoided; meanwhile, the silk fibroin/bioceramic composite material can have the characteristics of a high polymer material and an inorganic material, has excellent mechanical strength, has good bone conduction capacity and bone induction capacity, and can be used for repairing bones of bearing parts. In addition, the preparation method is simple, does not contain any organic solvent, is environment-friendly in processing process, and is suitable for industrial production.
In addition, the method for preparing the silk fibroin/bio-ceramic composite according to the above-described embodiments of the present invention may further have the following additional technical features:
in some embodiments of the invention, in step (1), the particle size of the silk fibroin lyophilized powder obtained by milling is 10nm to 200 μm, preferably 20nm to 500nm.
In some embodiments of the invention, in step (1), the silk protein solution is freeze-dried in a specific process of:
freezing the silk protein solution at the temperature of-20 ℃ to-196 ℃ for 5-360min; and (3) placing the frozen silk protein solution in a freeze dryer for freeze drying for 2-5 days.
In some embodiments of the invention, the mass fraction of silk proteins in the silk protein solution is 0.1-40%.
In some embodiments of the invention, in step (1), the silk protein solution is prepared by:
a) Placing natural silkworm cocoons into sodium carbonate aqueous solution or bicarbonate aqueous solution, and heating and boiling to degumm so as to obtain degummed silk;
b) Mixing the degummed silk with a lithium bromide aqueous solution, and dissolving to obtain a silk protein lithium bromide solution;
c) Dialyzing the silk fibroin lithium bromide solution to obtain a crude silk fibroin solution;
d) And (3) centrifuging the crude silk protein solution, and collecting supernatant to obtain the silk protein solution.
In some embodiments of the invention, in step (2), the mass ratio of the silk fibroin lyophilized powder to the bioceramic powder is 1: (0.01-3.00), preferably (9:1) - (1:3).
In some embodiments of the invention, in step (2), the bioceramic powder has a particle size of 10nm to 200 μm, preferably 20nm to 500nm.
In some embodiments of the invention, the bioceramic powder is selected from at least one of calcium phosphate powder and hydroxyapatite powder.
In some embodiments of the invention, in step (3), the hot pressing is performed at a temperature of 50-200 ℃ and a pressure of 1-1000MPa, and the hot pressing is performed for a time of 15-360min.
In a second aspect of the invention, the invention provides a silk fibroin/bioceramic composite. According to an embodiment of the invention, the silk fibroin/bioceramic composite is prepared by the method described in the above embodiment. Therefore, the silk fibroin/bioceramic composite material has good biological performance (including biocompatibility, biodegradability, bioabsorbable property and the like), so that the silk fibroin/bioceramic composite material can be processed into bone implants such as bone nails, vertebral body fillers and the like to replace the metal bone implants and degradable synthetic polymer bone implants widely used at present, and osteoporosis, possible secondary surgery, adverse immune reaction and the like caused by stress shielding after long-term implantation of the metal bone implants and the degradable synthetic polymer bone implants are avoided; meanwhile, the silk fibroin/bioceramic composite material can have the characteristics of a high polymer material and an inorganic material, has excellent mechanical strength, has good bone conduction capacity and bone induction capacity, and can be used for repairing bones of bearing parts.
In a third aspect of the invention, the invention provides a silk fibroin/bioceramic composite orthopaedic implant, which is prepared by adopting the silk fibroin/bioceramic composite material as a production raw material. Therefore, the silk fibroin/bioceramic composite bone nail has good mechanical properties and excellent biological properties, including biocompatibility, biodegradability, biological absorbability, bone conduction capacity, bone induction capacity and the like, can replace the metal orthopedic implant and the degradable synthetic polymer orthopedic implant which are widely used at present, and avoids osteoporosis, possible secondary operation, adverse immune reaction and the like caused by stress shielding after long-term implantation of the metal orthopedic implant and the degradable synthetic polymer orthopedic implant.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a flow chart of a method of preparing a silk fibroin/bioceramic composite according to one embodiment of the present invention;
FIG. 2 is an infrared spectrum of the silk fibroin lyophilized powder prepared in example 1 of the present invention;
FIG. 3 is a sectional scanning transmission electron microscope image of the silk fibroin/calcium phosphate composite material prepared in example 1 of the present invention;
FIG. 4 is a physical view of the silk fibroin/calcium phosphate composite bone nail prepared in example 1 of the present invention;
FIG. 5 is an infrared spectrum of a silk fibroin/calcium phosphate composite bone screw prepared in example 1 of the present invention;
FIG. 6 is a physical diagram of a silk fibroin/hydroxyapatite composite interface screw prepared in example 2 of the present invention;
FIG. 7 is an infrared spectrum of a silk fibroin/hydroxyapatite composite bone screw prepared in example 2 of the present invention.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings. The embodiments described below by referring to the drawings are illustrative and intended to explain the present invention and should not be construed as limiting the invention.
In one aspect of the invention, a method of preparing a silk fibroin/bioceramic composite is provided. According to an embodiment of the present invention, referring to fig. 1, the method includes:
s100: freeze drying silk protein solution, grinding
In this step, the silk protein solution is freeze-dried and ground to obtain silk protein freeze-dried powder. Silk protein as one kind of natural protein material has excellent mechanical performance, physical and chemical properties, excellent biocompatibility, high biological absorbability, capacity of promoting bone formation, etc. The purpose of the above-mentioned freeze-drying is to obtain amorphous powders with a low content of beta-sheet structure.
According to one embodiment of the invention, the silk protein solution is freeze-dried by the following steps: freezing the silk protein solution in a refrigerator or liquid nitrogen at-20 ℃ to-196 ℃ for 5-360min (for example 5/10/50/100/150/200/250/300/360min and the like); the silk fibroin solution after freezing is placed in a freeze dryer for freeze drying for 2-5 days (e.g., 2/3/4/5 days, etc.). Therefore, the silk fibroin freeze-dried powder prepared by adopting the conditions has a low-content beta-sheet structure, the particle size is uniform, and the particle diameter is in the range of 10nm-200 mu m.
According to a further embodiment of the invention, the mass fraction of silk proteins in the silk protein solution is 0.1-40% (e.g. 0.1/1/10/20/30/40%, etc.), whereby the silk protein solution in this mass fraction range further ensures that the prepared silk protein powder structure is controllable, with a low content of beta-sheet structure.
According to another embodiment of the invention, the preparation method of the silk fibroin solution comprises the following steps: a) Placing natural silk cocoons into a carbonate water solution or a bicarbonate water solution, heating and boiling to degumm, rinsing degummed silk and drying to obtain degummed silk; b) Mixing the degummed silk with a lithium bromide aqueous solution, and dissolving to obtain a silk protein lithium bromide solution; c) Dialyzing the silk fibroin lithium bromide solution, wherein the dialysate is ultrapure water, and removing lithium bromide in the solution so as to obtain a crude silk fibroin solution; d) And (3) carrying out centrifugal separation and purification on the crude silk protein solution, and collecting supernatant to obtain the silk protein solution. Therefore, the silk fibroin solution prepared by the method has stable quality and adjustable concentration.
According to a further embodiment of the invention, the particle size of the silk fibroin freeze-dried powder obtained by grinding is 10nm-200 μm, such as 10/100/200/400/600/800nm, 1/10/50/100/150/200 μm and the like, preferably 20nm-500nm, thereby limiting the particle size of the silk fibroin freeze-dried powder within the above range, and further ensuring better effect of the subsequent hot pressing step. The inventor finds that if the particle size of the silk fibroin freeze-dried powder is too large, the hot-pressing effect is poor, and the silk fibroin particles which are not plasticized appear; if the particle size is too small, the agglomeration of particles may be serious.
According to a further embodiment of the invention, the grinding is performed by: the freeze-dried silk protein powder is placed in a grinder, the grinding time is 1-10 min (such as 1/2/4/6/8/10min, etc.), the rotating speed is 5000-30000 r/min (such as 5000/10000/15000/20000/25000/30000r/min, etc.), and the silk protein freeze-dried powder with proper particle size is obtained.
S200: mixing the silk fibroin freeze-dried powder and the bioceramic powder
In this step, the silk fibroin lyophilized powder and the bioceramic powder are mixed to obtain a mixed powder.
According to a further specific embodiment of the invention, the mass ratio of the silk fibroin lyophilized powder to the bioceramic powder is 1: (0.01-3.00), for example 1:0.01/0.05/0.1/1/1.5/2/2.5/3, etc., preferably (9:1) - (1:3), whereby the mass ratio of the silk fibroin lyophilized powder to the bioceramic powder is limited within the above range, and a bone repair material excellent in both mechanical properties and degradation properties can be obtained. The inventors found that if the content of the bio-ceramic powder is too small, the mechanical properties of the composite material are affected, and if the content of the bio-ceramic powder is too large, the hot pressing properties of the composite material are poor. The mechanical strength and degradation performance of the silk fibroin/bioceramic composite material can be regulated and controlled by changing the mass ratio of silk fibroin to bioceramic.
According to a further embodiment of the invention, the particle size of the bioceramic powder is between 10nm and 200 μm, for example 10/100/200/400/600/800nm, 1/10/50/100/150/200 μm, etc., preferably between 20nm and 500nm, whereby the particle size of the bioceramic powder is limited to the above-mentioned range, further ensuring a good effect of the subsequent hot pressing step.
In the embodiment of the present invention, the specific kind of the bioceramic powder is not particularly limited, and may be arbitrarily selected according to actual needs by those skilled in the art, and as a preferred embodiment, the bioceramic powder is selected from at least one of calcium phosphate powder and hydroxyapatite powder.
S300: hot pressing the mixed powder
In the step, the mixed powder is put into a mould for hot pressing, and the silk fibroin-biological ceramic composite material is obtained after demoulding. The hot pressing causes the amorphous silk proteins to be largely converted into beta-sheet structures. The high temperature and high pressure promote the transformation of the structure of the silk fibroin on one hand and enable the bioceramic powder to be closely distributed in the silk fibroin on the other hand.
According to another specific embodiment of the present invention, the hot pressing temperature is 50-200 ℃ (for example 50/100/150/200 ℃ and the like), the pressure is 1-1000MPa (for example 1/10/100/200/400/600/800/1000MPa and the like), the time is 15-360min (for example 15/50/100/200/300/360min and the like), and the hot pressing condition is limited in the above range, so that the silk protein-biological ceramic composite material with excellent mechanical property and degradation property can be obtained. The inventor finds that if the hot pressing temperature is too low, the material plasticization is incomplete, so that the mechanical property of the composite material is poor, and if the hot pressing temperature is too high, the thermal degradation of the composite material is caused, so that the mechanical property is poor; if the pressure is too small, incomplete plasticization of the material is caused, so that the mechanical property of the composite material is deteriorated, and if the pressure is too large, the degradation property of the composite material is deteriorated; if the time is too short, incomplete plasticization of the material is caused, so that the mechanical property of the composite material is deteriorated, and if the time is too long, the thermal degradation of the composite material is caused, so that the mechanical property is deteriorated.
According to a further specific embodiment of the invention, the silk fibroin/bioceramic composite is in the shape of a square bar or a cylindrical bar, wherein the silk fibroin/bioceramic bulk of the square bar is 0.5-100mm in length, 0.5-100mm in width and 0.5-100mm in thickness; the diameter of the fibroin/bioceramic of the cylindrical bar is 0.5-100mm, and the length is 1-500mm.
According to the method for preparing the silk fibroin/bioceramic composite material, the silk fibroin/bioceramic composite material prepared by the method has good biological performance (including biocompatibility, biodegradability, bioabsorbable property and the like), so that the silk fibroin/bioceramic composite material can be processed into bone implants such as bone nails, vertebral body fillers and the like to replace the metal bone implants and degradable synthetic polymer bone implants which are widely used at present, and osteoporosis, possible secondary surgery, adverse immune reaction and the like caused by stress shielding after long-term implantation of the metal bone implants and the degradable synthetic polymer bone implants are avoided; meanwhile, the silk fibroin/bioceramic composite material can have the characteristics of a high polymer material and an inorganic material, has excellent mechanical strength, has good bone conduction capacity and bone induction capacity, and can be used for repairing bones of bearing parts. In addition, the preparation method is simple, does not contain any organic solvent, is environment-friendly in processing process, and is suitable for industrial production.
In a second aspect of the invention, the invention provides a silk fibroin/bioceramic composite. According to an embodiment of the invention, the silk fibroin/bioceramic composite is prepared by the method described in the above embodiment. Therefore, the silk fibroin/bioceramic composite material has good biological performance (including biocompatibility, biodegradability, bioabsorbable property and the like), so that the silk fibroin/bioceramic composite material can be processed into bone implants such as bone nails, vertebral body fillers and the like to replace the metal bone implants and degradable synthetic polymer bone implants widely used at present, and osteoporosis, possible secondary surgery, adverse immune reaction and the like caused by stress shielding after long-term implantation of the metal bone implants and the degradable synthetic polymer bone implants are avoided; meanwhile, the silk fibroin/bioceramic composite material can have the characteristics of a high polymer material and an inorganic material, has excellent mechanical strength, has good bone conduction capacity and bone induction capacity, and can be used for repairing bones of bearing parts.
In a third aspect of the invention, the invention provides a silk fibroin/bioceramic composite orthopaedic implant, which is prepared by adopting the silk fibroin/bioceramic composite material as a production raw material. Therefore, the silk fibroin/bioceramic composite bone nail has good mechanical properties and excellent biological properties, including biocompatibility, biodegradability, biological absorbability, bone conduction capacity, bone induction capacity and the like, can replace the metal orthopedic implant and the degradable synthetic polymer orthopedic implant which are widely used at present, and avoids osteoporosis, possible secondary operation, adverse immune reaction and the like caused by stress shielding after long-term implantation of the metal orthopedic implant and the degradable synthetic polymer orthopedic implant.
In the embodiment of the invention, the silk fibroin-bioceramic composite block material is manufactured into the silk fibroin/bioceramic composite orthopedic implant through a cutting process, the silk fibroin/bioceramic composite orthopedic implant is a bone screw, an interface screw or a lumbar vertebra fusion device, and the like, and the specific implant form can be customized according to clinical requirements.
In the embodiment of the invention, the mechanical property and the degradation property of the silk fibroin/bioceramic composite orthopedic implant can be adjusted through a post-treatment process. The post-treatment process is steam annealing treatment and/or heating treatment. The temperature range of the steam annealing treatment is 1-100 ℃, the time range is 1-1000 h, and the pressure range is vacuum degree-100 KPa to-25 KPa. The heating treatment temperature is 25-200 ℃ and the time is 1-1000 h.
The following detailed description of embodiments of the invention is provided for the purpose of illustration only and is not to be construed as limiting the invention. In addition, all reagents employed in the examples below are commercially available or may be synthesized according to methods herein or known, and are readily available to those skilled in the art for reaction conditions not listed, if not explicitly stated.
Example 1
1) Preparing silk protein solution and freeze-dried powder thereof: weighing 10g of sheared silkworm cocoon shell, putting the silkworm cocoon shell into 0.02mol/L sodium carbonate solution, boiling for 30min, and degumming. The degummed silk fibers were washed multiple times with deionized water and left to dry overnight in a fume hood. The dried degummed silk fiber was immersed in 9.3mol/L lithium bromide solution and placed in an oven at 60℃for 4h. The solution obtained after dissolution was dialyzed in deionized water for 3 days, with a dialysis membrane cutoff molecular weight of 3500Da. And after the dialysis is finished, centrifuging for two times to remove insoluble impurities, and taking the supernatant as the silk fibroin aqueous solution. The aqueous silk protein solution was placed in liquid nitrogen, transferred to a freeze dryer (-80 ℃,0.006 bar) after complete freezing, and freeze dried for 72h. And (3) placing the freeze-dried powder into a high-speed pulverizer, grinding to obtain the silk protein freeze-dried powder with the average particle size of 500nm, and hermetically storing the silk protein freeze-dried powder in a vacuum dryer at room temperature. The silk fibroin freeze-dried powder is subjected to infrared spectrum test, the test result is shown in figure 2, and no obvious peak appears near the wave number 1626 wave number in figure 2, which indicates that the beta-sheet structure content in the silk fibroin freeze-dried powder is low or not.
2) Preparing a silk protein/calcium phosphate composite bone nail: 1g of silk fibroin lyophilized powder and 1g of calcium phosphate powder (the average particle size of the calcium phosphate powder is 20 nm) were weighed and thoroughly mixed. Filling the mixed silk fibroin-calcium phosphate powder into a mould for hot pressing, wherein the hot pressing temperature is 120 ℃, the hot pressing time is 1h, and the hot pressing pressure is 250MPa. The silk protein/calcium phosphate composite material obtained by hot pressing is subjected to section scanning transmission electron microscopy observation, the observation result is shown in figure 3, the section appearance is not smooth and has granular feel, and the calcium phosphate is doped in the silk protein.
Turning the hot pressed silk protein-calcium phosphate composite block material to obtain silk protein/calcium phosphate composite bone nail, wherein the real image of the silk protein/calcium phosphate composite bone nail is shown in figure 4.
The infrared spectrum of the silk protein/calcium phosphate composite bone nail is tested, the test result is shown in figure 5, and a clear peak appears near the wave number 1626 wave number in figure 5, which shows that the silk protein contains a large amount of beta-sheet structure.
Example 2
1) Preparing silk solution and freeze-dried powder thereof: weighing 10g of sheared silkworm cocoon shell, putting the silkworm cocoon shell into 0.02mol/L sodium carbonate solution, boiling for 30min, and degumming. The degummed silk fibers were washed multiple times with deionized water and left to dry overnight in a fume hood. The dried degummed silk fiber was immersed in 9.3mol/L lithium bromide solution and placed in an oven at 60℃for 4h. The solution obtained after dissolution was dialyzed in deionized water for 3 days, with a dialysis membrane cutoff molecular weight of 3500Da. And after the dialysis is finished, centrifuging for two times to remove insoluble impurities, and taking the supernatant as the silk fibroin aqueous solution. The aqueous silk protein solution was placed in liquid nitrogen, transferred to a freeze dryer (-80 ℃,0.006 bar) after complete freezing, and freeze dried for 72h. And (3) placing the freeze-dried powder into a high-speed pulverizer, grinding to obtain the silk fibroin freeze-dried powder with the particle size of 200nm, and hermetically storing the silk fibroin freeze-dried powder in a vacuum dryer at room temperature.
2) Preparing a silk protein/hydroxyapatite composite bone screw: 1g of silk fibroin lyophilized powder and 0.3g of hydroxyapatite powder (particle size of calcium phosphate powder is 200 nm) were weighed and thoroughly mixed. Filling the mixed silk fibroin-hydroxyapatite powder into a mould for hot pressing, wherein the hot pressing temperature is 145 ℃, the hot pressing time is 1h, and the hot pressing pressure is 175MPa. Turning the hot pressed silk protein-hydroxyapatite composite block material to obtain the silk protein/hydroxyapatite composite interface screw, wherein the real object diagram of the silk protein/calcium phosphate composite bone screw is shown in figure 6.
The infrared spectrum of the silk protein/calcium phosphate composite bone nail is tested, the test result is shown in figure 7, and a clear peak appears near the wave number 1626 wave number in figure 7, which shows that the silk protein has a large amount of beta-sheet structures.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
1. A method of making a silk fibroin/bioceramic composite comprising:
(1) Freeze-drying and grinding the silk protein solution to obtain silk protein freeze-dried powder;
(2) Mixing the silk fibroin freeze-dried powder and the bioceramic powder so as to obtain mixed powder;
(3) And hot-pressing the mixed powder to obtain the silk fibroin/bioceramic composite material.
2. The method according to claim 1, wherein in step (1), the particle size of the silk protein lyophilized powder obtained by grinding is 10nm to 200 μm, preferably 20nm to 500nm.
3. The method according to claim 1, wherein in step (1), the silk protein solution is freeze-dried in the following steps:
freezing the silk protein solution at the temperature of-20 ℃ to-196 ℃ for 5-360min;
freeze-drying the frozen silk protein solution in a freeze dryer for 2-5 days;
optionally, the mass fraction of silk proteins in the silk protein solution is 0.1-40%.
4. The method according to claim 1, wherein in step (1), the silk protein solution is prepared by the method comprising:
a) Placing natural silk cocoons into a carbonate water solution or a bicarbonate water solution, and heating and boiling to degumm the cocoons so as to obtain degummed silk;
b) Mixing the degummed silk with a lithium bromide aqueous solution, and dissolving to obtain a silk protein lithium bromide solution;
c) Dialyzing the silk fibroin lithium bromide solution to obtain a crude silk fibroin solution;
d) And (3) centrifuging the crude silk protein solution, and collecting supernatant to obtain the silk protein solution.
5. The method according to any one of claims 1 to 4, wherein in step (2), the mass ratio of the silk protein lyophilized powder to the bioceramic powder is 1: (0.01-3.00), preferably (9:1) - (1:3).
6. The method according to any one of claims 1 to 4, wherein in step (2), the bio-ceramic powder has a particle size of 10nm to 200 μm, preferably 20nm to 500nm.
7. The method of any one of claims 1-4, wherein the bioceramic powder is selected from at least one of a calcium phosphate powder and a hydroxyapatite powder.
8. The method according to any one of claims 1 to 4, wherein in the step (3), the hot pressing is performed at a temperature of 50 to 200 ℃, a pressure of 1 to 1000MPa, and a time of 15 to 360 minutes.
9. A silk fibroin/bioceramic composite, characterized in that it is prepared by the method of any one of claims 1 to 8.
10. The silk fibroin/bioceramic composite orthopedic implant is characterized in that the silk fibroin/bioceramic composite orthopedic implant is prepared by using the silk fibroin/bioceramic composite material according to claim 9 as a raw material.
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