CN113797395A - Nano hydroxyapatite/block copolymer composite material and preparation method thereof - Google Patents

Nano hydroxyapatite/block copolymer composite material and preparation method thereof Download PDF

Info

Publication number
CN113797395A
CN113797395A CN202111095553.6A CN202111095553A CN113797395A CN 113797395 A CN113797395 A CN 113797395A CN 202111095553 A CN202111095553 A CN 202111095553A CN 113797395 A CN113797395 A CN 113797395A
Authority
CN
China
Prior art keywords
hydroxyapatite
nano
block copolymer
composite material
polyethylene glycol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202111095553.6A
Other languages
Chinese (zh)
Other versions
CN113797395B (en
Inventor
马骏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing AK Medical Co Ltd
Original Assignee
Beijing AK Medical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing AK Medical Co Ltd filed Critical Beijing AK Medical Co Ltd
Priority to CN202111095553.6A priority Critical patent/CN113797395B/en
Publication of CN113797395A publication Critical patent/CN113797395A/en
Application granted granted Critical
Publication of CN113797395B publication Critical patent/CN113797395B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • 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
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • 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
    • 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
    • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Dispersion Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Composite Materials (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Materials For Medical Uses (AREA)

Abstract

The invention provides a nano hydroxyapatite/block copolymer composite material and a preparation method thereof. The composite material comprises nano hydroxyapatite and a block copolymer, wherein the nano hydroxyapatite is blended with the block copolymer, and the block copolymer comprises a PLA-PEG-PLA block copolymer consisting of a polyethylene glycol chain segment and a polylactide chain segment. The nano-hydroxyapatite in the composite material improves the mechanical property of the block copolymer, so that the material can be applied to the parts needing bearing such as talus and the like, and because the specific surface area of the nano-hydroxyapatite is very large, the interior of the block copolymer is also provided with a porous microstructure and also has very high specific surface area, the problem of the interface between the traditional organic hydrogel and an inorganic filling matrix can be solved through the interaction of the nano-hydroxyapatite and the block copolymer, and the hydrogel is endowed with better mechanical property. PLA at two ends of the composite material is a hydrophobic molecular chain, PEG in the middle is a hydrophilic chain segment, and after being mixed with water, the composite material can generate sol-gel phase transition along with the temperature change.

Description

Nano hydroxyapatite/block copolymer composite material and preparation method thereof
Technical Field
The invention relates to the technical field of cartilage injury repair, in particular to a nano hydroxyapatite/block copolymer composite material and a preparation method thereof.
Background
Ankle cartilage damage (OLT) is a common ankle injury disease which involves articular cartilage and subchondral bone and can be accompanied by ankle swelling pain and flexion and extension disorder, and is mainly caused by Hepple V type. Since Hepple V-type talus cartilage damage is accompanied by subcarlary cystic degeneration, treatment requires repair of both cartilage damage and subchondral cystic space, which is a clinical problem.
The main treatment methods at present comprise autologous osteochondral transplantation and allogeneic osteochondral transplantation, the autologous osteochondral transplantation usually adopts ipsilateral knee joint osteochondral column to repair injury, and finally forms hyalin cartilage with good biomechanical property, but the defect of supply area complication exists, and the incidence rate is up to 16.9% according to literature reports. In addition, the difference of the anatomy and the biomechanics between the knee joint and the ankle joint exists, and the matching degree and the cure rate of the autologous osteochondral column transplanted from the knee joint to the lesion position of the ankle joint are still problems. Allogenic osteochondral transplantation can be used to repair large areas of talar cartilage damage, with the disadvantages of graft rejection and risk of disease transmission, and limited sources.
Therefore, the biomaterials used for repairing cartilage damage attract the attention of researchers, and a new idea is provided for treating Hepple V-type talus cartilage damage.
The hydrogel has high similarity with extracellular matrix, and the hydrogel biomaterial compounded with minerals such as calcium phosphate has advantages in the aspects of cartilage and bone regeneration. Meanwhile, the temperature-sensitive hydrogel is in a liquid state at a low temperature, can be injected into a cartilage defect part to fill irregular defects, and is heated in vivo and formed in situ, so that the combination of the hydrogel and bone tissues is facilitated. In recent years, the temperature-sensitive hydrogel has been successfully prepared, and has a huge application prospect in clinic.
However, the traditional temperature-sensitive hydrogel of mineral substances such as composite calcium phosphate has poor mechanical properties, and cartilage repair biomaterials with better mechanical properties are needed in load-bearing joints such as talus. Therefore, a temperature-sensitive hydrogel material with excellent mechanical properties is needed.
Disclosure of Invention
The invention mainly aims to provide a nano-hydroxyapatite/block copolymer composite material and a preparation method thereof, so as to solve the problem of poor mechanical properties of temperature-sensitive hydrogel composite materials in the prior art.
In order to accomplish the above object, according to one aspect of the present invention, there is provided a nano-hydroxyapatite/block copolymer composite comprising a nano-hydroxyapatite and a block copolymer, the nano-hydroxyapatite being blended with the block copolymer, the block copolymer comprising a PLA-PEG-PLA block copolymer composed of a polyethylene glycol segment and a polylactide segment.
Further, the content of the nano-hydroxyapatite in the composite material is 0.1-10 wt%, the structure of the nano-hydroxyapatite is preferably a rod-like structure, and the length of the nano-hydroxyapatite is more preferably 10-200 nm, and the diameter of the nano-hydroxyapatite is more preferably 1-50 nm.
Furthermore, the nano hydroxyapatite is doped with a modified metal, preferably the modified metal is one or more selected from strontium, zinc, magnesium, potassium and manganese, and preferably the molar ratio of calcium to the modified metal in the nano hydroxyapatite is 1: 0.01-1: 0.1.
Further, the content of the PLA-PEG-PLA block copolymer in the composite material is 90-99.9 wt%, the number average molecular weight of the PLA-PEG-PLA block copolymer is preferably 4000-12000, and the number average molecular weight of the polyethylene glycol chain segment in the PLA-PEG-PLA block copolymer is preferably 1000-3500.
According to another aspect of the present invention, there is provided a method for preparing a nano hydroxyapatite/block copolymer composite material, the method comprising: step S1, performing first mixing on the solvent, part of polyethylene glycol and nano hydroxyapatite to obtain a first dispersion liquid; step S2, removing the solvent in the first dispersion liquid to obtain a nano hydroxyapatite/polyethylene glycol intermediate product; step S3, under the first vacuum condition, the mixture system containing lactide monomer, residual polyethylene glycol and nano-hydroxyapatite/polyethylene glycol intermediate product is heated for the first time, so that the lactide monomer and the polyethylene glycol are copolymerized to obtain the nano-hydroxyapatite/block copolymer composite material.
Further, in the step S1, the first mixing is performed by ultrasonic dispersion, wherein the power of the ultrasonic dispersion is 100 to 1000W, the time is 20min to 4h, the concentration of the nano-hydroxyapatite in the first dispersion is preferably 2 to 6 wt%, the concentration of part of the polyethylene glycol is preferably 0.01 to 0.6 wt%, and the number average molecular weight of part of the polyethylene glycol is preferably 1000 to 3500.
Further, in the step S2, the removing the solvent in the first dispersion by vacuum heating, the step S2 includes: and under a second vacuum condition, carrying out second heating on the first dispersion liquid to obtain a nano hydroxyapatite/polyethylene glycol intermediate product, preferably, the second heating temperature is 100-120 ℃, the time is 20 min-4 h, and preferably, the vacuum degree under the second vacuum condition is 50-150 Pa.
Further, in the step S3, the heating temperature of the first heating is 130 to 140 ℃, the heating time is 5 to 10 hours, and the vacuum degree under the first vacuum condition is preferably 50 to 150 Pa; in the preferable mixture system, the content of lactide monomer is 50-85 wt%, the content of the rest polyethylene glycol is 10-40 wt%, the content of the nano hydroxyapatite/polyethylene glycol intermediate product is 0.1-10 wt%, the number average molecular weight of the rest polyethylene glycol is preferably 1000-3500, and the particle size of the nano hydroxyapatite/polyethylene glycol intermediate product is preferably 1-800 nm; preferably, the mixture system further comprises a catalyst, the catalyst comprises one or more of stannous octoate, stannous chloride and stannous acetate, and the content of the catalyst in the mixture system is preferably 0.01-0.5 wt%.
Further, the structure of the nano-hydroxyapatite is a rod-shaped structure, the length of the nano-hydroxyapatite is 10-200 nm, and the diameter of the nano-hydroxyapatite is 1-50 nm; the preparation method also comprises the following preparation process of the modified metal-doped nano hydroxyapatite: heating the second dispersion liquid containing a calcium source, a phosphorus source and a modified metal salt under an alkaline condition to obtain modified metal-doped hydroxyapatite; preferably, ammonia water is used for adjusting the pH value to 10-10.5, and the molar ratio of the modified metal salt to the calcium source to the phosphorus source is preferably 0.1-1: 10: 6; preferably, the calcium source is selected from one or two of calcium nitrate and calcium chloride, the phosphorus source is selected from any one or two of diammonium hydrogen phosphate and disodium hydrogen phosphate, and the modified metal salt is selected from nitrate of modified metal or hydrochloride of modified metal.
According to another aspect of the present invention, a temperature-sensitive hydrogel material is provided, which includes a temperature-sensitive material and water, wherein the temperature-sensitive material is any one of the above-mentioned nano-hydroxyapatite/block copolymer composite materials or a nano-hydroxyapatite/block copolymer composite material prepared by any one of the above-mentioned preparation methods, preferably, the temperature-sensitive material content in the temperature-sensitive hydrogel material is 10-20 wt%.
By applying the technical scheme of the invention, the composite material has the PLA-PEG-PLA block copolymer, so that on one hand, the composite material can be dispersed in water by utilizing the hydrophilicity of PLA, and the dispersion state in water can be changed according to the temperature change; meanwhile, due to the existence of hydrophobic PEG, excessive dissolution of the composite material in water is avoided, the composite material can form a sol or gel state in water due to the block copolymer, and the composite material has temperature sensitivity. The nano-hydroxyapatite in the composite material improves the mechanical property of the block copolymer, so that the material can be applied to the parts needing bearing such as talus and the like, and the specific surface area of the nano-hydroxyapatite is large, the interior of the block copolymer is also provided with a porous microstructure and also has a high specific surface area, so that the nano-hydroxyapatite and the block copolymer interact with each other, the problem of the interface between the traditional organic hydrogel and an inorganic filling matrix can be solved, and the hydrogel is endowed with better mechanical property. On the other hand, the nano-hydroxyapatite can adsorb biomolecules necessary for bone regeneration, and provides a good nutritional environment for osteoblasts. And the degradation speed of the nano-hydroxyapatite is higher, more Ca ions and P ions can be provided, and the bone regeneration speed is further improved.
In the PLA-PEG-PLA copolymer molecular chain structure of the composite material, PLA at two ends is a hydrophobic molecular chain, PEG in the middle is a hydrophilic chain segment, and after being mixed with water, the composite material can generate sol-gel phase transition along with the temperature change. The copolymer is self-assembled in the solution at low temperature to form micelles, the micelles are dispersed in the whole solution system to form liquid sol, and the liquid sol can be injected to cartilage defect parts and can fill various irregular-shaped defects. After the material is injected into a human body, the temperature of the material is raised in the body, PLA chain segments at two ends of the copolymer are diffused and respectively have bridging action with surrounding micelles, and the PLA chain segments are gradually aggregated and embedded to form a three-dimensional interpenetrating network structure which can be formed into a hydrogel state in situ, so that the cartilage defect part can be completely matched and firmly combined with bone tissues. In addition, the block copolymer and the nano-hydroxyapatite in the composite material are both easily degradable materials, and can be degraded in a human body to provide a growth space for new bones.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
In order to solve the above problems, the present application provides a nano-hydroxyapatite/block copolymer composite material and a method for preparing the same.
According to an exemplary embodiment of the present application, there is provided a nano-hydroxyapatite/block copolymer composite, the composite including nano-hydroxyapatite and a block copolymer, the nano-hydroxyapatite being blended with the block copolymer, the block copolymer including a PLA-PEG-PLA block copolymer composed of a polyethylene glycol segment and a polylactide segment.
The composite material has the PLA-PEG-PLA block copolymer, so that the composite material can be dispersed in water by utilizing the hydrophilicity of PLA, and the dispersion state in the water can be changed according to the temperature change; meanwhile, due to the existence of hydrophobic PEG, excessive dissolution of the composite material in water is avoided, the composite material can form a sol or gel state in water due to the block copolymer, and the composite material has temperature sensitivity. The nano-hydroxyapatite in the composite material improves the mechanical property of the block copolymer, so that the material can be applied to the parts needing bearing such as talus and the like, and the specific surface area of the nano-hydroxyapatite is large, the interior of the block copolymer is also provided with a porous microstructure and also has a high specific surface area, so that the nano-hydroxyapatite and the block copolymer interact with each other, the problem of the interface between the traditional organic hydrogel and an inorganic filling matrix can be solved, and the hydrogel is endowed with better mechanical property. On the other hand, the nano-hydroxyapatite can adsorb biomolecules necessary for bone regeneration, and provides a good nutritional environment for osteoblasts. And the degradation speed of the nano-hydroxyapatite is higher, more Ca ions and P ions can be provided, and the bone regeneration speed is further improved.
In the PLA-PEG-PLA copolymer molecular chain structure of the composite material, PLA at two ends is a hydrophobic molecular chain, PEG in the middle is a hydrophilic chain segment, and after being mixed with water, the composite material can generate sol-gel phase transition along with the temperature change. The copolymer is self-assembled in the solution at low temperature to form micelles, the micelles are dispersed in the whole solution system to form liquid sol, and the liquid sol can be injected to cartilage defect parts and can fill various irregular-shaped defects. After the material is injected into a human body, the temperature of the material is raised in the body, PLA chain segments at two ends of the copolymer are diffused and respectively have bridging action with surrounding micelles, and the PLA chain segments are gradually aggregated and embedded to form a three-dimensional interpenetrating network structure which can be formed into a hydrogel state in situ, so that the cartilage defect part can be completely matched and firmly combined with bone tissues. In addition, the block copolymer and the nano-hydroxyapatite in the composite material are both easily degradable materials, and can be degraded in a human body to provide a growth space for new bones.
In order to enable the composite material to have better mechanical property and bioactivity, the content of the nano-hydroxyapatite in the composite material is preferably 0.1-10 wt%. In order to further improve the mechanical property of the composite material, the structure of the nano-hydroxyapatite is preferably a rod-like structure, the length of the nano-hydroxyapatite is preferably 10-200 nm, the diameter of the nano-hydroxyapatite is preferably 1-50 nm, and the penetration capability of the nano-hydroxyapatite with the rod-like structure and the block copolymer is stronger when the nano-hydroxyapatite is blended with the block copolymer, so that the mechanical property of the composite material can be further improved.
In some embodiments, the nano-hydroxyapatite is doped with a modified metal, and the biological performance of the composite material can be further improved after the modified metal is added, for example, the modified metal is preferably selected from one or more of strontium, zinc, magnesium, potassium and manganese, wherein the strontium has the effects of reducing bone resorption and promoting bone regeneration, and the zinc can promote the proliferation and differentiation of osteoblasts, so that damaged cartilage tissue can be recovered more quickly. In order to better exert the functions of the nano hydroxyapatite and the modified metal at the same time, the molar ratio of calcium to the modified metal in the nano hydroxyapatite is preferably 1: 0.01-1: 0.1.
The content of the PLA-PEG-PLA block copolymer in the composite material can influence the mechanical property of the material, and the content of the PLA-PEG-PLA block copolymer in the composite material is preferably 90-99.9 wt%, so that the composite material has excellent temperature-sensitive property, and the mechanical property of the composite material is improved as much as possible. The number average molecular weight of the PLA-PEG-PLA block copolymer is 4000-12000 preferably, the number average molecular weight of a polyethylene glycol chain segment in the PLA-PEG-PLA block copolymer is 1000-3500 preferably, and within the range of the number average molecular weight, on one hand, the hydrophilicity of PEG can be fully exerted to promote the formation of hydrogel, and on the other hand, the effect of the PEG can be exerted to provide a composite material with more sufficient mechanical properties; and the limit of the number average molecular weight can ensure that the degradation speed of the composite material in a human body is more appropriate, thereby not only avoiding the poor repairing effect caused by the advanced degradation of the composite material, but also avoiding the influence of the too slow degradation speed on the bone regeneration.
According to another exemplary embodiment of the present application, there is provided a method for preparing a nano hydroxyapatite/block copolymer composite material, the method comprising: step S1, performing first mixing on the solvent, part of polyethylene glycol and nano hydroxyapatite to obtain a first dispersion liquid; step S2, removing the solvent in the first dispersion liquid to obtain a nano hydroxyapatite/polyethylene glycol intermediate product; and step S3, under the first vacuum condition, carrying out first heating on a second dispersion liquid containing lactide monomer, residual polyethylene glycol and nano-hydroxyapatite/polyethylene glycol intermediate product, so as to carry out copolymerization reaction on the lactide monomer and the polyethylene glycol, thus obtaining the nano-hydroxyapatite/block copolymer composite material.
According to the method, after the polyethylene glycol and the nano-hydroxyapatite are mixed in the solvent, the solvent is removed, so that the polyethylene glycol is adsorbed on the surface of the nano-hydroxyapatite through polar groups on the surface, the surface energy of the nano-hydroxyapatite is reduced, and the nano-hydroxyapatite is less prone to agglomeration after a dispersion liquid is formed. Then, the nano hydroxyapatite/polyethylene glycol intermediate product reacts with lactide monomer, so that the polyethylene glycol and the lactide monomer undergo copolymerization reaction to generate PLA-PEG-PLA block copolymer, and the surface of the copolymer is blended with the nano hydroxyapatite to form the nano hydroxyapatite/block copolymer composite material, such as the composite material described in the application.
The composite material obtained by the preparation method has the PLA-PEG-PLA block copolymer, so that the composite material can be dispersed in water by utilizing the hydrophilicity of PLA, and the dispersion state of the composite material in water can be changed according to the temperature change; meanwhile, due to the existence of hydrophobic PEG, excessive dissolution of the composite material in water is avoided, and the block copolymer enables the composite material to form a sol or gel state in water and endows the composite material with temperature sensitivity. The nano-hydroxyapatite in the composite material improves the mechanical property of the block copolymer, so that the material can be applied to the parts needing bearing such as talus and the like, and the specific surface area of the nano-hydroxyapatite is large, the interior of the block copolymer is also provided with a porous microstructure and also has a high specific surface area, so that the nano-hydroxyapatite and the block copolymer interact with each other, the problem of the interface between the traditional organic hydrogel and an inorganic filling matrix can be solved, and the hydrogel is endowed with better mechanical property. On the other hand, the nano-hydroxyapatite can adsorb biomolecules necessary for bone regeneration, and provides a good nutritional environment for osteoblasts. And the degradation speed of the nano-hydroxyapatite is higher, more Ca ions and P ions can be provided, and the bone regeneration speed is further improved.
In the molecular chain structure of the PLA-PEG-PLA copolymer of the prepared composite material, PLA at two ends is a hydrophobic molecular chain, PEG in the middle is a hydrophilic chain segment, and after being mixed with water, the phase change of sol-gel can be generated along with the temperature change. The copolymer is self-assembled in the solution at low temperature to form micelles, the micelles are dispersed in the whole solution system to form liquid sol, and the liquid sol can be injected to cartilage defect parts and can fill various irregular-shaped defects. After the material is injected into a human body, the temperature of the material is raised in the body, PLA chain segments at two ends of the copolymer are diffused and respectively have bridging action with surrounding micelles, and the PLA chain segments are gradually aggregated and embedded to form a three-dimensional interpenetrating network structure which can be formed into a hydrogel state in situ, so that the cartilage defect part can be completely matched and firmly combined with bone tissues. In addition, the block copolymer and the nano-hydroxyapatite in the composite material are both easily degradable materials, and can be degraded in a human body to provide a growth space for new bones. In some embodiments, in step S1, the first mixing is preferably performed by ultrasonic dispersion, where the power of the ultrasonic dispersion is 100-1000W, and the time is 20 min-4 h, and the ultrasonic dispersion can further increase the uniformity of the first dispersion, so that the nano-hydroxyapatite is fully dispersed, and can be more uniformly and fully surface-modified.
Preferably, the concentration of the nano-hydroxyapatite in the first dispersion liquid is 2-6 wt%, and the concentration of part of the polyethylene glycol is 0.01-0.6 wt%, so that in the numerical range, the agglomeration of the nano-hydroxyapatite caused by excessive addition of the nano-hydroxyapatite is avoided, and the reduction of the mechanical property of the material is further avoided. The number average molecular weight of part of the polyethylene glycol is preferably 1000-3500, so that on one hand, the hydrophilicity of the PEG can be fully exerted to promote the formation of hydrogel, and on the other hand, the effect of a surfactant can be better exerted to ensure that the dispersibility of the nano-hydroxyapatite is higher; and the limit of the number average molecular weight can ensure that the degradation speed of the composite material in a human body is better and proper, thereby not only avoiding the poor repairing effect caused by the advanced degradation of the composite material, but also avoiding the influence on bone regeneration caused by too slow speed reduction.
In order to remove the solvent in the first dispersion more quickly, in step S2, the solvent in the first dispersion is removed by vacuum heating. The step S2 includes: and under a second vacuum condition, carrying out second heating on the first dispersion liquid to obtain a nano hydroxyapatite/polyethylene glycol intermediate product, preferably, the second heating temperature is 100-120 ℃, the time is 20 min-4 h, and preferably, the vacuum degree under the second vacuum condition is 50-150 Pa. The solvent can be removed rapidly and thoroughly by vacuum heating, and then the nano hydroxyapatite/polyethylene glycol intermediate product with good combination is obtained.
In some embodiments, in the step S3, the heating temperature of the first heating is 130 to 140 ℃, the heating time is 5 to 10 hours, and the vacuum degree of the first vacuum condition is preferably 50 to 150 Pa. In the preferable mixture system, the content of lactide monomer is 50-85 wt%, the content of the preferable residual polyethylene glycol is 10-40 wt%, the content of the nano hydroxyapatite/polyethylene glycol intermediate product is 0.1-10 wt%, and the number average molecular weight of the preferable residual polyethylene glycol is 1000-3500. In the concentration range, the lactide and the polyethylene glycol are mixed according to the proportion to obtain the PLA-PEG-PLA block copolymer with the number average molecular weight of 4000-12000.
Before the composite material is prepared, the intermediate product can be crushed to improve the reaction speed, and the particle size of the nano hydroxyapatite/polyethylene glycol intermediate product is preferably 1-800 nm.
In some embodiments, the mixture system further comprises a catalyst, wherein the catalyst comprises one or more of stannous octoate, stannous chloride and stannous acetate, and preferably the amount of the catalyst in the mixture system is 0.01 wt% to 0.5 wt%. The catalyst is added, so that the reaction can be carried out more quickly, and the preparation efficiency is improved. After the polymerization reaction is finished, unreacted lactide monomer can be cleaned by adopting a method commonly used in the prior art, for example, a product after the reaction can be dissolved in acetone, ethanol is added for precipitation and solid-liquid separation are carried out, and then the solid product is dried in a drying oven to obtain the nano hydroxyapatite/block copolymer composite material.
As mentioned above, the nanometer hydroxyapatite can significantly improve the biological performance and the mechanical performance of the composite material, preferably, the nanometer hydroxyapatite has a rod-like structure, the length of the nanometer hydroxyapatite is 10-200 nm, and the diameter of the nanometer hydroxyapatite is 1-50 nm. In order to further improve the biological performance and the mechanical performance of the composite material, the nano hydroxyapatite is preferably the modified metal-doped nano hydroxyapatite. The preparation method also comprises the preparation process of the modified metal-doped nano hydroxyapatite: and heating the second dispersion liquid containing the calcium source, the phosphorus source and the modified metal salt under an alkaline condition to obtain the modified metal-doped nano-hydroxyapatite. The modified metal-doped nano-hydroxyapatite can be prepared by a common method in the prior art, for example, the following three-step method can be adopted: step A1, heating the dispersion liquid containing the calcium source and the modified metal salt to 40-60 ℃, and preserving heat for 30 min-4 h to obtain a first mixed system; step A2, mixing a phosphorus source and the first mixed system, adjusting the pH value to 10-10.5 by using ammonia water, heating to 60-80 ℃, and preserving heat for 3-4 hours to obtain a second mixed system; and A3, cooling the second mixed system to 15-25 ℃, and then aging for 24-48 h to obtain the modified metal-doped nano-hydroxyapatite. Through the preparation process, the nano hydroxyapatite doped with a proper amount of modified metal can be prepared. In addition, the surface energy of the nano-hydroxyapatite doped with the modified metal is increased, so that the method is more suitable for adopting a method of reheating after ultrasonic dispersion to avoid the agglomeration of the nano-hydroxyapatite doped with the modified metal.
In order to further improve the doping effect of the modified metal, the mol ratio of the modified metal salt to the calcium source to the phosphorus source is preferably 0.1-1: 10: 6; preferably, the calcium source is selected from one or two of calcium nitrate and calcium chloride, preferably the phosphorus source is selected from any one or two of diammonium hydrogen phosphate and disodium hydrogen phosphate, and preferably the modified metal salt comprises a nitrate of a modified metal or a hydrochloride of a modified metal. The preferable raw materials are common metal salts, so that the preparation method is more suitable for popularization, and the preparation cost is reduced.
According to another exemplary embodiment of the present application, there is provided a temperature-sensitive hydrogel material, including a temperature-sensitive material and water, wherein the temperature-sensitive material is any one of the nano-hydroxyapatite/block copolymer composite materials described above or a nano-hydroxyapatite/block copolymer composite material prepared by any one of the preparation methods described above.
The temperature-sensitive hydrogel material is obtained by dissolving the composite material in water, is liquid at low temperature, can be injected to cartilage defect parts, and can fill various defects with irregular shapes. After being injected into a human body, the material is heated in the body and is formed into a hydrogel state in situ, so that the cartilage defect part can be completely matched and the material is firmly combined with bone tissues. In addition, the temperature-sensitive material has good biological performance and mechanical performance, and can ensure the quick and effective recovery of the damaged cartilage part. Preferably, the content of the temperature-sensitive material in the temperature-sensitive hydrogel material is 10-20 wt%. Within the content range, the temperature-sensitive material has good temperature-sensitive performance, biological performance and mechanical performance.
The following examples and comparative examples are provided to further illustrate the advantageous effects of the present application.
Example 1
1) Mixing a strontium nitrate aqueous solution and a calcium nitrate aqueous solution (the molar ratio of the strontium nitrate to the calcium nitrate is 0.01:1), heating (the heating temperature is 60 ℃ and the time is 10min), then dropwise adding a diammonium hydrogen phosphate aqueous solution with the concentration of 0.5mol/L into the mixed solution at the speed of 10mL/min, adding ammonia water to adjust the pH value to 10-10.5, and stirring at the speed of 200rpm at the temperature of 60 ℃ for 3 h. Then, the temperature is reduced to 25 ℃, and the mixture is aged for 24 hours at room temperature. After the reaction is finished, the reaction solution is centrifuged and washed for 5 times by deionized water to obtain the strontium-doped nano-hydroxyapatite with the length of 66nm and the diameter of 22 nm.
2) Adding strontium-doped nano hydroxyapatite and polyethylene glycol with the number average molecular weight of 2000 into deionized water, stirring at the speed of 300rpm to form a suspension, then performing ultrasonic dispersion (power is 150W) for 2 hours to prepare a dispersion (the content of the strontium-doped nano hydroxyapatite is 5 wt%, the concentration of PEG is 0.2 wt%), and heating to 100 ℃ under the vacuum degree of 50Pa to obtain a dry strontium-doped nano hydroxyapatite/polyethylene glycol intermediate product.
3) Crushing the strontium-doped nano hydroxyapatite/polyethylene glycol intermediate product to the particle size of 1-800 nm, mixing with stannous octoate, polyethylene glycol and lactide monomer to form a mixed system (the content of stannous octoate in the mixed system is 0.05 wt%, the content of the strontium-doped nano hydroxyapatite/polyethylene glycol intermediate product is 0.95 wt%, the content of polyethylene glycol is 19 wt% and the content of lactide monomer is 80 wt%), heating in an oil bath to 130 ℃ under the vacuum degree of 50Pa, and stirring for reaction for 5 hours (the stirring speed is 180 r/min). After the reaction is finished, dissolving the reaction product by using acetone, adding ethanol for precipitation, and then placing the product in a vacuum drying oven for drying for 2 hours at the temperature of 60 ℃ to obtain the composite material of the strontium-doped nano hydroxyapatite/PLA-PEG-PLA block copolymer.
4) Mixing the composite material of the strontium-doped nano hydroxyapatite/PLA-PEG-PLA block copolymer with deionized water, and dissolving at 15 ℃ for 24 hours until the polymer is completely dissolved to form an aqueous solution with the mass concentration of 20% to obtain the temperature-sensitive hydrogel material.
Example 2
The difference from example 1 is that the number average molecular weight of polyethylene glycol in step 2) is 3500.
Example 3
The difference from example 1 is that the number average molecular weight of polyethylene glycol in step 2) is 1000.
Example 4
The difference from example 1 is that the number average molecular weight of polyethylene glycol in step 2) is 4000.
Example 5
The difference from example 1 is that the time for ultrasonic dispersion in step 2) is 20 min.
Example 6
The difference from example 1 is that the time for ultrasonic dispersion in step 2) is 4 h.
Example 7
The difference from example 1 is that the time for ultrasonic dispersion in step 2) is 10 min.
Example 8
The difference from example 1 is that the time for ultrasonic dispersion in step 2) is 6 h.
Example 9
The difference from the example 1 is that the concentration of the strontium-doped nano-hydroxyapatite in the step 2) is 2 wt%.
Example 10
The difference from the example 1 is that the concentration of the strontium-doped nano-hydroxyapatite in the step 2) is 6 wt%.
Example 11
The difference from the example 1 is that the concentration of the strontium-doped nano-hydroxyapatite in the step 2) is 1 wt%.
Example 12
The difference from the example 1 is that the concentration of the strontium-doped nano-hydroxyapatite in the step 2) is 10 wt%.
Example 13
The difference from example 1 is that the concentration of the first polyethylene glycol fraction in step 2) is 0.01 wt%.
Example 14
The difference from example 1 is that the concentration of the first polyethylene glycol fraction in step 2) is 0.6 wt%.
Example 15
The difference from example 1 is that the concentration of the first polyethylene glycol fraction in step 2) is 0.005% by weight.
Example 16
The difference from example 1 is that the concentration of the first polyethylene glycol fraction in step 2) is 1 wt%.
Example 17
The difference from example 1 is that the heating temperature in step 3) is 140 ℃.
Example 18
The difference from example 1 is that the heating temperature in step 3) is 110 ℃.
Example 19
The difference from example 1 is that the heating temperature in step 3) is 160 ℃.
Example 20
The difference from example 1 is that the heating time in step 3) is 10 h.
Example 21
The difference from example 1 is that the heating time in step 3) is 3 h.
Example 22
The difference from example 1 is that the heating time in step 3) is 13 h.
Example 23
The difference from example 1 is that the content of lactide monomer in the mixed system in step 3) is 60 wt% and the content of polyethylene glycol in the remaining portion is 39 wt%.
Example 24
The difference from example 1 is that the content of lactide monomer in the mixed system in step 3) is 85 wt% and the content of polyethylene glycol in the remaining portion is 14 wt%.
Example 25
The difference from example 1 is that the content of lactide monomer in the mixed system in step 3) is 50 wt% and the content of polyethylene glycol in the remaining portion is 49 wt%.
Example 26
The difference from example 1 is that the content of lactide monomer in the mixed system in step 3) is 90 wt% and the content of polyethylene glycol in the remaining portion is 9 wt%.
Example 27
The difference from the example 1 is that the content of the strontium-doped nano hydroxyapatite/polyethylene glycol intermediate product in the mixed system in the step 3) is 0.1 wt%, and the content of the lactide monomer is 80.85 wt%.
Example 28
The difference from the example 1 is that the content of the strontium-doped nano hydroxyapatite/polyethylene glycol intermediate product in the mixed system in the step 3) is 9 wt%, and the content of the lactide monomer is 71.95 wt%.
Example 29
The difference from the example 1 is that the content of the strontium-doped nano hydroxyapatite/polyethylene glycol intermediate product in the mixed system in the step 3) is 0.05 wt%, and the content of the lactide monomer is 80.9 wt%.
Example 30
The difference from the example 1 is that the content of the strontium-doped nano hydroxyapatite/polyethylene glycol intermediate product in the mixed system in the step 3) is 15 wt%, and the content of the lactide monomer is 65.95 wt%.
Example 31
The difference from the embodiment 1 is that,
in the step 1), mixing a strontium nitrate aqueous solution and a calcium nitrate aqueous solution (the molar ratio of strontium nitrate to calcium nitrate is 0.1:1), then dropwise adding a diammonium hydrogen phosphate aqueous solution with the concentration of 0.5mol/L into the mixed solution at the speed of 10mL/min, adding ammonia water to adjust the pH value to 10-10.5, and reacting for 3 hours at the temperature of 80 ℃. Then, the temperature is reduced to 15 ℃, and the mixture is aged for 48 hours at room temperature. After the reaction is finished, the reaction solution is centrifuged and washed for 5 times by deionized water to obtain the strontium-doped nano-hydroxyapatite with the length of 91nm and the diameter of 24 nm.
Performance testing
1. A method for testing the mass content of hydroxyapatite in the composite material and the number average molecular weight of the block copolymer.
Calcining the composite material at 850 ℃ to constant weight, oxidizing and volatilizing organic components in the composite material, and obtaining hydroxyapatite as a residue, wherein the mass content of the hydroxyapatite is equal to the mass of the residue per the mass of the composite material multiplied by 100%;
the number average molecular weight of the block copolymer was measured by a method of Gel Permeation Chromatography (GPC).
2. Hydroxyapatite size testing method
The shape of the hydroxyapatite in the composite material was observed by a scanning electron microscope to be rod-like, the size thereof was recorded, and the average value of the sizes was calculated, with the results shown in table 1.
3. Method for testing molar ratio of modified metal to calcium in hydroxyapatite
And (3) testing the contents of modified metal and calcium element in the modified metal-doped hydroxyapatite by adopting inductively coupled plasma/atomic emission spectrometry (ICP/AES), and calculating the molar ratio.
4. Test method for mechanical property characterization
The material is prepared into a cylinder with the diameter of 20mm and the height of 10mm by using a mould, and the compression strength of the composite material and the compression strength of the PLA-PEG-PLA material without adding hydroxyapatite are tested by using a universal mechanical testing machine.
TABLE 1
Figure BDA0003268983160000111
Figure BDA0003268983160000121
Figure BDA0003268983160000131
TABLE 2
Figure BDA0003268983160000132
Figure BDA0003268983160000141
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
the composite material has the PLA-PEG-PLA block copolymer, so that the composite material can be dispersed in water by utilizing the hydrophilicity of PLA, and the dispersion state in the water can be changed according to the temperature change; meanwhile, due to the existence of hydrophobic PEG, excessive dissolution of the composite material in water is avoided, the composite material can form a sol or gel state in water due to the block copolymer, and the composite material has temperature sensitivity. The nano-hydroxyapatite in the composite material improves the mechanical property of the block copolymer, so that the material can be applied to the parts needing bearing such as talus and the like, and the specific surface area of the nano-hydroxyapatite is large, the interior of the block copolymer is also provided with a porous microstructure and also has a high specific surface area, so that the nano-hydroxyapatite and the block copolymer interact with each other, the problem of the interface between the traditional organic hydrogel and an inorganic filling matrix can be solved, and the hydrogel is endowed with better mechanical property. On the other hand, the nano-hydroxyapatite can adsorb biomolecules necessary for bone regeneration, and provides a good nutritional environment for osteoblasts. And the degradation speed of the nano-hydroxyapatite is higher, more Ca ions and P ions can be provided, and the bone regeneration speed is further improved.
In the PLA-PEG-PLA copolymer molecular chain structure of the composite material, PLA at two ends is a hydrophobic molecular chain, PEG in the middle is a hydrophilic chain segment, and after being mixed with water, the composite material can generate sol-gel phase transition along with the temperature change. The copolymer is self-assembled in the solution at low temperature to form micelles, the micelles are dispersed in the whole solution system to form liquid sol, and the liquid sol can be injected to cartilage defect parts and can fill various irregular-shaped defects. After the material is injected into a human body, the temperature of the material is raised in the body, PLA chain segments at two ends of the copolymer are diffused and respectively have bridging action with surrounding micelles, and the PLA chain segments are gradually aggregated and embedded to form a three-dimensional interpenetrating network structure which can be formed into a hydrogel state in situ, so that the cartilage defect part can be completely matched and firmly combined with bone tissues. In addition, the block copolymer and the nano-hydroxyapatite in the composite material are both easily degradable materials, and can be degraded in a human body to provide a growth space for new bones.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. The composite material of the nano hydroxyapatite/block copolymer is characterized by comprising the nano hydroxyapatite and the block copolymer, wherein the nano hydroxyapatite is blended with the block copolymer, and the block copolymer comprises a PLA-PEG-PLA block copolymer consisting of a polyethylene glycol chain segment and a polylactide chain segment.
2. The composite material according to claim 1, wherein the content of the nano-hydroxyapatite in the composite material is 0.1 to 10 wt%, preferably the structure of the nano-hydroxyapatite is a rod-like structure, and further preferably the length of the nano-hydroxyapatite is 10 to 200nm, and the diameter of the nano-hydroxyapatite is 1 to 50 nm.
3. The composite material according to claim 1 or 2, wherein the nano-hydroxyapatite is doped with a modified metal, preferably the modified metal is selected from one or more of strontium, zinc, magnesium, potassium and manganese, and preferably the molar ratio of calcium to the modified metal in the nano-hydroxyapatite is 1: 0.01-1: 0.1.
4. The composite material according to claim 1, wherein the PLA-PEG-PLA block copolymer is present in the composite material in an amount of 90 to 99.9 wt.%, preferably the PLA-PEG-PLA block copolymer has a number average molecular weight of 4000 to 12000, preferably the polyethylene glycol segment in the PLA-PEG-PLA block copolymer has a number average molecular weight of 1000 to 3500.
5. A preparation method of a nano hydroxyapatite/block copolymer composite material is characterized by comprising the following steps:
step S1, performing first mixing on the solvent, part of polyethylene glycol and nano hydroxyapatite to obtain a first dispersion liquid;
step S2, removing the solvent in the first dispersion liquid to obtain a nano hydroxyapatite/polyethylene glycol intermediate product;
step S3, under the first vacuum condition, the mixture system containing lactide monomer, residual polyethylene glycol and the nano-hydroxyapatite/polyethylene glycol intermediate product is heated for the first time, so that the lactide monomer and the polyethylene glycol are subjected to copolymerization reaction, and the nano-hydroxyapatite/block copolymer composite material is obtained.
6. The preparation method according to claim 5, wherein in the step S1, the first mixing is performed by ultrasonic dispersion, the power of the ultrasonic dispersion is 100-1000W, the time is 20 min-4 h, preferably the concentration of the nano-hydroxyapatite in the first dispersion is 2-6 wt%, the concentration of the partial polyethylene glycol is 0.01-0.6 wt%, and preferably the number average molecular weight of the partial polyethylene glycol is 1000-3500.
7. The method as claimed in claim 5, wherein in step S2, the solvent in the first dispersion is removed by vacuum heating, and step S2 includes:
and under a second vacuum condition, carrying out second heating on the first dispersion liquid to obtain the nano hydroxyapatite/polyethylene glycol intermediate product, wherein the second heating temperature is preferably 100-120 ℃, the time is preferably 20 min-4 h, and the vacuum degree of the second vacuum condition is preferably 50-150 Pa.
8. The method according to claim 5, wherein in step S3, the first heating temperature is 130 to 140 ℃, the heating time is 5 to 10 hours, and preferably the degree of vacuum of the first vacuum condition is 50 to 150 Pa;
preferably, in the mixture system, the content of the lactide monomer is 50-85 wt%, the content of the residual polyethylene glycol is 10-40 wt%, the content of the nano hydroxyapatite/polyethylene glycol intermediate product is 0.1-10 wt%, the number average molecular weight of the residual polyethylene glycol is 1000-3500, and the particle size of the nano hydroxyapatite/polyethylene glycol intermediate product is 1-800 nm;
preferably, the mixture system further comprises a catalyst, the catalyst comprises one or more of stannous octoate, stannous chloride and stannous acetate, and the content of the catalyst in the mixture system is preferably 0.01 wt% to 0.5 wt%.
9. The preparation method according to any one of claims 5 to 8, wherein the structure of the nano-hydroxyapatite is a rod-like structure, the length of the nano-hydroxyapatite is 10 to 200nm, and the diameter of the nano-hydroxyapatite is 1 to 50 nm; preferably, the nano hydroxyapatite is the nano hydroxyapatite doped with modified metal, and the preparation method further comprises the following preparation process of the nano hydroxyapatite doped with modified metal:
heating a second dispersion liquid containing a calcium source, a phosphorus source and a modified metal salt under an alkaline condition to obtain the modified metal-doped hydroxyapatite; preferably, ammonia water is used for adjusting the pH value to 10-10.5, and the molar ratio of the modified metal salt to the calcium source to the phosphorus source is preferably 0.1-1: 10: 6; preferably, the calcium source is selected from one or two of calcium nitrate and calcium chloride, the phosphorus source is selected from any one or two of diammonium hydrogen phosphate and disodium hydrogen phosphate, and the modified metal salt is selected from nitrate of modified metal or hydrochloride of modified metal.
10. A temperature-sensitive hydrogel material comprises a temperature-sensitive material and water, and is characterized in that the temperature-sensitive material is the nano-hydroxyapatite/block copolymer composite material according to any one of claims 1 to 4 or the nano-hydroxyapatite/block copolymer composite material prepared by the preparation method according to any one of claims 5 to 9, and preferably, the temperature-sensitive material accounts for 10-20 wt% of the temperature-sensitive hydrogel material.
CN202111095553.6A 2021-09-17 2021-09-17 Nano hydroxyapatite/block copolymer composite material and preparation method thereof Active CN113797395B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111095553.6A CN113797395B (en) 2021-09-17 2021-09-17 Nano hydroxyapatite/block copolymer composite material and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111095553.6A CN113797395B (en) 2021-09-17 2021-09-17 Nano hydroxyapatite/block copolymer composite material and preparation method thereof

Publications (2)

Publication Number Publication Date
CN113797395A true CN113797395A (en) 2021-12-17
CN113797395B CN113797395B (en) 2023-02-21

Family

ID=78939583

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111095553.6A Active CN113797395B (en) 2021-09-17 2021-09-17 Nano hydroxyapatite/block copolymer composite material and preparation method thereof

Country Status (1)

Country Link
CN (1) CN113797395B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115040689A (en) * 2022-05-11 2022-09-13 上海摩漾生物科技有限公司 High-fluidity hydroxyapatite nano material and preparation method thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007084858A2 (en) * 2006-01-12 2007-07-26 Rutgers, The State University Biomimetic hydroxyapatite synthesis
CN101491690A (en) * 2009-02-16 2009-07-29 重庆大学 Preparation method of nano-micron hydroxylapatite powder
CN101757684A (en) * 2009-06-05 2010-06-30 新疆医科大学 Preparation and application of rod-like nanometer hydroxyapatite bone material
CN101974229A (en) * 2010-10-20 2011-02-16 中国科学院上海硅酸盐研究所 Polylactic acid-polyethylene glycol/europium doped calcium phosphate nano composite material, modified substance thereof and preparation of both
CN107902636A (en) * 2017-12-01 2018-04-13 华中科技大学 A kind of selenium doped hydroxyapatite and preparation method thereof
WO2019018443A1 (en) * 2017-07-17 2019-01-24 Stc.Unm Scaffolds for bone-soft tissue interface and methods of fabricating the same
CN110982335A (en) * 2019-12-30 2020-04-10 上海纳米技术及应用国家工程研究中心有限公司 Preparation method of self-curing hydroxyapatite 3D printing ink

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007084858A2 (en) * 2006-01-12 2007-07-26 Rutgers, The State University Biomimetic hydroxyapatite synthesis
CN101491690A (en) * 2009-02-16 2009-07-29 重庆大学 Preparation method of nano-micron hydroxylapatite powder
CN101757684A (en) * 2009-06-05 2010-06-30 新疆医科大学 Preparation and application of rod-like nanometer hydroxyapatite bone material
CN101974229A (en) * 2010-10-20 2011-02-16 中国科学院上海硅酸盐研究所 Polylactic acid-polyethylene glycol/europium doped calcium phosphate nano composite material, modified substance thereof and preparation of both
WO2019018443A1 (en) * 2017-07-17 2019-01-24 Stc.Unm Scaffolds for bone-soft tissue interface and methods of fabricating the same
CN107902636A (en) * 2017-12-01 2018-04-13 华中科技大学 A kind of selenium doped hydroxyapatite and preparation method thereof
CN110982335A (en) * 2019-12-30 2020-04-10 上海纳米技术及应用国家工程研究中心有限公司 Preparation method of self-curing hydroxyapatite 3D printing ink

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ZEYNEP BAL, FEZA KORKUSUZ, HIROYUKI ISHIGU ET AL: "A novel nano-hydroxyapatite/synthetic polymer/bone morphogenetic protein-2 composite for efficient bone regeneration", 《THE SPINE JOURNA》 *
樊国栋等: "聚乳酸在医学领域应用研究进展", 《科技导报》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115040689A (en) * 2022-05-11 2022-09-13 上海摩漾生物科技有限公司 High-fluidity hydroxyapatite nano material and preparation method thereof

Also Published As

Publication number Publication date
CN113797395B (en) 2023-02-21

Similar Documents

Publication Publication Date Title
Levengood et al. Chitosan-based scaffolds for bone tissue engineering
Cai et al. Preparation and characterization of homogeneous chitosan–polylactic acid/hydroxyapatite nanocomposite for bone tissue engineering and evaluation of its mechanical properties
Hossan et al. Preparation and characterization of gelatin-hydroxyapatite composite for bone tissue engineering
Xia et al. A biomimetic collagen–apatite scaffold with a multi-level lamellar structure for bone tissue engineering
Wang et al. Improved mechanical properties of hydroxyapatite/poly (ɛ-caprolactone) scaffolds by surface modification of hydroxyapatite
Ji Yin et al. Preparation and characterization of hydroxyapatite/chitosan–gelatin network composite
Zhu et al. Manufacture of layered collagen/chitosan-polycaprolactone scaffolds with biomimetic microarchitecture
Dey et al. Poly (vinylphosphonic acid‐co‐acrylic acid) hydrogels: The effect of copolymer composition on osteoblast adhesion and proliferation
CN110665063A (en) 3D biological printing ink and preparation method thereof, tissue engineering scaffold and preparation method thereof
CN107903336B (en) Creatine phosphate modified chitosan material and preparation method and application thereof
Kharaziha et al. Effects of surface modification on the mechanical and structural properties of nanofibrous poly (ε-caprolactone)/forsterite scaffold for tissue engineering applications
US20210121606A1 (en) Ionic-doped composition methods and uses thereof
Shen et al. Homogeneous chitosan/carbonate apatite/citric acid nanocomposites prepared through a novel in situ precipitation method
CN113797395B (en) Nano hydroxyapatite/block copolymer composite material and preparation method thereof
Zhang et al. Repair of volumetric bone defects with a high strength BMP-loaded-mineralized hydrogel tubular scaffold
Kim et al. Fabrication of nanofibrous macroporous scaffolds of poly (lactic acid) incorporating bioactive glass nanoparticles by camphene-assisted phase separation
CN108096629B (en) Polymethyl methacrylate bone cement and preparation method thereof
Wang et al. In situ processing and properties of nanostructured hydroxyapatite/alginate composite
Lu et al. Controllable porosity hydroxyapatite ceramics as spine cage: fabrication and properties evaluation
Pan et al. Preparation and characterization of nano-hydroxyapatite/polyvinyl alcohol gel composites
Prakasam et al. Chapter Fabrication Methodologies of Biomimetic and Bioactive Scaffolds for Tissue Engineering Applications
CN113332498A (en) Silk fibroin/hydroxyapatite composite material and preparation method and application thereof
TW201618797A (en) Porous composite body, bone regeneration material, and manufacturing method for porous composite body
CN110947034B (en) Bioactive calcium phosphate/fibrin compounded injectable bone repair hydrogel
JP5634754B2 (en) Bone hemostatic composition

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant