CN107233619A - A kind of Porous titanium bone implant material of functionalization and preparation method thereof - Google Patents

A kind of Porous titanium bone implant material of functionalization and preparation method thereof Download PDF

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Publication number
CN107233619A
CN107233619A CN201710575731.2A CN201710575731A CN107233619A CN 107233619 A CN107233619 A CN 107233619A CN 201710575731 A CN201710575731 A CN 201710575731A CN 107233619 A CN107233619 A CN 107233619A
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porous titanium
fibroin
porous
bone implant
functionalization
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胡晓帆
雷伟
冯亚非
王林
陆奕兆
相庚
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Fourth Military Medical University FMMU
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Fourth Military Medical University FMMU
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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
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/06—Titanium or titanium alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • 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
    • A61L27/56—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
    • 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
    • A61L31/022—Metals or alloys
    • 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
    • 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
    • A61L31/028—Other inorganic materials not covered by A61L31/022 - A61L31/026
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61L31/146—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
    • 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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  • Heart & Thoracic Surgery (AREA)
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Abstract

The invention discloses Porous titanium bone implant material of a kind of functionalization and preparation method thereof, belong to biology medical material technical field, be made up of the fibroin material of Porous titanium matrix and the mineralising being filled in Porous titanium matrix hole；Wherein, Porous titanium matrix is made by titanium metal particles by 3D printing；Fibroin material is the fibroin albumen of calcium phosphate mineralising.Preparation method includes：1) the 3D printing Porous titanium matrix of individuation customization is prepared according to demand, and prepares micro nano structure in Porous titanium matrix surface；2) calcic fibroin albumen is prepared；3) calcic fibroin albumen is filled in the hole of Porous titanium matrix, then carries out phosphate mineralising processing, eventually pass freeze-drying, the Porous titanium bone implant material of functionalization is made.The material can effectively improve the Bone Ingrowth of porous material and the sclerotin deposition of material surface, so as to improve the Integrated implant effect and steadiness of medical bone implant.

Description

A kind of Porous titanium bone implant material of functionalization and preparation method thereof
Technical field
The invention belongs to biology medical material technical field, and in particular to a kind of Porous titanium bone implantation material of functionalization Material and preparation method thereof.
Background technology
The Cranial defect that wound and disease etc. are caused causes great pain to patient.In bone injury reparation and reconstruction, The bone implants prepared by medical metal material, such as medical metal screw, joint prosthesis, mouth cavity planting body etc. are in Cranial defect Repair and play irreplaceable effect in reconstruction.Bone implant and host bone tissue good integration simultaneously remain long-term steady Though it is very crucial to the clinical prognosis of patient, the stability of implant depends on the Integrated implant effect of material.Studies have shown that bone The loose structure of implant metal material is due to that can reduce the modulus of elasticity of metal, reducing the stress screen of material and bone interface Barrier, so that the advantages of promoting the Integrated implant of material, it is considered to be following bone implant material design and the main trend prepared.It is medical The loose structure of material needs engineer and accurate structure to prepare, and this respect technical scheme waits to improve.
There is individual difference in the skeletal structure of patient, different parts bone is there is also morphological differences, Cranial defect usually form Irregularly, thus bone implant needs to be formed the profile and internal structure matched.This causes the concrete condition essence according to patient Really the skeleton implant of design and preparation individuation turns into the main trend of medical development, is also digital medical, accurate medical science and life The research emphasis of thing material association area.On the other hand, there are some researches prove different size of gradient-porosity inside porous implant Design, can effectively optimize its many performance, and the careful design of pore structure and preparation are then technology premises.
3D printing technique is a kind of new technology for merging near-net-shape and increasing material manufacturing, and fast development is achieved in recent years, It can complete the once-forming of complicated implant, therefore can complete the design that some conventional fabrication processes can not be completed, essence Really produce more complicated material structure.It is expected to the problem for solving material structure careful design and preparing, and is also personalization doctor Treat and provide opportunity.Titanium and its alloy are using one of most most reliable materials in medical treatment, especially in skeleton implant material Field is optimal selection all the time.It is accurate by 3D printing preparation structure recently as continuing to develop for material 3D printing technique The porous metal implants material of customization is more and more paid attention to.Asked however, 3D printing titanium implant is also faced with two aspects Topic：First, the material inertia of titanium metal material in itself causes bone tissue not good in the regeneration of material surface and sclerotin deposition, so as to make Skeletonization and material directly in conjunction with not firm enough；2nd, design of material is to promote bone group into one of main mesh of loose structure Knit and grown into by hole to material internal, but the Bone Ingrowth effect of the porous implant material of existing scheme preparation in vivo begins It is not good enough eventually, it is a problem to be solved.
It there is no that the microstructural bone implant material of material surface is prepared in 3D printing Porous titanium hole is excellent at present Change scheme.
The content of the invention
In order to overcome the defect that above-mentioned prior art is present, it is an object of the invention to provide a kind of POROUS TITANIUM of functionalization Metal bone implant material and preparation method thereof, the material can effectively improve the Bone Ingrowth of porous material and the sclerotin of material surface Deposition, so as to improve the Integrated implant effect and steadiness of bone implant.
The present invention is to be achieved through the following technical solutions：
A kind of functionalization Porous titanium bone implant material, the Porous titanium bone implant material of described functionalization is by more Hole titanium matrix and the biomimetic mineralization fibroin material composition being filled in Porous titanium matrix hole.Wherein, it is porous Titanium matrix is made by titanium metal particles by 3D printing technique, and fibroin material uses the fibroin egg of calcium phosphate mineralising In vain.
Preferably, Porous titanium matrix material of the present invention is beaten using pure titanium or medical titanium alloy powder by 3D Print is prepared from, and matrix material chemical composition is Ti6Al4V alloy or pure Ti.
Preferably, porous metal material porosity of the present invention is 60%~80%, and modulus of elasticity is less than 10GPa, hole A diameter of 100~1000 μm of gap；It can be selected according to the different implantation species of required preparation.Such as prepare bone fracture solid Optional 200 μm of smaller aperture when using metallic screw surely.
Alternately, the raw material metal diameier for 3D printing is 10~50 μm.Can be according to clinical needs The specific implantation species prepared are in optimized selection, such as a diameter of 10 μm optional to spinal bone screw of small powder, for people The larger powder for preparing optional 50 μm in work joint.
Preferably, 3D printing technique, which is that electron beam melting 3D printing, laser 3D printing etc. are all, can prepare porous metals material The 3D printing technique of material.
Preferably, (i.e. bumps are not in the dual microstructure of composite micro-nano rice for present invention Porous titanium matrix surface used Flat micrometer structure and the nanotube on micrometer structure surface), the dual microstructure of composite micro-nano rice is 15 by micron hole and caliber ~100nm nano-tube array is constituted.Wherein, micrometer structure is cheated for rough micron；
Preferably, nanotube uses titania nanotube, a diameter of 15~50nm of titania nanotube；More preferably Ground, a diameter of 15nm of titania nanotube.
The fibroin albumen of calcium phosphate mineralising used in the present invention is that deposited calcium phosphate crystal on fibroin fiber, Itself it is a kind of composite with irregular loose structure.Preferably, the dry ratio of calcium phosphate and fibroin albumen For 1:3~8；It is highly preferred that this ratio is 1:5.
The invention also discloses the preparation method of the Porous titanium bone implant material of above-mentioned functions, including following step Suddenly：
1) the 3D printing Porous titanium matrix of individuation customization is prepared according to demand, and in Porous titanium matrix surface Prepare micro nano structure；
2) calcic fibroin albumen is prepared；
3) calcic fibroin albumen is filled in the hole of Porous titanium matrix, then carries out phosphate mineralising processing, most By freeze-drying, the Porous titanium bone implant material of functionalization is made.
Specifically, step 1) concrete operations are：
First, the CT view data of patient is gathered, the porous implantation of individuation customization is designed in three-dimensional imaging software The profile and internal pore structure of thing；It is 100~800 μm to design rod member width, and pore diameter is 100~1000 μm, with pros Body or the filling of regular dodecahedron structural units and expanded images, obtain the 3-D view of target implant, by the target implant 3 D image file import metal material 3D printer, using Porous titanium material as raw material, Porous titanium matrix is made； Preferably, obtained Porous titanium matrix is cleaned by ultrasonic by alcohol, acetone and distilled water, and cleaning 15 in every kind of cleaning solution~ 20min, is washed away after drying or dry naturally in surface contaminants, 50 DEG C of baking ovens, standby.
Secondly, obtained Porous titanium matrix is immersed into acid etching in hydrofluoric acid solution, its surface is formed micron Cheat structure；Preferably, the concentration of hydrofluoric acid solution used is 50g/L, and the acid etching time is 30~60min；Anodic oxidation electricity Press as 1~20V, processing time is 1h.
Finally, 1h is handled in the electrolyte Anodic Oxidation containing phosphoric acid and hydrofluoric acid, voltage is set as 1~20V, micro- The nano-tube array that rice hole body structure surface formation caliber is about 15~100nm, i.e., be made micron in Porous titanium matrix surface With the dual microstructure of nano level composite micro-nano rice.
Preferably, a diameter of 20~50 μm of Porous titanium material；The rod member width of 3D printing Porous titanium is 100 ~800 μm, pore diameter is 100~1000 μm.
Step 2) concrete operations are：
First, (need can be estimated according to 3 d image data by the dry weight and material internal total pore volume of fibroin albumen The total pore volume of the porous metal material to be filled) ratio weigh the fibroin albumen of corresponding amount, fibroin albumen is added In 9.3mol/L LiBr solution, constant temperature processing makes it fully dissolve at 60 DEG C, is removed with deionized water dialysis 72h in solution LiBr, be prepared into mass volume ratio for 3%~6% silk fibroin protein solution；Weigh in the dry weight and porous material of fibroin albumen The ratio of portion's total pore volume is 0.1~0.3g：1cm3；Dialysis time is more than or equal to 72h；
Secondly, the CaCl of fibroin albumen dry weight 5% is added into silk fibroin protein solution2, stirring dissolves it, mixes Uniformly, calcic silk fibroin protein solution is made.
Step 3) concrete operations are：
Calcic silk fibroin protein solution is slowly added dropwise in step 1 from top) made from Porous titanium matrix surface, make molten Liquid is fully spread uniformly by interpore be interconnected in material, and the amount of dropwise addition is just defined by solution full of hole, so 12~24h of stewing process, makes calcic silk fibroin protein solution form hydrogel in material hole afterwards；Hydrogel material is immersed in Na2HPO4The aqueous solution in, at 37 DEG C constant temperature stand more than 48h, make in the calcium ion and solution in silk fibroin hydrogel Phosphate anion formation synthos, and crystallizing on fibroin fiber, obtaining composite, then by the composite vacuum Freeze-drying, is made the Porous titanium bone implant material of functionalization.
Preferably, Na2HPO4The concentration of the aqueous solution is 10~18mM, pH=8.5；Composite is in Na2HPO4In the aqueous solution The time of standing is 72h.
Compared with prior art, the present invention has following beneficial technique effect：
The Porous titanium bone implant material of functionalization disclosed by the invention, by Porous titanium matrix and be filled in it is porous Fibroin material composition in titanium matrix hole；Wherein, Porous titanium matrix passes through 3D printing by titanium metal particles It is made；For the fibroin albumen of calcium phosphate mineralising, (fibroin albumen and azelon surface combine upper calcium in fibroin material Phosphate is two kinds of materials, and what " mineralising " referred to is exactly inorganic salts in fibroin fiber surface crystallization).Fibroin albumen and calcium phosphoric acid The reticulated porous structures of salt crystal formation have the property of " porous artificial bionic bone " in itself：The essence of fibroin albumen is fiber egg In vain, equivalent to the organic principle in sclerotin --- collagenous fibres, and the main inorganic composition of calcium phosphate inherently sclerotin, two The combination of hydroxyapatite crystal and a Collagen Type VI in the similar natural sclerotin of combination of person.Therefore, it is of the invention by calcium The silk fibroin micropore Material cladding of phosphate mineralising can be bone and its cells in intrapore adhesion in porous metals hole Good microenvironment is provided, induction bone tissue is quickly grown into hole, so that it is not good to solve porous metal material Bone Ingrowth Problem, promotes the good integration of Porous titanium implant material and bone and consolidates for a long time.
Further, Porous titanium matrix surface of the invention is in the dual microstructure of composite micro-nano rice, composite micro-nano Meter Shuan Chong microstructures are made up of the nanotube on micrometer structure and micrometer structure surface.By micron order and Nanoscale Surface pattern Advantage and effect are merged, and are formed surfacing functional layer, can effectively be reduced the biologically inert of titanium metal material, improve it Tissue compatibility；Adhesion for a variety of cells for participating in osteanagenesis process such as Gegenbaur's cell in metal surface provides more preferable micro-loop Border, the titanium nanometer micro-pipe of suitable size can produce influence by adhesion molecule on cell membrane etc. on intracellular metabolism process, Improve the stress situation of material-bone interface cell, promote the Function and material surface sclerotin deposition of cell, so as to finally promote Enter formed between metal implant material and bone it is stronger directly in conjunction with.
The preparation method of the Porous titanium bone implant material of functionalization disclosed by the invention, whole process mild condition, Natural original attribute of the components such as fibroin albumen can be effectively kept, and harmful accessory substance will not be produced, biological safety is high.
Brief description of the drawings
Fig. 1 is the porous titanium alloy material matrix in embodiment 1 using 3D printing preparation.
Fig. 2 is the photo for the functionalization Porous titanium bone implant material being finally prepared into embodiment 1.
Fig. 3 is the stereoscan photograph (microcosmic) for the composite being prepared into embodiment 1, it is shown that filled in hole Synthos mineralising fibroin albumen.
The influence that Fig. 4 breeds for different materials in embodiment 4 to material surface osteoblast cells.
Fig. 5 is different materials in embodiment 4 to alkaline phosphatase enzymatic activity (Osteoblast Differentiation journey in material surface Gegenbaur's cell Degree) influence.
Fig. 6 is the synosteosis fractional statisticses number of 6 weeks materials after different bone implant material implantation in rabbit femur condyles in embodiment 5 According to.
Data are all average ± standard deviations in accompanying drawing；* represent and common titanium sheet group (common medical solid titanium material Material) to compare, data have significant difference (p<0.05).
Embodiment
With reference to specific embodiment, the present invention is described in further detail, it is described be explanation of the invention and It is not to limit.
The invention discloses a kind of preparation method of functionalization Porous titanium bone implant material, comprise the following steps：
Step one：Prepare the 3D printing titanium bone implant material matrix of individuation customization.
The CT view data of patient is gathered, the target implantation of individuation is analyzed and design in three-dimensional imaging software CAD Thing material profile and internal void size.Filled with square or hexahedron structure unit and extend the image, obtain target The 3-D view of implant.The 3 D image file is imported into metal material 3D printer, with Ti6Al4V alloy or pure Ti metals Microballoon sprills are raw material, and 3D printing is prepared into profile and pore structure and is implanted into the completely the same porous metals of design configuration Thing.Porous metal implants material is cleaned by ultrasonic by alcohol, acetone and distilled water, 20min in every kind of cleaning solution, washes away surface Dry or dry naturally standby in dirt, 50 DEG C of baking ovens.
Step 2：The preparation of Porous titanium surface micronano structure.
Porous titanium material matrix immerses hydrofluoric acid acid etching, its surface is formed micron hole structure；Then containing There is the electrolyte Anodic Oxidation of phosphoric acid and hydrofluoric acid, by adjusting anodic oxidation voltage, topographical surface forms spy in micron hole The nano-tube array of fixed-caliber.So as to form micron and nano level dual microstructure on metal matrix material surface.
Step 3：Prepare silk fibroin protein solution.
The total pore volume for the porous metal material for needing to fill is estimated according to 3 d image data.Weigh appropriate fibroin egg In vain, the LiBr solution for adding 9.3M makes fibroin albumen fully dissolve in 60 DEG C of constant temperature 4h, afterwards deionized water is dialysed to remove LiBr in solution, is prepared into the silk fibroin protein solution that mass volume ratio is 3~6%, standby.
Step 4：The silk fibroin hydrogel of calcium ions is combined in porous metal material hole.
Appropriate CaCl is added in the silk fibroin protein solution prepared to step 32, it is well mixed.The solution is delayed from top Slowly it is added dropwise on dry Porous titanium matrix, solution is passed through interpore full and uniform in material expand that be interconnected Dissipate, the amount of dropwise addition is just defined by solution full of hole.This composite is put into 50 DEG C of baking ovens and stands 12-24h, makes calcic silk Fibroin solution forms hydrogel in material hole.
Step 5：Mineralising deposition of the synthos on fibroin fiber.
Material prepared by step 4 is immersed in containing Na2HPO4In the aqueous solution, 37 DEG C of constant temperature are stood more than 48h, make fibroin egg Phosphate anion formation synthos in calcium ion and solution in plain boiled water gel, and crystallize on fibroin fiber.Again This composite is freeze-dried 48h in vacuum freeze drier, being finally prepared into surface has micro-nano pattern and in hole The 3D printing Porous titanium bone implant material of synthos mineralising fibroin albumen is compounded with gap.
Embodiment 1
1. prepare the 3D printing titanium alloy implants material of individuation customization
(1) the CT view data of patient bone defect is gathered, is imported in three-dimensional imaging software CAD, it is specific according to patient Situation analysis and design individuation target implants material profile and internal pore structure.Wherein, rod member width is 200 μm, average pore diameter is 400 μm, is filled with cube structure unit and extends the image, obtains the three-dimensional of target implants Image.
(2) 3 D image file is imported into electron beam melting (EBM) metal material 3D printer, utilizes a diameter of 30 μm Ti6Al4V alloy powder, is prepared into the porous metals implants that individuation is customized, referring to Fig. 1 by 3D printing.
(3) porous metals implants material is cleaned by ultrasonic by alcohol, acetone and distilled water, 20min in every kind of cleaning solution, Wash away in surface contaminants, 50 DEG C of baking ovens and dry or dry naturally standby.
2. porous titanium alloy material surface prepares micro-nano microstructure
(1) the Porous titanium material prepared in step 1 immerses 50g/L hydrofluoric acid acid etching 30min, makes its surface Form micron hole structure.
(2) and then in the electrolyte Anodic Oxidation 1h containing phosphoric acid and hydrofluoric acid, voltage is set as 7.5V, in micron hole The nano-tube array that body structure surface formation caliber is about 20nm.So as to form micron and nano level on metal matrix material surface Composite Double representation micro-structural.
3. prepare silk fibroin protein solution
The total pore volume for the porous metal material for needing to fill is estimated according to 3 d image data.By fibroin albumen dry weight Ratio with material internal total pore volume is 0.2g：1cm3Ratio weigh fibroin albumen.Configure 9.3M's with deionized water LiBr solution is used to dissolve fibroin albumen.The LiBr of fibroin albumen 5 times of volumes of quality is added in the centrifuge tube of suitable size Solution, fibroin albumen submerges wherein completely, 60 DEG C of constant temperature 4h, fibroin albumen is dissolved completely in solution.Again with retention molecule The bag filter for measuring the suitable size for 3500D dialyses the solution to deionized water, common 72h, to remove in solution LiBr.12000rmp/min rotating speeds centrifuge 20min after the completion of dialysis, take supernatant, obtain the fibroin that mass volume ratio is 3~6% Protein solution, it is standby.
4. the silk fibroin hydrogel of calcium ions is combined in porous metal material hole.
Into silk fibroin protein solution CaCl is added in 5wt% ratio2, stirring dissolves it, well mixed.By the solution It is slowly added dropwise from top on dry Porous titanium matrix, solution is interconnected by interpore in material fully Uniform diffusion, the amount of dropwise addition is just defined by solution full of hole.This composite is put into 50 DEG C of baking ovens and stands 12h, makes to contain Calcium silk fibroin protein solution forms hydrogel in material hole.
5. mineralising deposition of the synthos on fibroin fiber.
Material prepared by step 4 is immersed in 18mM Na2HPO4In the aqueous solution (pH=8.5), 37 DEG C of constant temperature stand 72h, Make the phosphate anion formation synthos in the calcium ion and solution in silk fibroin hydrogel, and crystallize fine in fibroin albumen In dimension.Again by this composite in vacuum freeze drier, pressure value is less than 1Pa in vacuum chamber, and temperature is -20 DEG C, freezing 48h is dried, the 3D that surface has micro-nano pattern and synthos mineralising fibroin albumen is compounded with hole is finally prepared into Porous titanium alloy bone implant material is printed, referring to Fig. 2 and Fig. 3.As seen from Figure 3, the phosphate filled in porous material hole The loose and porous structure of level of different sizes is presented in mineralising fibroin albumen, not only participates in osteanagenesis cell beneficial to Gegenbaur's cell etc. Adhesion and propagation, can also effectively adsorb the activated protein composition in body fluid, provide good microenvironment for local organization regeneration, profit Grown into freshman bone tissue into hole, promote the Integrated implant of material.
Embodiment 2
1. prepare the 3D printing pure titanium metal bone implant material of individuation customization
(1) the CT view data of patient bone defect is gathered, is imported in three-dimensional imaging software CAD, it is specific according to patient Situation analysis and design individuation target implants material profile and internal pore structure.Wherein, rod member width is 200 μm, average pore diameter is 400 μm, is filled with regular dodecahedron structural units and extends the image, obtains target implants 3-D view.
(2) 3 D image file is imported into electron beam melting (EBM) metal material 3D printer, is about 30 using diameter μm pure titanium metal powder, by 3D printing be prepared into individuation customize porous pure titanium metal material.
(3) porous pure titanium metal material is cleaned by ultrasonic by alcohol, acetone and distilled water, 20min in every kind of cleaning solution, washes Go in surface contaminants, 50 DEG C of baking ovens to dry or dry naturally standby.
2. porous titanium alloy material surface prepares micro-nano microstructure
(1) the porous pure titanium metal material prepared in step 1 immerses 50g/L hydrofluoric acid acid etching 30min, makes its table Face forms micron hole structure.
(2) and then in the electrolyte Anodic Oxidation 1h containing phosphoric acid and hydrofluoric acid, voltage is set as 7.5V, in micron hole The nano-tube array that body structure surface formation caliber is about 20nm.So as to form micron and nano level on metal matrix material surface Composite Double representation micro-structural.
3. prepare silk fibroin protein solution
The total pore volume for the porous metal material for needing to fill is estimated according to 3 d image data.By fibroin albumen dry weight Ratio with material internal total pore volume is 0.2g：1cm3Ratio weigh fibroin albumen.Configure 9.3M's with deionized water LiBr solution is used to dissolve fibroin albumen.The LiBr of fibroin albumen 5 times of volumes of quality is added in the centrifuge tube of suitable size Solution, fibroin albumen submerges wherein completely, 60 DEG C of constant temperature 4h, fibroin albumen is dissolved completely in solution.Again with retention molecule The bag filter for measuring the suitable size for 3500D dialyses the solution to deionized water, common 72h, to remove in solution LiBr.12000rmp/min rotating speeds are centrifuged 20 minutes after the completion of dialysis, take supernatant, obtain the fibroin that mass volume ratio is 3~6% Protein solution, it is standby.
4. the silk fibroin hydrogel of calcium ions is combined in porous pure titanium metal material hole.
Into silk fibroin protein solution CaCl is added in 5wt% ratio2, stirring dissolves it, well mixed.By the solution It is slowly added dropwise from top on dry Porous titanium matrix, solution is interconnected by interpore in material fully Uniform diffusion, the amount of dropwise addition is just defined by solution full of hole.This composite is put into 50 DEG C of baking ovens and stands 12h, makes to contain Calcium silk fibroin protein solution forms hydrogel in material hole.
5. mineralising deposition of the synthos on fibroin fiber.
Material prepared by step 4 is immersed in Na containing 18mM2HPO4The aqueous solution (pH=8.5) in, 37 DEG C of constant temperature are stood 72h, makes the phosphate anion formation synthos in the calcium ion and solution in silk fibroin hydrogel, and crystallize in fibroin egg On white fiber.Again by this composite in vacuum freeze drier, pressure value is less than 1Pa in vacuum chamber, and temperature is -20 DEG C, 48h is freeze-dried, being finally prepared into surface has micro-nano pattern and synthos mineralising fibroin albumen is compounded with hole 3D printing porous pure titanium metal bone implant material.
Embodiment 3
1. prepare the 3D printing titanium alloy bone implant material of individuation customization
(1) the CT view data of patient bone defect is gathered, is imported in three-dimensional imaging software CAD, it is specific according to patient Situation analysis and design individuation target implants material profile and internal pore structure.Wherein, rod member width is 400 μm, average pore diameter is 800 μm, is filled with regular dodecahedron structural units and extends the image, obtains target implants 3-D view.
(2) 3 D image file is imported into laser metal material 3D printer, is about 40 μm of pure titanium using diameter Belong to powder, the porous pure titanium metal material that individuation is customized is prepared into by 3D printing.
(3) porous titanium alloy material is cleaned by ultrasonic by alcohol, acetone and distilled water, 20min in every kind of cleaning solution, washes away Dry or dry naturally standby in surface contaminants, 50 DEG C of baking ovens.
2. porous titanium alloy material surface prepares micro-nano microstructure
(1) the porous titanium alloy material prepared in step 1 immerses 50g/L hydrofluoric acid acid etching 30min, makes its surface Form micron hole structure.
(2) and then in the electrolyte Anodic Oxidation 1h containing phosphoric acid and hydrofluoric acid, voltage is set as 10V, in micron hole The nano-tube array that body structure surface formation caliber is about 30nm.So as to form micron and nano level on metal matrix material surface Composite Double representation micro-structural.
3. prepare silk fibroin protein solution
The total pore volume for the porous metal material for needing to fill is estimated according to 3 d image data.By fibroin albumen dry weight Ratio with material internal total pore volume is 0.2g：1cm3Ratio weigh fibroin albumen.Configure 9.3M's with deionized water LiBr solution is used to dissolve fibroin albumen.The LiBr of fibroin albumen 5 times of volumes of quality is added in the centrifuge tube of suitable size Solution, fibroin albumen submerges wherein completely, 60 DEG C of constant temperature 4h, fibroin albumen is dissolved completely in solution.Again with retention molecule The bag filter for measuring the suitable size for 3500D dialyses the solution to deionized water, common 72h, to remove in solution LiBr.12000rmp/min rotating speeds are centrifuged 20 minutes after the completion of dialysis, take supernatant, obtain the fibroin that mass volume ratio is 3~6% Protein solution, it is standby.
4. the silk fibroin hydrogel of calcium ions is combined in porous metal material hole.
Into silk fibroin protein solution CaCl is added in 5wt% ratio2, stirring dissolves it, well mixed.By the solution It is slowly added dropwise from top on dry Porous titanium matrix, solution is interconnected by interpore in material fully Uniform diffusion, the amount of dropwise addition is just defined by solution full of hole.This composite is put into 50 DEG C of baking ovens and stands 18h, makes to contain Calcium silk fibroin protein solution forms hydrogel in material hole.
5. mineralising deposition of the synthos on fibroin fiber.
Material prepared by step 4 is immersed in Na containing 12mM2HPO4The aqueous solution (pH=8.5) in, 37 DEG C of constant temperature are stood 72h, makes the phosphate anion formation synthos in the calcium ion and solution in silk fibroin hydrogel, and crystallize in fibroin egg On white fiber.Again by this composite in vacuum freeze drier, pressure value is less than 1Pa in vacuum chamber, and temperature is -20 DEG C, 48h is freeze-dried, being finally prepared into surface has micro-nano pattern and synthos mineralising fibroin albumen is compounded with hole 3D printing porous titanium alloy bone implant material.
Influence of the evaluation function porous titanium alloy bone implant material of embodiment 4 to osteoblast cells function
The present embodiment is by functionalization porous titanium alloy bone implant material prepared in embodiment 1 to being sent out in bone tissue regeneration The influence of the cell of key effect --- Gegenbaur's cell --- cell function is waved, that is, provides the material and the cell of Gegenbaur's cell is increased Grow the castering action with Osteoblast Differentiation.
Experimental method：Using common solid medical titanium alloy sheet metal as control group material, with prepared in embodiment 1 Functionalization porous titanium alloy bone implant material is experimental group material, by each group material under equal conditions in alcohol, deionization It is cleaned by ultrasonic respectively 10 minutes in two kinds of liquid of water, room temperature is dried naturally, and C is utilized afterwards60Radiation exposure sterilizes for 1 hour.Utilize The Gegenbaur's cell for the SD rat suckling mouse skulls being separately cultured, 1 × 10 is pressed by it4The cell density of individual/milliliter is on each material Inoculation 5 × 104Individual cell, using the DMEM cell culture mediums containing 10%FBS, carries out material and thin in 12 porocyte culture plates The co-cultivation of born of the same parents.
It is divided into 2 groups：
1) common titanium sheet group
2) functionalization porous titanium alloy bone implant material group
The the 3rd and the 7th day of culture, the difference of osteoblast cells proliferation activity in varying environment is detected with mtt assay；Culture The 7th day, detect material Gegenbaur's cell Osteoblast Differentiation degree (ALP activity with alkaline phosphatase (ALP) enzyme activity detection kit React Osteoblast Differentiation degree), evaluate influence of the varying environment to Gegenbaur's cell Osteoblast Differentiation state.
As a result referring to Fig. 4 and Fig. 5：Compared with the cell in common titanium sheet, on functionalization porous titanium alloy bone implant material Cells Cell Proliferation 63% and 69% (Fig. 4) has been respectively increased at the 3rd and the 7th day, and ALP enzymatic activitys are then the former 1.51 Times (Fig. 5), the statistically significant (p of data difference between two groups<0.05).
Interpretation of result：The above results show that the functionalization porous titanium alloy bone prepared by technical scheme of the present invention is planted Enter material and effect is obviously promoted to the cell propagation and Osteoblast Differentiation function of Gegenbaur's cell, thus surrounding materials can be effectively facilitated Osteanagenesis and material Integrated implant.
The functionalization porous titanium alloy bone implant material of embodiment 5 is made to internal osteanagenesis and the lifting of material Integrated implant effect With
By functionalization porous titanium alloy bone implant material prepared in embodiment 1 to the material week in diabetic animal body Enclose the facilitation of osteanagenesis and material Integrated implant effect.
Experimental method：Alloxan (STZ) 50mg/kg tail vein injections is white in body weight about 3.5kg Male New Zealand Rabbit, 1 time a day, for three days on end.7 days, survey fasting blood-glucose, fasting blood-glucose after last time is injected>300mg/dl is dynamic for diabetes Thing, for follow-up test.The solid plain medical titanium of form size identical (diameter 10mm, thickness 3mm round pie) is taken to close Prepared functionalization porous titanium alloy bone implant material in golden material and embodiment one, under surgical conditions, implantation in rabbit Bilateral femur condyle is implanted into.Animal is randomly divided into 2 groups, every group 12：
1) common titanium sheet group；
2) functionalization porous titanium alloy bone implant material group.
6 weeks materials after material implantation, take the femur specimen for implanting material, sample fix 3 days through 4% formaldehyde after with micro- CT scan (GE companies) is detected.The synosteosis fraction of bone implant is calculated using microscopic CT scanning data, each group titanium alloy is evaluated Surrounding materials bone rege-neration and material Integrated implant effect.
As a result it is as shown in Figure 6：It is porous compared with the 55.4% of common medical solid titanium alloy on synosteosis fraction The data between 71.3%, group that brought up to of titanium alloy bone implant material have significant difference (p<0.05).
Interpretation of result：The above results illustrate that functionalization porous titanium alloy bone implant material prepared by the present invention can effectively promote Enter the osteanagenesis around internal bone implant and in material void, lift the Integrated implant effect of material, so as to strengthen the plant of metal bone Enter the stability of thing.
In summary, the present invention is compared with prior art, with the obvious advantage：
1st, the present invention is formed well to improve the intrapore Bone Ingrowth effect of porous material in porous material hole Chemistry and structure microenvironment, thus induce and promotes the newborn of bone tissue and grown into hole, it is necessary in hole composite number Amount, structure and chemical composition all suitable functional activity materials.The fibroin albumen that the present invention is selected is extracted from silk Natural fiber albumen, containing 18 kinds of amino acid, 11 kinds therein are essential amino acid.Fibroin albumen has good in itself Mechanical performance and physicochemical property, such as good pliability and tensile strength, breathable moisture permeability, slow release, and by not Different forms, such as fiber, solution, powder, film and gel can be obtained with processing.Fibroin albumen abundance, be easy to plus Work and modification, safety non-toxic, can degradation in vivo, can property material suitable for succeeding in developing.
2nd, by biomimetic mineralization method make calcium phosphate in solution environmental uniform deposition fibroin albumen formed it is irregular Holey fibre structure surface, overcomes problems with：First, calcium phosphate is constituted into as the host inorganic thing of natural sclerotin Point, with good osteoinductive, but it is unable to firm attachment in metal material surface, it is easy to come off, and it is in fibroin egg Formed on the reticular fibre constituted in vain it is homogeneously crystallized after can firmly be compound in material hole；2nd, the osteoinductive of fibroin albumen Limited, rationally compound with calcium phosphate can effectively improve its osteoinductive, can advantageously promote the bone of material-bone interface again It is raw.
3rd, the reticulated porous structures of fibroin albumen and calcium phosphate Crystallization have " porous artificial bionic bone " in itself Property：The essence of fibroin albumen is fibrin, equivalent to the organic principle in sclerotin --- collagenous fibres；And calcium phosphate sheet Body is exactly the inorganic constituents of sclerotin；The knot of hydroxyapatite crystal and a Collagen Type VI in both similar natural sclerotin of combination Conjunction mode.The silk fibroin micropore Material cladding of this calcium phosphate mineralising is in porous metals hole, being bone and its cells Good microenvironment is provided in intrapore adhesion, induction bone tissue is quickly grown into hole, so as to solve porous metals material Expect the problem of Bone Ingrowth is not good, promote the good integration of Porous titanium implant material and bone and consolidate for a long time.
4th, can be uniform on 3D printing Porous titanium surface (including in hole) by acid etching in solution and anodizing Ground prepares micro-nano microstructure, and the advantage and effect of micron order and Nanoscale Surface pattern are merged, and forms surface Material function layer.It can effectively reduce the biologically inert of titanium metal material, improve its tissue compatibility；It is a variety of for Gegenbaur's cell etc. Participate in adhesion of the cell of osteanagenesis process in metal surface and more preferable microenvironment is provided, the titanium nanometer micro-pipe of suitable size can lead to Adhesion molecule on cell membrane etc. produces influence to intracellular metabolism process, and improve material-bone interface cell stress shape State, promotes the Function and material surface sclerotin deposition of cell, so as to finally promote shape between metal implant material and bone Into it is stronger directly in conjunction with.
5th, the sclerotin deposition effect that Bone Defect Repari process in which materials surface is depended on directly in conjunction with effect of material and bone.Material Behavior of the topology on surface on surrounding tissue cells makes a significant impact, and the microstructure optimization of material surface can promote material Expect osteanagenesis and the sclerotin deposition on surface.The material surface pattern of different scale produces Different Effects, micron order to cell behavior It can promote the cell viability of metal surface, protein adsorption, inostosis and heavy by different mechanisms with nano level surface texture Product.

Claims (10)

1. the Porous titanium bone implant material of a kind of functionalization, it is characterised in that the Porous titanium bone implant material is by more Hole titanium matrix and the fibroin material composition being filled in Porous titanium matrix hole；Wherein, Porous titanium base Body is made by titanium metal particles by 3D printing；Fibroin material is the fibroin albumen of calcium phosphate mineralising.
2. the Porous titanium bone implant material of functionalization according to claim 1, it is characterised in that Porous titanium is Pure titanium or medical titanium alloy.
3. the Porous titanium bone implant material of functionalization according to claim 1, it is characterised in that Porous titanium base Body surface face is in the dual microstructure of composite micro-nano rice, and the dual microstructure of composite micro-nano rice is by micrometer structure and micrometer structure surface Nanotube constitute.
4. the Porous titanium bone implant material of functionalization according to claim 1, it is characterised in that calcium phosphate mineralising Fibroin albumen be to deposit synthos by biomimetic mineralization on fibroin fiber to crystallize, fibroin albumen uses natural silk Albumen.
5. the Porous titanium bone implant material of functionalization according to claim 1, it is characterised in that by per cubic centimeter Pore volume fill 0.1~0.3g fibroin materials ratio, fibroin material is filled in Porous titanium matrix Hole in.
6. the Porous titanium bone implant material of functionalization according to claim 1, it is characterised in that Porous titanium base The porosity of body is 60%~80%, and modulus of elasticity is less than 10GPa, and pore diameter is 100~1000 μm.
7. the preparation method of the Porous titanium bone implant material of the functionalization in claim 1~6 described in any one, it is special Levy and be, comprise the following steps：
1) the 3D printing Porous titanium matrix of individuation customization is prepared according to demand, and is prepared in Porous titanium matrix surface Micro nano structure；
2) calcic fibroin albumen is prepared；
3) calcic fibroin albumen is filled in the hole of Porous titanium matrix, then carries out phosphate mineralising processing, most passed through afterwards Freeze-drying, is made the Porous titanium bone implant material of functionalization.
8. the preparation method of the Porous titanium bone implant material of functionalization according to claim 7, it is characterised in that step Rapid 1) concrete operations are：
First, the CT view data of patient is gathered, the porous implant of individuation customization is designed in three-dimensional imaging software Profile and internal pore structure；It is 100~800 μm to design rod member width, and pore diameter is 100~1000 μm, with square or Regular dodecahedron structural units fills and expanded images, the 3-D view of target implant is obtained, by the three of the target implant Tie up image file and import metal material 3D printer, using titanium metal material particle as raw material, Porous titanium matrix is made in printing；
Secondly, obtained Porous titanium matrix is immersed into acid etching in hydrofluoric acid solution, its surface is formed micron hole knot Structure；
Finally, in the electrolyte Anodic Oxidation processing containing phosphoric acid and hydrofluoric acid, voltage is set as 1~20V, cheats and tie in micron Structure surface forms the nano-tube array that caliber is about 15~100nm, i.e., micron and nanometer is made in Porous titanium matrix surface The dual microstructure of composite micro-nano rice of level.
9. the preparation method of the Porous titanium bone implant material of functionalization according to claim 7, it is characterised in that step Rapid 2) concrete operations are：
First, the fibroin albumen of corresponding amount is weighed in the dry weight of fibroin albumen and the ratio of material internal total pore volume, by silk Fibroin is added in LiBr solution, and constant temperature processing makes it fully dissolve at 60 DEG C, and dialysis removes the LiBr in solution, is prepared into Silk fibroin protein solution；
Secondly, the CaCl of fibroin albumen dry weight 5%~8% is added into silk fibroin protein solution2, stirring dissolves it, mixes Uniformly, calcic silk fibroin protein solution is made.
10. the preparation method of the Porous titanium bone implant material of functionalization according to claim 9, it is characterised in that Step 3) concrete operations are：
By calcic silk fibroin protein solution from top be added dropwise in step 1) made from Porous titanium matrix surface to be full of matrix table The hole in face, 12~24h of stewing process, is immersed in Na2HPO4The aqueous solution in, at 37 DEG C constant temperature stand more than 48h, obtain Composite, then by the composite vacuum freeze drying, the Porous titanium bone implant material of functionalization is made.
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CN108853578A (en) * 2018-06-15 2018-11-23 南京冬尚生物科技有限公司 A kind of 3D printing Ti- hydrogel-osteoblast bone tissue engineering scaffold and preparation method thereof
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CN114732945A (en) * 2022-04-13 2022-07-12 广西农业职业技术大学 Method for improving bioactivity of titanium alloy bone
CN114732945B (en) * 2022-04-13 2023-01-03 广西农业职业技术大学 Method for improving bioactivity of titanium alloy bone
CN115068686A (en) * 2022-05-18 2022-09-20 复旦大学附属中山医院 Natural-source black phosphorus-silk protein-cellulose biological scaffold
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Application publication date: 20171010