CN105664259B - The construction method of medical titanium alloy implant surface drug sustained release system - Google Patents

The construction method of medical titanium alloy implant surface drug sustained release system Download PDF

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CN105664259B
CN105664259B CN201610030777.1A CN201610030777A CN105664259B CN 105664259 B CN105664259 B CN 105664259B CN 201610030777 A CN201610030777 A CN 201610030777A CN 105664259 B CN105664259 B CN 105664259B
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titanium alloy
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CN105664259A (en
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黄啸
郑曦
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Tongren University
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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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular 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
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
    • 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
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment

Abstract

The invention discloses the construction method of medical titanium alloy implant surface drug sustained release system, feature be include the steps that grafted maleic anhydride prepares maleic anhydride grafted polylactic acid in polylactic acid by solvent blending method；The step of by being self-assembled into ball to be prepared including the MPLA microballoons of streptomycin sulphate；By surface graft modification so that titanium alloy surface amination, so that titanium surface is positively charged, pass through layer-by-layer again, using MPLA microballoons and PEI as anions and canons, utilize electrostatic adsorption, the multilayer antibacterial film of titanium surface construction SS MPLA microballoons/PEI the step of, advantage be implant surfaces in vivo multilayer film degradation while streptomycin sulphate slowly release, achieve the effect that long-term antibacterial, it is good with compatibility, stability is high, is firmly combined with, the effect of slow-release time length.

Description

The construction method of medical titanium alloy implant surface drug sustained release system
Technical field
The present invention relates to a kind of medical titanium alloy implants, more particularly, to a kind of medical titanium alloy implant surface drug The construction method of slow-released system.
Background technology
Bio-medical material (biomedical material) is diagnosis, treatment or tissue, organ in replacement organism Or promote tissue, organ corresponding function, and there is no dysgenic material to human body.Bio-medical material can be natural Can also be synthesis such as high molecular material, ceramics and carbon materials, artificial such as biologically active cell, tissue, organ Synthetic material either metal and alloy material.Equally can also be the compound of natural material and synthetic material will such as have life Active cell assembling is ordered on synthetic material with as the implant with therapeutic effect.Since titanium and titanium alloy surface are formed The TiO stablized2Film, mechanical strength is high, and elasticity modulus is low to have good fatigue resistance and mouldability, excellent biology Compatibility and corrosion resistance are a kind of comparatively ideal surgical implants.Currently, titanium alloy material has been widely used in people Work joint, Fracture internal fixaiion and backbone correcting and the fixed material of fusion, however due to the implantation of titanium alloy, lead to organizational interface Immunocompetence reduces so that implant is easy to happen infection after entering human body, and bacterium will be attached in implant surfaces, go forward side by side Row quickly a large amount of breeding, forms fine and close biomembrane in implant surfaces, and conventional antibiotherapy is difficult to pass through people Body circulation enters implant surfaces by killing bacteria, generally requires multiple debridement surgical to make up and not only increases expense but also to trouble Person brings secondary insult.Therefore implant of the structure with bacteriostasis property is the effective way for preventing postoperative infection.It is at present Only, the antibiotic property of titanium is mainly improved using following two categories method.First, the physicochemical properties by changing material surface For example property is charged on surface moist, hydrophilic and hydrophobic, surface freedom and surface, or change the pattern of implant surfaces to reach To the effect for inhibiting bacterial adhesion；Second is that carrying antibiotic in implant surfaces to achieve the effect that antibacterial.
Polylactic acid (Polylactic acid, PLA) is a kind of novel degradable high polymer material, through U.S.'s food and Drug administration (FDA) approval is medical, and rapid development has been obtained since the 1990s.PLA has biodegradable Property by internal enzyme decompose the final product biocompatibility that be that carbonoxide and water can be excluded by complete metabolism internal, excellent, It is non-toxic and it prepares that raw material is easy to get these advantages and characteristic determines that it can become preferably biomedical material.PLA There is relatively broad application to be included in tissue engineering bracket, operation suture thread, medicine controlled release carrier etc. in biomedical sector. In drug controlled release field, PLA is commonly used for being prepared into microballoon, and drug is dissolved, is dispersed in the matrix type ball formed in PLA Shape particle.The characteristics of PLA microballoons：Property is stablized；There is suitable rate of release；It is nontoxic, nonirritant；Can with main ingredient compatibility, no Influence the assay of drug；There are certain intensity and plasticity；With satisfactory viscosity, permeability, dissolubility etc., it is Good slow releasing carrier of medication.PLA drug bearing microspheres are in bone defect healing at present, protein microsphere preparation, antineoplaston, are immunized Learn etc. is widely used.
Self-assembled multilayer film deposition technique (LBL) is pushed away in early 1990s by Decher, Moehwald and Lvov Go out, this general technology has been obtained for more and more paying close attention to.Electrostatic interaction, hydrogen bond, hydrophobic interaction, with And Van der Waals interaction can be as the driving force of adsorption.The continuous of modified metaboly will be needed to be soaked in band Have in two kinds of different solutions of opposite charges, pass through electrostatic interaction so that the metaboly with different charges is deposited on Material surface obtains certain multi-layer film structure as needed.Therefore, it in titanium surface construction antibacterials slow-released system, uses Carrier (such as polylactic acid) with good degradability and biocompatibility contains antibiotic and forms targeting, long-acting drug biography System is passed, the validity for the treatment of is improved, the toxicity for reducing system is with a wide range of applications.
Invention content
It is good that technical problem to be solved by the invention is to provide a kind of compatibilities, and stability is high, is firmly combined with, slow-release time The construction method of long medical titanium alloy implant surface drug sustained release system,
Technical solution is used by the present invention solves above-mentioned technical problem：Medical titanium alloy implant surface medicament slow release The construction method of system, includes the following steps：
(1) preparation of streptomycin sulphate polydactyl acid nanoparticle is contained
A. by D, l-polylactic acid is dissolved in dichloromethane, adds maleic anhydride and dibenzoyl peroxide, is sufficiently stirred After uniformly, it is put into the vacuum desiccator for filling dry silica gel, vacuum sealing under nitrogen protection is dried in vacuo 96h at room temperature；
B. the product after drying is heated to 100 DEG C of reaction 10h, appropriate chloroform is substantially soluble in after being cooled to room temperature, then Excess diethyl ether is instilled, fibery precipitate is obtained, precipitation is collected, precipitation is dissolved in appropriate chloroform, then instills excess diethyl ether, is received Collection precipitation, appropriate chloroform is again dissolved in by precipitation, then instills excess diethyl ether, and collection is deposited in drying at room temperature in vacuum desiccator 5d obtains polydactyl acid；
C. polydactyl acid is dissolved in prepare in acetone and obtains a concentration of 6mg/mL polydactyl acids acetone mixture, so Polydactyl acid acetone mixture is added dropwise to the sulphur of a concentration of 0.001-0.1mg/mL under 550rpm magnetic agitations afterwards In sour Streptomycin Solution, then room temperature volatilizees 12h under 550rpm magnetic agitations, then is centrifuged under the conditions of 20000rpm, Take supernatant to get to containing streptomycin sulphate polydactyl acid nanoparticle solution (SS-MPLA microspheres solutions)；
(2) titanium surface contains streptomycin sulphate polydactyl acid nanoparticle/polyethyleneimine (SS-MPLA/PEI) multilayer The structure of film
A. titanium alloy surface amination：After titanium sand paper sanding and polishing, it is cleaned by ultrasonic in acetone soln, then be placed in It impregnates 6 hours in 10mol/L NaOH solutions, after deionized water rinses drying, is placed in containing 5wt%3- aminopropyl-triethoxies After being heated at reflux 6h in the isobutanol solution of silane (APTES), then cooling 12h uses toluene, absolute ethyl alcohol, deionization successively Water is respectively washed 3 times, and drying is for use；
B. the assembling of multilayer SS-PPLA nanoparticles：By n-hydroxysuccinimide (NHS) and 1- (3- dimethylaminos third Base) -3- ethyl-carbodiimide hydrochlorides (EDC) are added to and contain in streptomycin sulphate polydactyl acid nanoparticle solution, obtain To the SS-PPLA nanoparticle solution of activated carboxylic；Polyethyleneimine is dissolved in the NaCl solution that molar concentration is 150mM/L In, it is configured to 5mg/mL polyethylenimine solutions；
C. the titanium sheet after amination is fixed on photoresist spinner, the SS-PPLA that activated carboxylic is added dropwise successively on its surface receives Rice microspheres solution and polyethylenimine solution obtain titanium surface (SS-MPLA/PEI) n multilayer films, and as medical titanium alloy is implanted into Object surface drug slow-released system, wherein n indicate the alternate cycle number or the alternating number of plies of single layer SS-MPLA and single layer PEI films, Any integer of the value between 2-9.
The mixed volume ratio of D described in step (1) A, l-polylactic acid and the dichloromethane is 1：5；The D, The mixing quality ratio of l-polylactic acid and the maleic anhydride is 10：1, the additive amount of the dibenzoyl peroxide is Malaysia The 3% of acid anhydrides quality.
Vacuum desiccator described in step (1) A is pre-charged with nitrogen, then vacuumizes, and repetition is filled with nitrogen and then takes out Vacuum is until driving away air all in vacuum desiccator and keeping vacuum state.
Chloroform additive amount described in step (1) B is 3 times of product quality, and the ether additive amount is product quality 10 times.
A concentration of 6mg/mL of polydactyl acid acetone mixture described in step (1) C.
Polydactyl acid acetone mixture described in step (1) C is with the streptomycin sulfate solution volume ratio 2.5：100.
N-hydroxysuccinimide (NHS), the 1- (3- dimethylamino-propyls) -3- ethyls described in step (2) B Carbodiimide hydrochloride (EDC) is 1 with the mixing molar ratio for containing streptomycin sulphate polydactyl acid nanoparticle：1： 0.5。
The SS-PPLA nanoparticles solution of activated carboxylic described in step (2) C is dripped with the polyethylenimine solution It is 3 to add volume ratio：1.
Step (2) C is specially：Titanium sheet after amination is fixed on photoresist spinner, 100 μ L carboxyls, which are added dropwise, on its surface lives The SS-PPLA nanoparticle solution of change after rotating 30s under the conditions of 60RMP, then rotates 40s under the conditions of 3000RMP, is added dropwise In triplicate, the SS-PPLA nanoparticle solution of 300 μ L activated carboxylics is added dropwise altogether in rotation；Take 100 μ L polyethyleneimines molten again Drop is added to titanium surface, after rotating 30s under the conditions of 60RMP, then rotates 40s under the conditions of 3000RMP, constantly repeats that carboxylic is added dropwise The SS-PPLA nanoparticles solution and polyethylenimine solution of base activation are until titanium surface prepares (SS-MPLA/PEI) n multilayers Film, as medical titanium alloy implant surface drug sustained release system, wherein n indicate the friendship of single layer SS-MPLA and single layer PEI films For periodicity or the alternating number of plies, any integer of the value between 2-9.
Compared with the prior art, the advantages of the present invention are as follows：Medical titanium alloy implant surface medicament slow release of the present invention system The construction method of system, by solvent blending method, grafted maleic anhydride (MA) prepares maleic anhydride grafting in polylactic acid (PDLLA) Polylactic acid (MPLA)；Be prepared by being self-assembled into ball include streptomycin sulphate MPLA microballoons；Pass through surface grafting It is modified to make titanium alloy surface amination so that titanium surface is positively charged, then by layer-by-layer, passes through MPLA microballoon tables The amino of the carboxyl and the surfaces PEI of face activation, it is micro- in titanium surface construction SS-MPLA using Electrostatic Absorption and covalent bond effect The multilayer antibacterial film of ball/PEI, in vivo the multilayer film of implant surfaces degradation while streptomycin sulphate slowly release Come, has achieved the effect that long-term antibacterial.Advantage is as follows：
(1) be prepared by being self-assembled into ball include streptomycin sulphate MPLA microballoons.The microballoon size is more It is uniform, and there is good hydrophily, charged group is outwardly so that is more easy to carry out in self-assembled multilayer film；
(2) titanium alloy surface amination is made by surface graft modification, passes through the obtained amino of surface graft modification Layer be firmly combined with titanium alloy it is not easily to fall off, after amination so that material surface with more positive charge group have instead Answer active amino, more conducively the LBL self-assembly step in later stage；
(3) SS-MPLA microballoons/PEI films with multi-layer structure, this method operation letter are built with layer-by-layer It is single, and the content of the thickness of film, microsphere particle can be controlled well, there is good biocompatibility；
(4) SS-MPLA Nanospheres are prepared first, form first layer sustained release protection；Using LBL self-assembly mode, by medicine Ball chuck can increase drugloading rate and form sustained release, the antibacterial film release in vitro time is more than 120h, is had good in layer Slow release effect.
In conclusion the present invention has the film of antibacterial effect, the NH in titanium surface construction2/(SS-MPLA/PEI)nIt is more Tunic has the effect of that preferable hydrophily and slow releasing pharmaceutical, topical application high concentration antibiotic improve the validity for the treatment of, The effect of reducing system toxicity, improving implant to reach and service life can have extensive in terms of body implanting material Application prospect.
Description of the drawings
Fig. 1 is streptomycin sulphate UV absorption canonical plotting in specific embodiment one；
Fig. 2 is titanium surface amination and further LBL self-assembly process schematic；Surface A is expressed as three second of 3- aminopropyls The surface oxysilane (APTES)；Surface M is the imine modified surface of maleic anhydride；A is SS-MPLA and polyethyleneimine (PEI) Orderly level forms multilayer film in surface A；B is SS-MPLA/PEI multilayer film hydrolytic processes；
Fig. 3 is contact angle variation diagram；
Fig. 4 is NH2/(SS-MPLA/PEI)5Drug release patterns；
Fig. 5 is NH2/(SS-MPLA/PEI)10Drug release patterns.
Specific implementation mode
Below in conjunction with attached drawing embodiment, present invention is further described in detail.
Specific embodiment one
Build the nanoparticle with anti-inflammatory effect
There is the case where mycobacterial infections that streptomycin sulphate is selected to be assembled in as antibacterial material for implantation material surface Titanium alloy surface.Streptomycin sulphate has powerful antibacterial action to mycobacterium tuberculosis.This experiment is prepared by being self-assembled into ball Obtain include streptomycin sulphate MPLA microballoons, and by ultraviolet light absorption spectroscopic assay MPLA microballoons for streptomycin sulphate Wrapped rate.
1, experiment material
D, l-polylactic acid, maleic anhydride (MA analyzes pure Chongqing Chuan Dong Chemical Co., Ltd.s), dibenzoyl peroxide (BPO Analyze pure Chongqing Chuan Dong Chemical Co., Ltd.s), deionized water, dichloromethane (analyzing pure Chengdu Ke Long chemical reagents factory), three Chloromethanes (analyzing pure Chengdu Ke Long chemical reagents factory), ether (analyzing pure Chongqing Chuan Dong Chemical Co., Ltd.s), tetrahydrofuran (analysis is pure for (THF analyzes pure Chongqing Chuan Dong Chemical Co., Ltd.s), streptomycin sulphate (Huabei Pharmaceutic Co., Ltd), acetone Chongqing Chuan Dong Chemical Co., Ltd.s), ammonium ferric sulfate ((NH4)2SO4·Fe2(SO4)3·24H2O, which analyzes pure Chongqing Chuan Dong chemical industry, to be had Limit company), sodium hydroxide (analyzing pure Chongqing Chuan Dong Chemical Co., Ltd.s), the concentrated sulfuric acid acid (it is limited to analyze pure Chongqing Chuan Dong chemical industry Company).
2, the preparation of streptomycin sulphate polydactyl acid nanoparticle is contained
(1) preparation of polydactyl acid (MPLA)
A. by D, l-polylactic acid is dissolved in dichloromethane, adds maleic anhydride and dibenzoyl peroxide, is sufficiently stirred After uniformly, it is put into the vacuum desiccator for filling dry silica gel, vacuum sealing under nitrogen protection is dried in vacuo 96h at room temperature；Its Middle D, the molten mixed volume ratio with the dichloromethane of l-polylactic acid are 1：5；The mixing matter of D, l-polylactic acid and maleic anhydride Amount is than being 10：1, the additive amount of dibenzoyl peroxide is the 3% of maleic anhydride quality, and vacuum desiccator is pre-charged with nitrogen, Then it vacuumizes, repetition is filled with nitrogen and then vacuumizes until driving away air all in vacuum desiccator and keeping vacuum shape State；
B. the product after drying is heated to 100 DEG C of reaction 10h, appropriate chloroform is substantially soluble in after being cooled to room temperature, then Excess diethyl ether is instilled, fibery precipitate is obtained, precipitation is collected, precipitation is dissolved in appropriate chloroform, is then instilled in excess diethyl ether, Precipitation is collected, precipitation is again dissolved in appropriate chloroform, is then instilled in excess diethyl ether, collection is deposited in room temperature in vacuum desiccator Dry 5d obtains polydactyl acid；5 times of chloroform additive amount product quality, 10 times of ether additive amount product quality；
(2) preparation of polydactyl acid (MPLA) nanoparticle
Precise 0.5,1.0,1.5,2.0mg polydactyl acids, are dissolved separately in 0.25mL acetone, then will be modified PLA solution is added dropwise under 550rpm magnetic agitations in 10mL deionized waters, then the room temperature under 550rpm magnetic agitations Volatilize 12h；
The MPLA acetone solns of above-mentioned various concentration are dissolved in the microballoon of water formation, wherein when MPLA dosages reach 2.0mg When, there is macroscopic white precipitate in solution.And when MPLA dosages are 0.5,1.0,1.5mg when, it is heavy not generate in solution It forms sediment.In order to prepare microballoon as much as possible, so in subsequent experimental procedure, contained using being dissolved in 10ml deionized waters The 0.25ml acetone of 1.5mgMPLA；
(3) polydactyl acid (MPLA) nanoparticle containing and measuring to streptomycin sulphate (SS)
A. accurately weigh 0.01,0.05,0.1,0.5,1.0mg streptomycin sulphates, be dissolved in respectively in 10mL deionized waters；It is accurate 1.5mg polydactyl acids are really weighed, are dissolved in 0.25mL acetone, then by polydactyl acid solution in 550rpm magnetic agitations Under be added dropwise in 10mL streptomycin sulfate solutions, then the room temperature 12h under 550rpm magnetic agitations；Then in 20000rpm items It is centrifuged under part, takes supernatant；
B. supernatant 3ml is taken, it is each that 2mol/LNaOH solution 1.0mL are added, and 20min is heated in 60 DEG C of water-baths, it is cooling To room temperature, then it is each the sulfuric acid solution 3.0mL containing 1wt% ammonium ferric sulfates is added, be settled to 10mL with water, shake up, survey its UV absorption at 519nm.
3, streptomycin sulphate UV absorption standard curve is prepared
Streptomycin sulphate 0.0224g accurately is weighed, is placed in 50mL volumetric flasks, adds water to scale, shake up to get a concentration of The streptomycin sulphate Standard Reserving Solution of 33.55 ten thousand units per liters；Precision draws stock solution 0.1,0.5,1.0,2.0, the 4.0mL, point It is not placed in the test tube of 10mL scales, it is each that 2mol/LNaOH solution 1.0mL are added, and 20min is heated in 60 DEG C of water-baths, it is cooling To room temperature, then it is separately added into the sulfuric acid solution 3.0mL containing 1wt% ammonium ferric sulfates, with deionized water constant volume 10mL, shaken up.Separately Ibid operation is reference for water intaking, is scanned in 350nm-700nm wave-length coverages, selects suitable absorption peak 519.00nm；Gained sulphur Sour streptomysin UV absorption standard curve is as shown in Figure 1.
MPLA is measured to the encapsulation ratio of streptomycin sulphate between 40%~60% according to gained standard curve, and works as sulfuric acid Content of streptomycin increases, the reduction of the encapsulation ratios of MPLA microballoons level off to 40% but amplitude of variation it is little, drugloading rate gradually increases change Change more apparent.Experimental result shows that made MPLA microballoons can effectively wrap up Streptomycin sulfale.
The inventory ratio of PDLLA and MA is 10 in above-mentioned experiment:MA grafting rates on 1, gained MPLA are 2.36%, after being The anhydride bond of continuous experiment activation MA provides the foundation of quantity.In the experiment for wrapping up streptomycin sulphate with MPLA microballoons, work as sulphur When a concentration of 0.1mg/ml of sour streptomysin, encapsulation ratio 41.0%, drugloading rate 27.3%.Encapsulation ratio when compared with 0.05mg/ml 1.1% is only had dropped, amplitude is smaller, but drugloading rate considerably increases, so we take streptomycin sulphate dense in follow-up test 0.1mg/ml is spent to carry out.MPLA has water-wet side and hydrophobic side, its hydrophobic side of the microballoon prepared under this experimental program is inside, Water-wet side is outside, therefore prepared MPLA microballoon ratios MPLA has better hydrophily, makes it have better biocompatibility, There can be wider application prospect in terms of body implanting material.
Specific embodiment two
The structure of titanium surface SS-MPLA/PEI multilayer films
In conclusion this experiment is using titanium alloy as base material, by surface graft modification so that titanium alloy surface amination, Be firmly combined with titanium alloy by the obtained amino layer of surface graft modification it is not easily to fall off, so that material table after amination Face carries more positive charge group, more conducively the LBL self-assembly step in later stage.By layer-by-layer, in amination Titanium surface construction multilayer film establishes antibacterials streptomycin sulphate slow-released system, using MPLA microballoons and PEI as it is poly- it is cloudy, Cation, using electrostatic adsorption, SS-MPLA microballoons/PEI plural layers judge the shape of multilayer film by contact angle indirectly At.Fig. 2 is titanium surface amination and further LBL self-assembly process schematic.
1, experiment material
Deionized water；Sodium hydroxide (analyzes pure Chongqing Chuan Dong Chemical Co., Ltd.s)：Acetone (analyzes pure Chongqing Chuan Dong chemical industry Co., Ltd)；Isobutanol (analyzes pure Chengdu Ke Long chemical reagents factory)；3- aminopropyl triethoxysilanes (APTES Adamas Reagent co,ltd.)；Absolute ethyl alcohol (analyzes pure Chongqing Chuan Dong Chemical Co., Ltd.s)；Streptomycin sulphate (North China Pharmacy stock Co., Ltd)；1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC Adamas Reagent co,ltd.)；N-hydroxysuccinimide (PIERCE companies of the U.S. NHS)；Polyethyleneimine (PEI Mw=800 U.S. Sigma- Aldrich)；Sodium chloride (analyzes pure Chongqing Chuan Dong Chemical Co., Ltd.s)：
2, the structure of titanium surface SS-MPLA/PEI multilayer films
(1) titanium alloy surface amination
After titanium sand paper sanding and polishing, it is cleaned by ultrasonic in acetone soln；It is placed in 10mol/L NaOH solutions and soaks again Bubble 6 hours, deionized water rinse drying；It is subsequently placed in the isobutanol solution containing 5wt%APTES and is heated at reflux 6h, solution After middle cooling 12h；Toluene, absolute ethyl alcohol, deionized water is used respectively to wash successively 3 times, drying is for use；
(2) assembling of multilayer SS-PPLA nanoparticles
A. 10.0mg streptomycin sulphates are accurately weighed, are dissolved in 100mL deionized waters, MPLA is taken from vacuum desiccator Go out, precise 15mgMPLA is dissolved in 2.5mL acetone；By MPLA solution under 550rpm magnetic agitations, it is added dropwise to In 100mL streptomycin sulfate solutions, and the 12h that volatilizees under 550rpm magnetic agitations, it is spare to obtain SS-PPLA microspheres solutions；
B. n-hydroxysuccinimide (NHS) in molar ratio in SS-MPLA solution：1- (3- dimethylamino-propyls) -3- Ethyl-carbodiimide hydrochloride (EDC)：Carboxyl=1:1:The carboxyl on NHS and EDC activation SS-MPLA microballoons is added in 1 ratio, Solution after activated carboxylic is solution A；The inventory ratio of PDLLA and MA is 10:MA grafting rates on 1, gained MPLA are 2.36%, so it is that 0.0072mmol (contains two on a MPLA that MA contents, which are 0.0036mmol carboxyl-contents, in 15mgMPLA A carboxyl), so EDC (191.70) 1.38mg, NHS (115.09) 0.83mg is added；
C. a certain amount of polyethyleneimine is weighed, is dissolved in the NaCl solution that molar concentration is 150mM/L, is configured to 5mg/mL Polyethylenimine solution is solution B；
D. the titanium sheet after amination is fixed on photoresist spinner, 100 μ L solution As is added dropwise on its surface, under the conditions of 60RMP After rotating 30s, then 40s is rotated under the conditions of 3000RMP, rotation is added dropwise in triplicate, 300 μ L solution As are added dropwise altogether, remove titanium Piece is labeled as (SS-MPLA/PEI)0.5；
E. after separately taking one piece of titanium sheet to repeat step D, then 100 μ L solution Bs are taken, titanium surface is added drop-wise to, in 60RMP condition backspins After turning 30s, then 40s is rotated under the conditions of 3000RMP, removes titanium sheet and be labeled as (SS-MPLA/PEI)1；
F. 100 μ L solution As are added dropwise again after repeating step E, after rotating 30s under the conditions of 60RMP, then in 3000RMP conditions Solution A and rotation is added dropwise in lower rotation 40s in triplicate；It removes titanium sheet and is labeled as (SS-MPLA/PEI)1.5, in this approach constantly It repeats until preparation (SS-MPLA/PEI)0.5To (SS-MPLA/PEI)9.0；
G. contact angle measurement is used, the contact angle of different film layer numbers is measured, measurement at two is taken to connect on each surface Feeler obtains six data.
3, contact angle detection
Contact angle is the measurement of body surface moistening degree, if θ<90 °, then the surface of solids is hydrophilic, i.e., liquid is easier to Solid is soaked, angle is smaller, indicates that wettability is better；If θ>90 °, then the surface of solids is hydrophobic, i.e., liquid is not easy to moisten Wet solid is easy to move on the surface.
This experiment measures the titanium surface of polishing, after titanium surface amination, and with LBL self-assembly mode is loaded with SS- MPLA/PEI films, from (SS-MPLA/PEI)0.5To (SS-MPLA/PEI)9.0The contact angle on totally 20 surfaces takes on each surface Contact angle is measured at two, obtains six data, calculates average value, and deviation is not more than 5 percent.Average contact angle size such as 1 institute of table Show.
1 Contact-angle measurement average value of table
Shown in Fig. 3 contact angle variation diagrams, compared with hydrophobic titanium surface, make it after titanium surface amination Surface is rich in-NH2So its hydrophily is enhanced, contact angle reduces nearly 45 °, with the increase of film layer number, titanium The contact angle of alloy surface has change.In NH2/(SS-MPLA/PEI)1.5Before, contact angle is gradually reduced.From layer 5 NH2/ (SS-MPLA/PEI)2.0Start contact angle and regular variation is presented between 26 ° to 15 °, when outermost layer is SS-MPLA layers When, contact angle is smaller, film surface present hydrophily it is smaller, when outermost layer be PEI when contact angle it is relatively large, hydrophily compared with It is weak.The alternating variation of contact angle is demonstrated from NH2/(SS-MPLA/PEI)2.0Start, titanium alloy surface has formd all standing , the SS-MPLA microballoons or PEI films of single layer.
In conclusion by contact angle determination can determine this Success in Experiment by layer-by-layer, lived with EDC The SS-MPLA microballoons and PEI of change are anti-using electrostatic adsorption and EDC and the amino on PEI respectively as poly- anions and canons The covalent bond that should be formed plays NH in amination titanium surface construction2/(SS-MPLA/PEI)nMultilayer film.Wherein SS-MPLA microballoons, shape It is sustained and protects at first layer；LBL self-assembly mode, medicine ball is clipped in layer, can be increased drugloading rate and be formed sustained release. The NH prepared under this experimental program2/(SS-MPLA/PEI)nThere is multilayer film preferable hydrophily to make it have better biofacies Capacitive can have wider application prospect in terms of body implanting material.
Specific embodiment three
The slow release effect of titanium alloy surface antibacterial film is verified
1, experiment material
The titanium plate surface NH being prepared according to two method of above-mentioned specific embodiment2/(SS-MPLA/PEI)5；NH2/(SS- MPLA/PEI)10Multilayer film；Phosphate buffer (PBS, 0.1M, pH=7.4)：Ammonium ferric sulfate ((NH4)2SO4·Fe2(SO4)3· 24H2O analyzes pure Chongqing Chuan Dong Chemical Co., Ltd.s)；Sodium hydroxide (analyzes pure Chongqing Chuan Dong Chemical Co., Ltd.s)；The concentrated sulfuric acid Sour (analyzing pure Chongqing Chuan Dong Chemical Co., Ltd.s)；Deionized water.
2, experimental method
5 NH that will be prepared by two method of above-mentioned specific embodiment2/(SS-MPLA/PEI)5Titanium sheet, 5 NH2/(SS- MPLA/PEI)5Titanium sheet is respectively put into Tissue Culture Dish, and 3ml is separately added into 10 Tissue Culture Dish, and the phosphoric acid of 0.1M is slow Fliud flushing (pH=7.4), lid envelope, is placed at room temperature；Within 1,3,6,12,24,36,48,84,120h period, taken with pipette Go out 3ml leachates, while the phosphate buffer (pH=7.4) of 3mL 0.1M is added；Liquid will be taken out and be respectively placed in 10mL scales It is each that 2mol/LNaOH solution 1.0mL are added in test tube, and 20min is heated in 60 DEG C of water-baths, it is cooled to room temperature, then add respectively Enter the sulfuric acid solution 3.0mL containing 1wt% ammonium ferric sulfates, with deionized water constant volume 10mL, shakes up, survey it at the beginning of 519.00nm Absorption value.
3, interpretation of result
Every group of OD value removes a peak and a minimum, takes the average value of remaining three groups of data, substitutes into formula sulphur Sour streptomysin concentration (mg/ml)=value/1.0056 OD, calculate the burst size of streptomycin sulphate, converse the hundred of release drug Divide ratio, draws drug release patterns, wherein NH2/(SS-MPLA/PEI)5Drug release patterns are as shown in figure 4, NH2/(SS- MPLA/PEI)10Drug release patterns are as shown in Figure 5.
Wherein NH2/(SS-MPLA/PEI)5Be of five storeys SS-MPLA films altogether, is made of 300 μ LSS-MPLA solution per tunic, 1500 μ L solution are shared, so containing MPLA microballoon 0.225mg, by specific embodiment one it is found that MPLA microballoon drugloading rates are 27.3%, so package streptomycin sulphate 0.0614mg altogether.Same reasoning can obtain NH2/(SS-MPLA/PEI)10Sulfuric acid is wrapped up altogether Streptomysin 0.1229mg.The drug release kinetic equation of calculating is shown in Table 2.
2 drug release kinetic equation of table
As shown in Table 2, titanium surface NH2/(SS-MPLA/PEI)nThe drug release characteristic of multilayer film relatively meets first order kinetics mould The synergistic effect of type, i.e. drug diffusion and skeleton dissolving, with slow release effect, Mt is the cumulative release amount of t times, M ∞ in formula For ∞ when cumulative release amount, Mt/M ∞ be t when preparation.It is learnt by this experiment, titanium surface NH2/(SS-MPLA/PEI)n For multilayer antibacterial film in vitro in drug release process, the release time of drug is more than 120h, and it is good to illustrate that this multilayer antibacterial film has Slow releasing pharmaceutical effect.By NH2/(SS-MPLA/PEI)5And NH2/(SS-MPLA/PEI)10Compare the number of plies it is found that antibacterial film The amount of more entrained antibacterials is bigger, and the time of sustained release is also longer, and the effect of antibacterial also can be better.
Certainly, above description is not limitation of the present invention, and the present invention is also not limited to the example above.The art Those of ordinary skill is in the essential scope of the present invention, the variations, modifications, additions or substitutions made, and should also belong to the present invention's Protection domain.

Claims (3)

1. the construction method of medical titanium alloy implant surface drug sustained release system, it is characterised in that include the following steps：
(1) preparation of streptomycin sulphate polydactyl acid nanoparticle is contained
A. by D, l-polylactic acid is dissolved in dichloromethane, adds maleic anhydride and dibenzoyl peroxide, is stirred Afterwards, it is put into the vacuum desiccator for filling dry silica gel, vacuum sealing under nitrogen protection is dried in vacuo 96h at room temperature；Wherein institute The mixed volume ratio of the D stated, l-polylactic acid and the dichloromethane is 1：5；The D, l-polylactic acid and the Malaysia The mixing quality ratio of acid anhydrides is 10：1, the additive amount of the dibenzoyl peroxide is the 3% of maleic anhydride quality；
B. the product after drying is heated to 100 DEG C of reaction 10h, appropriate chloroform is substantially soluble in after being cooled to room temperature, is then instilled Excess diethyl ether obtains fibery precipitate, collects precipitation, precipitation is dissolved in appropriate chloroform, then instills excess diethyl ether, and it is heavy to collect It forms sediment, precipitation is again dissolved in appropriate chloroform, then instill excess diethyl ether, collection is deposited in drying at room temperature 5d in vacuum desiccator and obtains To polydactyl acid；Wherein the chloroform additive amount is 3 times of product quality, and the ether additive amount is product quality 10 times；
C. polydactyl acid is dissolved in prepare in acetone and obtains a concentration of 6mg/mL polydactyl acids acetone mixture, then will The streptomycin sulphate that polydactyl acid acetone mixture is added dropwise to a concentration of 0.1mg/mL under 550rpm magnetic agitations is molten In liquid, then room temperature volatilizees 12h under 550rpm magnetic agitations, then is centrifuged under the conditions of 20000rpm, takes supernatant, i.e., It obtains containing streptomycin sulphate polydactyl acid nanoparticle solution；The wherein described polydactyl acid acetone mixture with it is described Streptomycin sulfate solution volume ratio be 2.5：100；
(2) titanium surface contains the structure of streptomycin sulphate polydactyl acid nanoparticle/polyethyleneimine SS-MPLA/PEI multilayer films It builds
A. titanium alloy surface amination：After titanium sand paper sanding and polishing, it is cleaned by ultrasonic in acetone soln, then be placed in 10mol/ It impregnates 6 hours in L NaOH solutions, after deionized water rinses drying, is placed in containing 5wt%3- aminopropyl triethoxysilanes After being heated at reflux 6h in isobutanol solution, then cooling 12h uses toluene, absolute ethyl alcohol, deionized water respectively to wash 3 times, dries successively For use；
B. the assembling of multilayer SS-MPLA nanoparticles：By n-hydroxysuccinimide (NHS) and 1- (3- dimethylamino-propyls)- 3- ethyl-carbodiimide hydrochlorides, which are added to, to be contained in streptomycin sulphate polydactyl acid nanoparticle solution, and activated carboxylic is obtained SS-MPLA nanoparticle solution；Polyethyleneimine is dissolved in the NaCl solution that molar concentration is 150mM/L, is configured to 5mg/mL polyethylenimine solutions；The wherein n-hydroxysuccinimide, the 1- (3- dimethylamino-propyls) -3- second Base carbodiimide hydrochloride is 1 with the mixing molar ratio for containing streptomycin sulphate polydactyl acid nanoparticle：1： 0.5；
C. the titanium sheet after amination is fixed on photoresist spinner, the SS-MPLA nanometers that activated carboxylic is added dropwise successively on its surface are micro- Ball solution and polyethylenimine solution obtain titanium surface (SS-MPLA/PEI) n multilayer films, as medical titanium alloy implant table Face drug sustained release system, wherein n indicate the alternate cycle number or the alternating number of plies of single layer SS-MPLA and single layer PEI films, value Any integer between 2-9, wherein the SS-MPLA nanoparticles solution of the activated carboxylic and the polyethyleneimine It is 3 that volume ratio, which is added dropwise, in solution：1.
2. the construction method of medical titanium alloy implant surface drug sustained release system according to claim 1, feature exist In：Vacuum desiccator described in step (1) A is pre-charged with nitrogen, then vacuumizes, and repetition is filled with nitrogen and then vacuumizes straight To driving away air all in vacuum desiccator and keep vacuum state.
3. the construction method of medical titanium alloy implant surface drug sustained release system according to claim 1, feature exist In step (2), C is specially：Titanium sheet after amination is fixed on photoresist spinner, 100 μ L activated carboxylics are added dropwise on its surface SS-MPLA nanoparticle solution after rotating 30s under the conditions of 60RMP, then rotates 40s under the conditions of 3000RMP, and rotation is added dropwise In triplicate, the SS-MPLA nanoparticle solution of 300 μ L activated carboxylics is added dropwise altogether；100 μ L polyethylenimine solutions are taken to drip again It is added to titanium surface, after rotating 30s under the conditions of 60RMP, then 40s is rotated under the conditions of 3000RMP, constantly repeats that carboxyl work is added dropwise The SS-MPLA nanoparticles solution and polyethylenimine solution of change are until titanium surface prepares (SS-MPLA/PEI) n multilayer films, i.e., For medical titanium alloy implant surface drug sustained release system, wherein n indicates the alternating week of single layer SS-MPLA and single layer PEI films Issue or the alternately number of plies, any integer of the value between 2-9.
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