CN109966559A - A kind of medical implant and preparation method thereof - Google Patents
A kind of medical implant and preparation method thereof Download PDFInfo
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- CN109966559A CN109966559A CN201711456533.0A CN201711456533A CN109966559A CN 109966559 A CN109966559 A CN 109966559A CN 201711456533 A CN201711456533 A CN 201711456533A CN 109966559 A CN109966559 A CN 109966559A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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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
- 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
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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
- 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
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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
- 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
- A61L2300/622—Microcapsules
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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
- 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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Abstract
The present invention provides a kind of medical implant and preparation method thereof, including medical macromolecular materials matrix and the fast release microcapsules being supported on matrix, the wall material of fast release microcapsules is phase-change material of the phase transition temperature close to body temperature, and the core material of fast release microcapsules is biological functional activity substance.By loading fast release microcapsules of the specific phase-change material as wall material on the matrix of medical implant, to assign common medical implant certain bioactivity, it is made to obtain new function.It can be fallen off, be lost caused by by external interference during transport, operation etc. to avoid core material by the introducing of fast release microcapsules, and can realize the quick release of bioactive functions substance after implanting.
Description
Technical field
The invention belongs to field of medical materials, and in particular to a kind of medical implant and preparation method thereof.
Background technique
China human mortality Aging Problem becomes increasingly conspicuous, and compatriots' health perception is continuously improved and the rapid hair of domestic medical level
Exhibition, China will become global maximum Orthopedic medical implant consumption market, and also possess great potential in gear division market.In recent years
Surround orthopaedics and gear division is implanted into the developmental research of medical instrument and achieves a series of progress, with the progress of contemporary science and technology,
For the orthopaedics such as bone tissue engineering scaffold, guide tissue regeneration film, bone nail, bone plate, web plate, gear division class medical instrument research not
Disconnected deeply various new materials and technology are applied in medical instrument successively, enrich the type of medical instrument, while also assigning
Conventional appliances some new functions and effect are given, however research focuses mostly in new material application, structure design, compound
The fields such as technology, it is still less to the research in terms of medical instrument improvement in functionality.
The present invention mainly sets about from the angle of functional medical instrument, with existing or part that is designing orthopaedics, gear division
Implantation material is main base, and biological functional activity substance is loaded on matrix, to realize related activity particle in vivo
Or the release of functional particle, common implantation material is had certain bioactivity, part new function is obtained.
Summary of the invention
The object of the present invention is to provide a kind of medical implant and preparation method, by the matrix of medical implant with
Specific mode loads biological functional activity substance appropriate, keeps the activity of associated biomolecule functional activity substance, and realizes
Its in due course release in vivo.
To achieve the goals above, the present invention adopts the following technical scheme:
The present invention provides a kind of medical implant, micro- including medical macromolecular materials matrix and the quick release being supported on matrix
The wall material of capsule, the fast release microcapsules is phase-change material, and the phase-change material is solid-state at room temperature, is under body temperature melting
Liquid, the core material of the fast release microcapsules are biological functional activity substance.
One embodiment of medical implant according to the present invention has been also loaded slow-release microcapsule in described matrix, institute
The wall material of slow-release microcapsule is stated as biological resorbable polymeric materials, the core material of the slow-release microcapsule is biological functional activity object
Matter.
One embodiment of medical implant according to the present invention, the phase-change material be acrylic acid esters co-polymer or
Polyethylene glycol.
One embodiment of medical implant according to the present invention, the relative molecular mass of the polyethylene glycol are
1000。
One embodiment of medical implant according to the present invention, the acrylic acid esters co-polymer are methyl acrylate
With the copolymer of acrylate fatty alcohol.
One embodiment of medical implant according to the present invention, the acrylate fatty alcohol are fatty alcohol alkyl chain
For C12~18Acrylate, preferably octadecyl acrylate and Process Conditions of Cetane Acrylate.
One embodiment of medical implant according to the present invention, the methyl acrylate and acrylate fatty alcohol
Mass ratio is (1~3): (8~10).
One embodiment of medical implant according to the present invention, the outer diameter of the fast release microcapsules and slow-release microcapsule
Respectively 10-380 μm.
One embodiment of medical implant according to the present invention, the biological absorbable high molecular material, which is selected from, to drop
The one or more of natural macromolecular material, biologically absorbable polymer or its copolymer are solved, wherein the degradable natural is high
Molecular material is selected from one of gelatin, agar, chitosan, sodium alginate, starch, cellulose, type i collagen or a variety of, wherein
The biologically absorbable polymer is selected from polylactic acid, l-lactic acid, dextrorotation polylactic acid, racemic polylactic acid, polyglycolic acid, gathers
The derivative carbonic ester of caprolactone, polyvinyl alcohol, polydioxanone, polyaminoacid, polyorthoester, in polytrimethylene carbonate
It is one or more.
One embodiment of medical implant according to the present invention, the biological functional activity substance be selected from growth promotion,
Antibacterial, induced growth functional materials it is one or more.
One embodiment of medical implant according to the present invention, the biological functional activity of the fast release microcapsules core material
Substance is selected from hydroxyapatite, tricalcium phosphate, chitosan, cucoline, bone morphogenetic protein, antibiotic, anticoagulant, micro- life
One of object immune formulation, anticancer drug are a variety of, preferably antibiotic, anticoagulant, immune formulation, hydroxyapatite or
One of tricalcium phosphate is a variety of.
One embodiment of medical implant according to the present invention, the biological functional activity of the slow-release microcapsule core material
Substance is selected from hydroxyapatite, tricalcium phosphate, chitosan, cucoline, bone morphogenetic protein, antibiotic, anticoagulant, micro- life
One of object immune formulation, anticancer drug are a variety of, preferably one of bone morphogenetic protein, chitosan or a variety of.
One embodiment of medical implant according to the present invention, described matrix are selected from guide tissue regeneration film, tissue
One of engineering rack, absorbable-bone plate, absorbable interference screw fixation, adsorbable bone stick.
One embodiment of medical implant according to the present invention, the guide tissue regeneration film includes weaker zone and cause
Close layer, the weaker zone in the method electrostatic spraying to the compacted zone of coaxial electrostatic spinning by forming, wherein coaxial electrostatic
The core structure that spinning obtains weaker zone is biological functional activity substance.
One embodiment of medical implant according to the present invention, the biological function in the weaker zone and/or compacted zone
Energy active material is respectively selected from hydroxyapatite, tricalcium phosphate, chitosan, cucoline, bone morphogenetic protein, antibiotic, resists
One of coagulant, microorganism immune formulation, anticancer drug are a variety of, preferably one of bone morphogenetic protein, chitosan
Or it is a variety of.
The present invention also provides a kind of methods for preparing above-mentioned medical implant, include the following steps:
1) fast release microcapsules are prepared: using the phase-change material as wall material raw material, the biological functional activity substance conduct
Core material raw material prepares fast release microcapsules, wherein the method for preparing fast release microcapsules is selected from situ aggregation method, phase separation method, solvent
One of volatility process, complex coacervation, spray drying process；
2) by the fast release microcapsules of preparation in conjunction with described matrix, the medical implant is obtained, wherein the combination side
Method is selected from one of electrostatic spraying, coating, dipping, absorption.
One embodiment of the method for medical implant produced according to the present invention further includes that sustained release is prepared before step 2
The step of microcapsules, comprising:
Prepare slow-release microcapsule: the biological absorbable high molecular material is living as wall material raw material, the biological function
Property substance as core material raw material, be prepared into slow-release microcapsule, wherein prepare slow-release microcapsule method be selected from interfacial polymerization, original
One of position polymerization, phase separation method, solvent evaporation method, complex coacervation, spray drying process；
The gentle release microcapsules of the fast release microcapsules of preparation are obtained into the doctor in conjunction with described matrix by the step 2
Use implantation material.
One embodiment of the method for medical implant produced according to the present invention, the phase-change material are esters of acrylic acid
The method that fast release microcapsules are prepared when copolymer, in step 1 includes the following steps:
By the wall material raw material monomer, core material raw material, emulsifier mixing, which are added to the water, prepares solution, carries out shearing or ultrasound
Emulsification, gained emulsion carry out mechanical stirring under inert gas protection, are heated to constant be added after 65-95 DEG C of temperature and cause
Agent, after reacting 5-30min, reaction temperature is down to 35-60 DEG C, and the reaction was continued, stops stopping stirring after heating is cooled to room temperature anti-
It should be to get the fast release microcapsules.
One embodiment of the method for medical implant produced according to the present invention, the emulsifier are selected from polyethylene glycol-
400, sodium salt of acrylic acid-co-maleic anhydride, Arlacel-80, Arlacel-60, Tween-80, Tween-60, Tween-20, alkyl phenol
One of polyoxyethylene ether -10 or its composite emulsifier are a variety of, and the initiator is selected from potassium peroxydisulfate, ammonium persulfate, idol
One of nitrogen bis-isobutyronitrile, azobisisoheptonitrile, benzoyl peroxide, cumyl peroxide.
One embodiment of the method for medical implant produced according to the present invention, emulsifier accounts for described in the step 1
The 5%~30% of emulsion gross mass, core material raw material and wall material raw material account for the 3%~15% of the emulsion gross mass.
One embodiment of the method for medical implant produced according to the present invention, described matrix is guide tissue regeneration film
When, further include the steps that preparing matrix before step 1:
Using biological absorbable high molecular material as raw material, using solution plastic film mulch, hot-forming, extrusion molding, casting film-forming,
One or more of 3D printing molding, nonwovens process method prepare compacted zone；
Using the solution of biological absorbable high molecular material as shell layer spinning solution, using the solution of biological functional activity substance as core
Layer spinning solution, two kinds of spinning solutions is injected separately into shell and sandwich layer solution injector, the mode through electrostatic spraying sprays to cause
Close layer surface obtains the guide tissue regeneration film with weaker zone and compacted zone double-layer structure after dry.
Description according to the above technical scheme it is found that the beneficial effects of the present invention are:
By loading fast release microcapsules on the matrix of medical implant, since fast release microcapsules select specific phase transformation material
Material is used as wall material, and when which enters human body, variation with temperature can become fused solution from solid-state, to realize quick release
Core material (biological functional activity substance) therein.Fast release microcapsules can effectively keep the bioactivity of core material simultaneously, and avoid
Core material during transport, operation etc. by external interference and caused by fall off, lose.
The present invention can also be on the basis of loading fast release microcapsules, in conjunction with biological absorbable macromolecule material on matrix
Expect the slow-release microcapsule as wall material, constructs the release system with time gradient.Using slow-release microcapsule in human body by
Step degradation, further realizes the slow release of another part core material, so that it is living to assign medical implant gradient release biological function
The ability of property substance.
The method provided by the invention for preparing medical implant, relatively easy convenience and can also according to actual needs flexibly
Addition different kind organism functional activity substance also can use the special of matrix that is, not only on fast release microcapsules, slow-release microcapsule
Structure design addition mutually in requisition for biological functional activity substance, make medical implant function have flexibility and diversity.
In short, this functional medical implant provided by the invention, it being capable of quick release biology function after implanting
Can active material, enabling particular actives matter, the phase quickly and effectively plays its biological function before implantation, it is further possible to hold
The biological functional activity substance that continuous release needs to work for a long time, thus make common medical implant according to active material not
Together, while realizing basic role, other beneficial resultant effects such as antibacterial, growth promotion are obtained.
Specific embodiment
Illustrate embodiments of the present invention below by way of particular specific embodiment, those of ordinary skill in the art can be by this
Specification disclosure of that understands advantages of the present invention and effect easily.The present invention can also pass through other different embodiment party
Formula is implemented or is applied, and the various details in this specification may be based on different viewpoints and application, is not departing from institute of the present invention
Different modification and change are assigned under disclosed design.In addition, all ranges and value all include and annexable herein.Fall in this
Any numerical value or point in range described in text, such as any integer all can serve as minimum value or maximum value to export bottom
Range etc..
Term " microcapsules " used herein refers to by the polymer shell as wall forming material and being wrapped in shell
Seal the spherical particle of active material composition.The term is different from microballoon, and microballoon is by dispersing active material in the polymer
Spherical uniform particle composition, is spherical empty particle narrowly.Microcapsules technology is exactly by solid, liquid or gas entrapment, envelope
There are the technologies for becoming a kind of solia particle product in a kind of microencapsulation.The diameter of microcapsules is generally grade to micron
Grade.
Embodiment 1
1) preparation of fast release microcapsules:
Using octadecyl acrylate 10g, methyl acrylate 1g as wall material raw material monomer, with hydroxyapatite 0.1g and water solubility
Chitosan 0.1g is core material raw material, using sodium salt of acrylic acid-co-maleic anhydride 20g as emulsifier, with potassium peroxydisulfate 0.011g
For initiator, wall material raw material monomer, core material raw material, emulsifier are added in deionized water 100mL, clipped mulser with
8000r/min emulsifies 5min, lotion is poured into the 250mL three-necked flask with mechanical agitator, mixing speed 300r/
Min, and flask is heated to 80 DEG C (nitrogen atmospheres), initiator is added after temperature is constant, gradually drops reaction temperature after 10min
To 40 DEG C, heating device is closed after reacting 2h, continues to stir, until being cooled to room temperature, stopped reaction, lotion is poured into saturation
It is demulsified in calcium chloride solution, then filters and obtain microcapsules crude product, cleaned, filtered repeatedly using alcohol, so three times
Microscapsule powder can be obtained in normal-temperature vacuum drying afterwards.Gained microcapsules outer diameter is 80-150 μm.
2) preparation of matrix:
There is the guide tissue regeneration film (GTRM) of weaker zone and compacted zone double-layer structure, side using electrostatic spinning machine preparation
Method is as follows:
With poly lactide-glycolide acid-trimethylene carbonate (PLGA-TMC) for raw material, through melt blending, squeeze
Combination process prepares chitosan/PLGA-TMC composite membrane out, and using chitosan/PLGA-TMC composite membrane as compacted zone.
PLGA is dissolved in chloroform, prepares and obtains the electrostatic spinning liquid that concentration is 17%, spinning solution is injected into solution
In syringe, fltting speed 1.4mL/h；Spinning voltage 20kV, receives distance 11cm, and the mode through electrostatic spraying is by Nanowire
Dimension sprays to fine and close layer surface, obtains the guide tissue regeneration film with weaker zone and compacted zone double-layer structure after dry
(GTRM)。
3) preparation of medical implant:
0.3g octadecyl acrylate-fast release microcapsules of methyl acrylate copoly are dispersed in 15mL ethanol solution, it will
GTRM is impregnated in the ethanol solution, is put into oscillator and vibrates 0.5h, and frequency of oscillation can be 60-180r/min, then will
GTRM takes out, and is dried in vacuo (room temperature) by upper surface of weaker zone, the GTRM of load microcapsules can be obtained.
Embodiment 2
1) preparation of fast release microcapsules:
Using octadecyl acrylate 11g, methyl acrylate 3g as wall material raw material monomer, using bata-tricalcium phosphate 0.2g as core material original
Material, using sodium salt of acrylic acid-co-maleic anhydride 20g as emulsifier, using potassium peroxydisulfate 0.011g as initiator, by wall material monomer
Raw material, core material raw material, emulsifier are added in deionized water 100mL, and clipped mulser emulsifies 10min with 10000r/min,
Lotion is poured into the 250mL three-necked flask with mechanical agitator, mixing speed 300r/min, and flask is heated to 80
DEG C (nitrogen atmosphere) is added initiator, reaction temperature is gradually down to 40 DEG C after 10min, close after reacting 2h after temperature is constant
Heating device continues to stir, until being cooled to room temperature, stops reaction, lotion is poured into the calcium chloride solution of saturation and carried out brokenly
Then cream is filtered and obtains microcapsules crude product, cleaned, filtered repeatedly using alcohol, so rear normal-temperature vacuum is dry three times
Obtain microscapsule powder.Gained microcapsules outer diameter is 10-40 μm.
2) preparation of slow-release microcapsule:
It, will with 0.4 μ g bone morphogenetic protein 2 (BMP-2) for core material raw material using 0.7g PLGA-TMC as wall material raw material
PLGA-TMC and 0.1g polyethylene glycol are dissolved in 30mL ethyl acetate, BMP-2 are dissolved in the deionized water of 400 μ L, by BMP-2
Solution be added PLGA-TMC solution in and ultrasonic emulsification 30min, obtain colostric fluid A, by 0.5g polyethylene glycol be dissolved in 50mL go from
In sub- water, simultaneously ultrasonic emulsification 20min is added dropwise in such as Aqueous Solutions of Polyethylene Glycol in colostric fluid A, mixed emulsion is mechanical at 35 DEG C
3h volatile organic solvent is stirred, then PLGA-TMC microcapsules can be obtained in centrifugation, washing, drying.Gained microcapsules outer diameter is
100-180μm。
3) preparation of matrix:
There is the guide tissue regeneration film (GTRM) of weaker zone and compacted zone double-layer structure, side using electrostatic spinning machine preparation
Method is as follows:
Using PLGA-TMC as raw material, chitosan/PLGA-TMC composite membrane is prepared through combination process such as melt blending, extrusions,
And using chitosan/PLGA-TMC composite membrane as compacted zone.
PLGA is dissolved in chloroform, prepares and obtains the electrostatic spinning liquid that concentration is 17%, spinning solution is injected into solution
In syringe, fltting speed 1.4mL/h；Spinning voltage 20kV, receives distance 12cm, and the mode through electrostatic spraying is by Nanowire
Dimension sprays to fine and close layer surface, obtains the GTRM with weaker zone and compacted zone double-layer structure after dry.
4) preparation of medical implant:
0.4g octadecyl acrylate-methyl acrylate copoly microcapsules, 0.6g PLGA microcapsules are dispersed in 15mL ethyl alcohol
In solution, GTRM being impregnated in the ethanol solution, is put into oscillator and vibrates 0.5h, frequency of oscillation can be 60-180r/min,
Then GTRM is taken out, is dried in vacuo (room temperature) by upper surface of weaker zone, the GTRM of load microcapsules can be obtained.
Embodiment 3
1) preparation of fast release microcapsules:
Using octadecyl acrylate 9g, methyl acrylate 2g as wall material raw material monomer, using bata-tricalcium phosphate 0.2g as core material original
Material, using sodium salt of acrylic acid-co-maleic anhydride 20g as emulsifier, using potassium peroxydisulfate 0.011g as initiator, by monomer original
Material, core material raw material, emulsifier are added in deionized water 100mL, and clipped mulser emulsifies 10min with 10000r/min, will
Lotion is poured into the 250mL three-necked flask with mechanical agitator, mixing speed 300r/min, and flask is heated to 80 DEG C
(nitrogen atmosphere) is added initiator, reaction temperature is gradually down to 40 DEG C after 10min after temperature is constant, closing adds after reacting 2h
Thermal continues to stir, until being cooled to room temperature, stops reaction, lotion is poured into the calcium chloride solution of saturation and is demulsified,
Then it filters and obtains microcapsules crude product, cleaned, filtered repeatedly using alcohol, so rear normal-temperature vacuum drying can be obtained three times
Microscapsule powder.Gained microcapsules outer diameter is 10-40 μm.
2) preparation of slow-release microcapsule:
It, will with 0.4 μ g bone morphogenetic protein 2 (BMP-2) for core material raw material using 0.7g PLGA-TMC as wall material raw material
PLGA-TMC and 0.1g polyethylene glycol are dissolved in 30mL ethyl acetate, BMP-2 are dissolved in the deionized water of 400 μ L, by BMP-2
Solution be added PLGA-TMC solution in and ultrasonic emulsification 30min, obtain colostric fluid A, by 0.5g polyethylene glycol be dissolved in 50mL go from
In sub- water, simultaneously ultrasonic emulsification 20min is added dropwise in such as Aqueous Solutions of Polyethylene Glycol in colostric fluid A, mixed emulsion is mechanical at 35 DEG C
3h volatile organic solvent is stirred, then PLGA-TMC microcapsules can be obtained in centrifugation, washing, drying.Gained microcapsules outer diameter is
100-180μm。
3) preparation of matrix:
PLGA is dissolved in chloroform, prepares and obtains the shell layer spinning solution for the coaxial electrostatic spinning that concentration is 10%；It will
Chitosan is dissolved in the acetic acid aqueous solution that concentration is 0.1%, obtains the sandwich layer spinning solution of coaxial electrostatic spinning；By two kinds of spinning solutions
It is injected separately into shell and sandwich layer solution injector, the fltting speed of shell solution is 1.6mL/h, the fltting speed of sandwich layer solution
For 1.3mL/h；Spinning voltage 20kV, receives distance 12cm, and nanofiber is sprayed to compacted zone table by the mode through electrostatic spraying
Face obtains the GTRM with weaker zone and compacted zone double-layer structure after dry.
4) preparation of medical implant
0.4g octadecyl acrylate-methyl acrylate copoly microcapsules, 0.6g PLGA microcapsules are dispersed in 15mL ethyl alcohol
In solution, GTRM being impregnated in the ethanol solution, is put into oscillator and vibrates 0.5h, frequency of oscillation can be 60-180r/min,
Then GTRM is taken out, is dried in vacuo (room temperature) by upper surface of weaker zone, the GTRM of load microcapsules can be obtained.
Embodiment 4
1) preparation of fast release microcapsules:
Using Process Conditions of Cetane Acrylate 10g, methyl acrylate 1g as wall material raw material monomer, using bata-tricalcium phosphate 0.2g as core material original
Material, using sodium salt of acrylic acid-co-maleic anhydride 20g as emulsifier, using potassium peroxydisulfate 0.011g as initiator, by monomer original
Material, core material raw material, emulsifier are added in deionized water 100mL, and clipped mulser emulsifies 5min with 10000r/min, will be newborn
Liquid pours into the 250mL three-necked flask with mechanical agitator, mixing speed 300r/min, and flask is heated to 80 DEG C
(nitrogen atmosphere) is added initiator, reaction temperature is gradually down to 40 DEG C after 30min after temperature is constant, closing adds after reacting 2h
Thermal continues to stir, until being cooled to room temperature, stops reaction, lotion is poured into the calcium chloride solution of saturation and is demulsified,
Then it filters and obtains microcapsules crude product, cleaned, filtered repeatedly using alcohol, so rear normal-temperature vacuum drying can be obtained three times
Microscapsule powder.Gained microcapsules outer diameter is 20-70 μm.
2) preparation of slow-release microcapsule:
It, will with 0.4 μ g bone morphogenesis protein-2 (BMP-2) for core material raw material using 0.7g PLGA-TMC as wall material raw material
PLGA-TMC and 0.1g polyethylene glycol are dissolved in 30mL ethyl acetate, BMP-2 are dissolved in the deionized water of 400 μ L, by BMP-2
Solution be added PLGA-TMC solution in and ultrasonic emulsification 30min, obtain colostric fluid A, by 0.5g polyethylene glycol be dissolved in 50mL go from
In sub- water, simultaneously ultrasonic emulsification 30min is added dropwise in such as Aqueous Solutions of Polyethylene Glycol in colostric fluid A, mixed emulsion is mechanical at 35 DEG C
3h volatile organic solvent is stirred, then PLGA-TMC microcapsules can be obtained in centrifugation, washing, drying.Gained microcapsules outer diameter is
80-130μm。
3) preparation of medical implant:
Matrix of the tissue engineering bracket as medical implant is made by the method for 3D printing, by the tissue engineering bracket
It immerses in the ethanol solution containing the fast release microcapsules of 0.2g and 0.8g slow-release microcapsule, is put into oscillator and vibrates 0.5h, vibrate
Frequency is 60-180r/min.It is put into vacuum oven and is dried to get the group weaver of load microcapsules after major part of volatilizing solvent
Engineering support.
Embodiment 5
1) preparation of fast release microcapsules:
It is cream with Span-80 using bata-tricalcium phosphate 0.2g as core material raw material using 10g polyethylene glycol-1000 as wall material raw material
Wall material raw material, core material raw material, 47g emulsifier are added in dehydrated alcohol 100mL, ultrasonic emulsification 30min, by lotion by agent
It pours into the 250mL beaker with mechanical agitator, mixing speed 100r/min, and flask is heated to 60 DEG C, to solvent
Heating device is closed after volatilization and microscapsule powder can be obtained in stirring.Gained microcapsules outer diameter is 30-100 μm.
2) preparation of slow-release microcapsule:
It, will with 0.4 μ g bone morphogenetic protein 2 (BMP-2) for core material raw material using 0.7g PLGA-TMC as wall material raw material
PLGA-TMC and 0.1g polyethylene glycol are dissolved in 30mL ethyl acetate, BMP-2 are dissolved in the deionized water of 400 μ L, by BMP-2
Solution be added PLGA-TMC solution in and ultrasonic emulsification 30min, obtain colostric fluid A, by 0.5g polyethylene glycol be dissolved in 50mL go from
In sub- water, simultaneously ultrasonic emulsification 30min is added dropwise in such as Aqueous Solutions of Polyethylene Glycol in colostric fluid A, mixed emulsion is mechanical at 35 DEG C
3h volatile organic solvent is stirred, then PLGA-TMC microcapsules can be obtained in centrifugation, washing, drying.Gained microcapsules outer diameter is
80-130μm。
3) preparation of medical implant:
Matrix of the tissue engineering bracket as medical implant is made by the method for 3D printing, by dry 0.4g quick release
Microcapsules and 0.6g slow-release microcapsule powder are sprayed directly on tissue engineering bracket surface and vibrate 0.5h in an oscillator.
Embodiment 6
1) fast release microcapsules
Using 10g polyethylene glycol-1000 as wall material raw material, using nanoscale bata-tricalcium phosphate 0.2g as core material raw material, by wall material
Raw material, core material raw material etc. are added in 100mL methylene chloride, the ultrasonic disperse bata-tricalcium phosphate after polyethylene glycol is completely dissolved
20min obtains uniform dispersion liquid, and using this dispersion liquid as injection liquid, is ejected into above-mentioned solution using the method that solution sprays
In 30 DEG C of baking ovens, fltting speed 20mL/h, air pressure 0.02MPa, collection obtain polyglycol microcapsule.
2) slow-release microcapsule
It, will with 0.4 μ g bone morphogenetic protein 2 (BMP-2) for core material raw material using 0.7g PLGA-TMC as wall material raw material
PLGA-TMC and 0.1g polyethylene glycol are dissolved in 30mL ethyl acetate, BMP-2 are dissolved in the deionized water of 400 μ L, by BMP-2
Solution be added PLGA-TMC solution in and ultrasonic emulsification 30min, obtain colostric fluid A, by 0.5g polyethylene glycol be dissolved in 50mL go from
In sub- water, simultaneously ultrasonic emulsification 30min is added dropwise in such as Aqueous Solutions of Polyethylene Glycol in colostric fluid A, mixed emulsion is mechanical at 35 DEG C
3h volatile organic solvent is stirred, then PLGA-TMC microcapsules can be obtained in centrifugation, washing, drying.Gained microcapsules outer diameter is
80-130μm。
3) base of the tissue engineering bracket as medical implant is made by the method for 3D printing in the preparation of medical implant
The dry fast release microcapsules of 0.4g and 0.6g slow-release microcapsule powder are sprayed directly on tissue engineering bracket surface and shaken by body
It swings and vibrates 0.5h in device.
Embodiment 7
1) preparation of fast release microcapsules:
Using octadecyl acrylate 9g, methyl acrylate 2g as wall material raw material monomer, using bata-tricalcium phosphate 0.2g as core material original
Material, using sodium salt of acrylic acid-co-maleic anhydride 20g as emulsifier, using potassium peroxydisulfate 0.011g as initiator, by wall material monomer
Raw material, core material raw material, emulsifier are added in deionized water 335mL, and clipped mulser emulsifies 5min with 8000r/min, will
Lotion is poured into the 250mL three-necked flask with mechanical agitator, mixing speed 300r/min, and flask is heated to 80 DEG C
(nitrogen atmosphere) is added initiator, reaction temperature is gradually down to 40 DEG C after 10min after temperature is constant, closing adds after reacting 2h
Thermal continues to stir, until being cooled to room temperature, stops reaction, lotion is poured into the calcium chloride solution of saturation and is demulsified,
Then it filters and obtains microcapsules crude product, cleaned, filtered repeatedly using alcohol, so rear normal-temperature vacuum drying can be obtained three times
Microscapsule powder.Gained microcapsules outer diameter is 80-150 μm.
2) preparation of slow-release microcapsule:
It, will with 0.4 μ g bone morphogenetic protein 2 (BMP-2) for core material raw material using 0.7g PLGA-TMC as wall material raw material
PLGA-TMC and 0.1g polyethylene glycol are dissolved in 30mL ethyl acetate, BMP-2 are dissolved in the deionized water of 400 μ L, by BMP-2
Solution be added PLGA-TMC solution in and ultrasonic emulsification 30min, obtain colostric fluid A, by 0.5g polyethylene glycol be dissolved in 50mL go from
In sub- water, colostric fluid A is added dropwise in Aqueous Solutions of Polyethylene Glycol simultaneously ultrasonic emulsification 30min, mixed emulsion is mechanical at 35 DEG C
3h volatile organic solvent is stirred, then PLGA-TMC microcapsules can be obtained in centrifugation, washing, drying.Gained microcapsules outer diameter is
80-130μm。
3) preparation of medical implant:
Absorbable matrix of the free bone plate as medical implant is made by injection moulding process, by the fast release microcapsules of 0.3g
With 0.6g slow-release microcapsule ultrasonic disperse in the polyethylene glycol-1000 dehydrated alcohol that concentration is 0.1g/mL, dispersion liquid is sprayed
To absorbable free synthetism plate surface, it is dried in vacuo under room temperature to get the absorbable free bone plate of load microcapsules.
Embodiment 8
1) preparation of fast release microcapsules:
Using octadecyl acrylate 9g, methyl acrylate 2g as wall material raw material monomer, using bata-tricalcium phosphate 0.2g as core material original
Material, using sodium salt of acrylic acid-co-maleic anhydride 20g as emulsifier, using potassium peroxydisulfate 0.011g as initiator, by wall material monomer
Raw material, core material raw material, emulsifier are added in deionized water 42mL, and clipped mulser emulsifies 5min with 8000r/min, will be newborn
Liquid pours into the 250mL three-necked flask with mechanical agitator, mixing speed 300r/min, and flask is heated to 65 DEG C
(nitrogen atmosphere) is added initiator, reaction temperature is gradually down to 60 DEG C after 30min, close after reacting 1.5h after temperature is constant
Heating device continues to stir, until being cooled to room temperature, stops reaction, lotion is poured into the calcium chloride solution of saturation and carried out brokenly
Then cream is filtered and obtains microcapsules crude product, cleaned, filtered repeatedly using alcohol, so rear normal-temperature vacuum is dry three times
Obtain microscapsule powder.Gained microcapsules outer diameter is 80-150 μm.
2) preparation of slow-release microcapsule:
It, will with 0.4 μ g bone morphogenetic protein 2 (BMP-2) for core material raw material using 0.7g PLGA-TMC as wall material raw material
PLGA-TMC and 0.1g polyethylene glycol are dissolved in 30mL ethyl acetate, BMP-2 are dissolved in the deionized water of 400 μ L, by BMP-2
Solution be added PLGA-TMC solution in and ultrasonic emulsification 30min, obtain colostric fluid A, by 0.5g polyethylene glycol be dissolved in 50mL go from
In sub- water, simultaneously ultrasonic emulsification 30min is added dropwise in such as Aqueous Solutions of Polyethylene Glycol in colostric fluid A, mixed emulsion is mechanical at 35 DEG C
3h volatile organic solvent is stirred, then PLGA-TMC microcapsules can be obtained in centrifugation, washing, drying.Gained microcapsules outer diameter is
80-130μm。
3) preparation of medical implant:
Absorbable matrix of the synthetism stick as medical implant is made by injection moulding process, by the fast release microcapsules of 0.3g with
0.6g slow-release microcapsule ultrasonic disperse sprays to dispersion liquid in the polyethylene glycol-1000 dehydrated alcohol that concentration is 0.1g/mL
Adsorbable bone stick surface is dried in vacuo under room temperature to get the adsorbable bone stick of load microcapsules.
Embodiment 9
1) preparation of fast release microcapsules:
Using octadecyl acrylate 8g, methyl acrylate 3g as wall material raw material monomer, using bata-tricalcium phosphate 0.2g as core material original
Material, using sodium salt of acrylic acid-co-maleic anhydride 20g as emulsifier, using potassium peroxydisulfate 0.011g as initiator, by wall material monomer
Raw material, core material raw material, emulsifier are added in deionized water 100mL, and clipped mulser emulsifies 10min with 2000r/min, will
Lotion is poured into the 250mL three-necked flask with mechanical agitator, mixing speed 300r/min, and flask is heated to 80 DEG C
(nitrogen atmosphere) is added initiator, reaction temperature is gradually down to 40 DEG C after 10min after temperature is constant, closing adds after reacting 2h
Thermal continues to stir, until being cooled to room temperature, stops reaction, lotion is poured into the calcium chloride solution of saturation and is demulsified,
Then it filters and obtains microcapsules crude product, cleaned, filtered repeatedly using alcohol, so rear normal-temperature vacuum drying can be obtained three times
Microscapsule powder.Gained microcapsules outer diameter is 250-380 μm.
2) preparation of slow-release microcapsule:
It, will with 0.4 μ g bone morphogenetic protein 2 (BMP-2) for core material raw material using 0.7g PLGA-TMC as wall material raw material
PLGA-TMC and 0.1g polyethylene glycol are dissolved in 30mL ethyl acetate, BMP-2 are dissolved in the deionized water of 400 μ L, by BMP-2
Solution be added PLGA-TMC solution in and ultrasonic emulsification 30min, obtain colostric fluid A, by 0.5g polyethylene glycol be dissolved in 50mL go from
In sub- water, simultaneously ultrasonic emulsification 10min is added dropwise in such as Aqueous Solutions of Polyethylene Glycol in colostric fluid A, mixed emulsion is mechanical at 35 DEG C
3h volatile organic solvent is stirred, then PLGA-TMC microcapsules can be obtained in centrifugation, washing, drying.Gained microcapsules outer diameter is
260-350μm。
3) preparation of medical implant:
Matrix of the absorbable interference screw fixation as medical implant is made by injection moulding process, by the fast release microcapsules of 0.5g and
0.5g slow-release microcapsule ultrasonic disperse sprays to dispersion liquid in the polyethylene glycol-1000 dehydrated alcohol that concentration is 0.1g/mL
Absorbable interference screw fixation surface is dried in vacuo under room temperature to get the absorbable interference screw fixation of load microcapsules.
It should be understood that medical implant prepared by the present invention, the core material institute of the gentle release microcapsules of fast release microcapsules
The active function substance of use may include cited one or more being appointed to can be realized the biologically active grain of the function
Son, for example, " bone morphogenetic protein " be can induce animal or human mesenchymal's cell differentiation be bone, cartilage, ligament,
The albumen of any one of tendon and nerve fiber form, such as bone morphogenesis protein-2, bone morphogenesis protein-7.
Above-described embodiment is only to be illustrated, and is not intended to limit the present invention.Any those of ordinary skill in the art are equal
Can without prejudice to design of the invention and under the scope of, modifications and changes are made to the above embodiments.Therefore, right of the invention is protected
Shield range is defined by claims appended hereto, as long as not influencing effect of the invention and implementing purpose, Ying Han
It is placed in the displosure technology contents.
Claims (21)
1. a kind of medical implant, which is characterized in that micro- including medical macromolecular materials matrix and the quick release being supported on matrix
The wall material of capsule, the fast release microcapsules is phase-change material, and the phase-change material is solid-state at room temperature, is under body temperature melting
Liquid, the core material of the fast release microcapsules are biological functional activity substance.
2. medical implant as described in claim 1, which is characterized in that be also loaded slow-release microcapsule, institute in described matrix
The wall material of slow-release microcapsule is stated as biological resorbable polymeric materials, the core material of the slow-release microcapsule is biological functional activity object
Matter.
3. medical implant as claimed in claim 1 or 2, which is characterized in that the phase-change material is acrylic ester copolymerization
Object or polyethylene glycol.
4. medical implant as claimed in claim 3, which is characterized in that the relative molecular mass of the polyethylene glycol is
1000。
5. medical implant as claimed in claim 3, which is characterized in that the acrylic acid esters co-polymer is methyl acrylate
With the copolymer of acrylate fatty alcohol.
6. medical implant as claimed in claim 5, which is characterized in that the acrylate fatty alcohol is fatty alcohol alkyl chain
For C12~18Acrylate, preferably octadecyl acrylate and Process Conditions of Cetane Acrylate.
7. medical implant as claimed in claim 5, which is characterized in that the methyl acrylate and acrylate fatty alcohol
Mass ratio is (1~3): (8~10).
8. such as the described in any item medical implants of claim 2-7, which is characterized in that the fast release microcapsules and the micro- glue of sustained release
The outer diameter of capsule is respectively 10-380 μm.
9. such as the described in any item medical implants of claim 2-8, which is characterized in that the biological absorbable high molecular material
Selected from the one or more of degradable natural high molecular material, biologically absorbable polymer or its copolymer, wherein described can drop
It solves natural macromolecular material and is selected from one of gelatin, agar, chitosan, sodium alginate, starch, cellulose, type i collagen or more
Kind, wherein the biologically absorbable polymer is selected from polylactic acid, l-lactic acid, dextrorotation polylactic acid, racemic polylactic acid, poly- hydroxyl
Acetic acid, polycaprolactone, polyvinyl alcohol, polydioxanone, polyaminoacid derivative carbonic ester, polyorthoester, polytrimethylene
One of carbonic ester is a variety of.
10. such as the described in any item medical implants of claim 1-9, which is characterized in that the biological functional activity substance choosing
From growth promotion, antibacterial, induced growth functional materials it is one or more.
11. such as the described in any item medical implants of claim 1-9, which is characterized in that the life of the fast release microcapsules core material
Object functional activity substance is selected from hydroxyapatite, tricalcium phosphate, chitosan, cucoline, bone morphogenetic protein, antibiotic, resists
One of coagulant, microorganism immune formulation, anticancer drug are a variety of, preferably antibiotic, anticoagulant, immune formulation,
One of hydroxyapatite or tricalcium phosphate are a variety of.
12. such as the described in any item medical implants of claim 2-9, which is characterized in that the life of the slow-release microcapsule core material
Object functional activity substance is selected from hydroxyapatite, tricalcium phosphate, chitosan, cucoline, bone morphogenetic protein, antibiotic, resists
One of coagulant, microorganism immune formulation, anticancer drug are a variety of, preferably one of bone morphogenetic protein, chitosan
Or it is a variety of.
13. such as the described in any item medical implants of claim 1-12, which is characterized in that described matrix is selected from guidance tissue again
One of filming, tissue engineering bracket, absorbable-bone plate, absorbable interference screw fixation, adsorbable bone stick.
14. medical implant as claimed in claim 13, which is characterized in that the guide tissue regeneration film include weaker zone and
Compacted zone, the weaker zone in the method electrostatic spraying to the compacted zone of coaxial electrostatic spinning by forming, wherein coaxial quiet
The core structure that Electrospun obtains weaker zone is biological functional activity substance.
15. medical implant as claimed in claim 14, which is characterized in that the biology in the weaker zone and/or compacted zone
Functional activity substance be respectively selected from hydroxyapatite, tricalcium phosphate, chitosan, cucoline, bone morphogenetic protein, antibiotic,
One of anticoagulant, microorganism immune formulation, anticancer drug are a variety of, preferably bone morphogenetic protein, one in chitosan
Kind is a variety of.
16. a kind of method for preparing the described in any item medical implants of claim 1-15, includes the following steps:
1) prepare fast release microcapsules: using the phase-change material as wall material raw material, the biological functional activity substance is as core material
Raw material prepares fast release microcapsules, wherein the method for preparing fast release microcapsules is selected from situ aggregation method, phase separation method, solvent volatilization
One of method, complex coacervation, spray drying process；
2) by the fast release microcapsules of preparation in conjunction with described matrix, the medical implant is obtained, wherein the combination method choosing
From one of electrostatic spraying, coating, dipping, absorption.
17. the method for preparing medical implant as claimed in claim 16, which is characterized in that further include being prepared before step 2
The step of slow-release microcapsule, comprising:
Prepare slow-release microcapsule: using the biological absorbable high molecular material as wall material raw material, the biological functional activity object
Matter is prepared into slow-release microcapsule as core material raw material, wherein the method for preparing slow-release microcapsule is selected from interfacial polymerization, original position is gathered
One of legal, phase separation method, solvent evaporation method, complex coacervation, spray drying process；
The gentle release microcapsules of the fast release microcapsules of preparation are obtained into the medical plant in conjunction with described matrix by the step 2
Enter object.
18. the method for preparing medical implant as claimed in claim 17, which is characterized in that the phase-change material is acrylic acid
The method that fast release microcapsules are prepared when lipin polymer, in step 1 includes the following steps:
By the wall material raw material monomer, core material raw material, emulsifier mixing, which are added to the water, prepares solution, carries out shearing or ultrasound cream
Change, gained emulsion carries out mechanical stirring under inert gas protection, is heated to constant be added after 65-95 DEG C of temperature and causes
Agent, after reacting 5-30min, reaction temperature is down to 35-60 DEG C, and the reaction was continued, stops stopping stirring after heating is cooled to room temperature anti-
It should be to get the fast release microcapsules.
19. the method for preparing medical implant as claimed in claim 18, which is characterized in that the emulsifier is selected from poly- second two
Alcohol -400, sodium salt of acrylic acid-co-maleic anhydride, Arlacel-80, Arlacel-60, Tween-80, Tween-60, Tween-20, alkyl
One of phenol polyethenoxy ether -10 or its composite emulsifier are a variety of, the initiator be selected from potassium peroxydisulfate, ammonium persulfate,
One of azodiisobutyronitrile, azobisisoheptonitrile, benzoyl peroxide, cumyl peroxide.
20. the method for preparing medical implant as described in claim 18 or 19, which is characterized in that emulsified in the step 1
Agent accounts for the 5%~30% of the emulsion gross mass, core material raw material and wall material raw material account for the emulsion gross mass 3%~
15%.
21. such as the described in any item methods for preparing medical implant of claim 16-20, which is characterized in that described matrix is
When guide tissue regeneration film, further include the steps that preparing matrix before step 1:
Using biological absorbable high molecular material as raw material, beaten using solution plastic film mulch, hot-forming, extrusion molding, casting film-forming, 3D
It is printed as one or more of type, nonwovens process method and prepares compacted zone；
Using the solution of biological absorbable high molecular material as shell layer spinning solution, spun by sandwich layer of the solution of biological functional activity substance
Silk liquid, two kinds of spinning solutions is injected separately into shell and sandwich layer solution injector, the mode through electrostatic spraying sprays to compacted zone
Surface obtains the guide tissue regeneration film with weaker zone and compacted zone double-layer structure after dry.
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