CN105343937B - A kind of compound porous matter sponge material and preparation method thereof - Google Patents
A kind of compound porous matter sponge material and preparation method thereof Download PDFInfo
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- CN105343937B CN105343937B CN201510760178.0A CN201510760178A CN105343937B CN 105343937 B CN105343937 B CN 105343937B CN 201510760178 A CN201510760178 A CN 201510760178A CN 105343937 B CN105343937 B CN 105343937B
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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
- A61L27/56—Porous materials, e.g. foams or sponges
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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
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
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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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
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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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
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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
- 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
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
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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
- A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
Abstract
The present invention provides a kind of compound porous matter sponge material, macromolecule is synthesized by the bioresorbable of peripheral skeleton to be kneaded filled with the natural porous polymer plastid bigger than the peripheral skeleton porosity with internal crosslinking, contain hollow bulb in bioresorbable synthesis macromolecule, the hollow bulb is filled with the one or more in bioresorbable natural porous polymer material, Porcine HGF, cell differentiation controlling elements.Specific preparation method includes the preparation that bioresorbable synthesizes high-molecular porous matter sponge material；The preparation and filling of bioresorbable natural polymer solution；It is freeze-dried to will be filled with the high-molecular porous matter sponge material of synthesis of natural polymer solution, then builds bridge, compound porous matter sponge material is made.This composite material central portion after freeze-dried forms aperture and is connected structure, and biological cell is easily sowed into aperture, cell quick wall attaching under high-affinity environment, and the rapid environment that adapts to absorbs nutrition and various cytokine profiles.
Description
Technical field
The present invention relates to the regeneration for using polymer composite guiding human organ, for example repairing articular cartilage is again
The raw, regeneration of bone is specially compound porous matter sponge material and preparation method thereof, it is intended to cultivate patient in Porous sponge material
The cell of oneself, in vitro culture for a period of time after, be implanted into organism.
Background technology
Because of traffic accident, sports, productive labor, the age becomes larger, the reasons such as disease, and organism is often damaged and unfortunate
The tissues such as cartilage and bone are lost, in hospital orthopedics also common joints cartilage damage, because without blood vessel, cartilage cell in cartilaginous tissue
Lack in no blood transports environment and migrate ability.Be difficult regeneration after cartilage damage, in art of orthopedic surgery, how to repair or treat because
Traumatic and degenerative cartilage tissue loss caused by disease, wound etc., is all problem in the whole world, and impacting injury is not given immediately
Treatment is given, wound will be increasing, finally must not be without prosthetic replacement, but joint replacement wound is big, special to patient
It is not that gerontal patient bears weight, and infection risk is high and faces the problems such as overhauling and replacing again below for many years, generally believes morning
The damage of phase repairing articular cartilage is very necessary.Traditional treatment cartilage damage has and promotes regenerating bone or cartilage using medicine irritation, also there is hand
Art such as joint grinding forming art, drilling, micro fractures and arthroscope lavation art make in marrow cartilage derived, bone source property cell and thin
Intracellular cytokine penetrates into damaged cartilage region, promotes, to Chondrocyte Differentiation, to generate fibrocartilage.This surgical procedure is simple, right
Small area cartilage damage is relatively satisfactory in some sense, is widely used.
But research shows that actually these methods cannot will damage repair of cartilage, and cartilage abrasion, marrow stimulation etc.
The fibrocartilage tissue of formation that heals still lacks ideal with the reparation of the current articular cartilage defects of hyaline cartilage difference efficacious prescriptions
Method.It is also a kind of method with the tissue transplantation of donation, but there is donation wretched insufficiency in China, and also the organ that others contributes also has
The variety of problems such as immune response repulsion.The final result that cartilage disease cannot be effectively treated, causes joint replacement, however people
It makes articular organs often to relax breakage etc. because abrasion generates, causes function insufficient, therefore clinically arthropathy patient's is huge
Demand promotes researcher constantly to explore new feasible method.
Cartilage transplantation art is one of wider technology of reparation cartilage damage of current application, and self cartilaginous tissue is transplanted
Curative effect is preferably but limited for material；After clinic extraction autologous patient cartilage cell, cell is adsorbed in biocompatibility well and can quilt
In the carrier that human body gradually absorbs, carrier offer three dimensions, favourable cell acquisition nutrition, gas exchanges, discharged waste, carefully
Born of the same parents are grown by three-dimensional rack.Clinically MACI (Matrix-induced autologous chondrocyte
Implantation) technology is more ripe.The cartilage cell of acquisition is planted on biomembrane, then fixed with viscose be transplanted to it is scarce
At damage.The advantage is that cell is fixed, it will not post-surgical cell loss.Collagem membrane is carrier, is not required to cut periosteum, avoids bone
The various complication of film transplanting.Suture closing small, the hand that is not required to suture, operative incision is substituted with the better viscose of biocompatibility
The art time is short, and postoperative rehabilitation is fast.Using the cartilage (such as pig, ox) of animal origin, first cartilaginous tissue decellularization, Ran Houbo
Kind of autologous patient cell, after in vitro culture, clinical transplantation patient, this therapy also achieves certain effect, but heteroplastic transplantation is deposited
In immunological rejection and virus infection equivalent risk.Mescenchymal stem cell SMSCs (synovial mesenchymal stem cells)
Pass on reproductive capacity it is strong, continuous several times passage can still keep good Proliferation, Differentiation characteristic, in host material compound implant after can
It forms transparent sample cartilage and area forms bone tissue under cartilage, and reach integration.These methods only exist in zoopery rank at present
Section, it is also informal for clinic because the differentiation control of mescenchymal stem cell SMSCs is more difficult, differentiation efficiency than relatively low, and
Stem cell is taken from patient's body, to patient and a kind of burden.At present square hole honeycomb micro-structure is printed with 3D printing device
Polycaprolactone-hydroxyapatite 3D stents, be incorporated in vitro culture with marrow blood, induction stem cell to Chondrocyte Differentiation,
Also would be possible to repair cartilage defect.But this technology also has from application with a distance from suitable or a ways makes conceptual researches scope.
Since the nineties in last century, organizational project is risen, and starts from artificial human organ -- in vitro (laboratory)
Organism (cartilage) cell is cultivated, is proliferated them, cellular affinity timbering material is made first, then biological cell is sowed
On material, tissue (cell) is viscous to be paid on compatibility material, under appropriate culture solution, in vitro culture for a period of time, shape
Into after biological tissue, in operation transplantation to organism.Biological cell (such as stem cell) can also be sowed to after material, do not trained in vitro
It supports, directly in embedment biology, in biology biological tissue's (such as cartilage or bone) is induced to regenerate.It is in Buried body or straight after long-term cultivation
Connect in Buried body, this require material have some strength so as to can facilitate transplanting or transplanting after will not deform easily, so as to
The form of biological tissue is maintained, this is induced to promote to the material of making, and to form biological tissue extremely important.Therefore organizational project
It is required that material has biological affinity, there is appropriate intensity etc., and material does not bring adverse effect, raw body tissue shape to organism
Into while, material is also required to be decomposed absorption.
Organizational project development cartilage substitute is very promising, and the organization engineered cartilage of American-European Japan is in clinical medical at present
On, the mature technology used is to use collagen gel entrapment Autologous Chondrocyte, is implanted into disease damage, cell is when stent absorbs
Multiplication, while matrix is secreted, the cartilaginous tissue of new in situ tissue form and function is formed, at present in the field clinic, China
The regenerating bone or cartilage system (Cartilage Regeneration System, CaReS) that Germany and Britain is introduced in Tianjin is nowadays international comparison
The mature technology of apex.The clinical test license of 2009 Nian Huo Bureau of Drugs Supervision, Grade A hospital, which is carried out, at home applies, and curative effect is demonstrate,proved by case
It is real, adapt to treatment defect area 2.5-10cm2.But shortcoming is collagen colloid without elasticity, insufficient strength, easily contraction.
Therefore how many mechanisms make excellent regrown material in research regenerative medicine engineering gimmick, research now in the whole world, such as
The cell of patient oneself is cultivated in various Porous sponge materials, then regeneration transplanting.
Nowadays making Porous sponge material, mostly using more lactic acid Poly lactic acid, (PLA includes PDLA or
PLLA), the copolymerization of polyglycolic acid Poly glycol acid (PGA), lactic acid lactic acid and glycolic glycol acid
Body (PLGA), Poly (ε-caprolactone) polycaprolactones (PCL) etc., they and collagen, hyaluronic acid, albumen are more
The cooperation of the bioresorbables such as sugar, Glucosamine, chondroitin sulfate natural macromolecular material, which makes, becomes composite material.PLA
(PDLA or PLLA) and PGA, PLGA, PCL etc. are bioresorbable synthesis macromolecules, add water that can decompose, are easily absorbed,
Clinical application for many years, it was demonstrated that their security and validity, according to different situations, the decomposition product of these materials will be logical
It crosses internal metabolic pathway to be absorbed, therefore controls the planform thickness of these high molecular materials that can just control synthesis high molecular
Absorb decomposition rate, these synthesis high molecular materials have many advantages, such as that intensity is high, and processing performance is good, but, making it is more
The hole matter sponge material porosity is relatively low, and compatibility is also not as good as organisms natural origin substances such as collagens.Another aspect collagen
The bioresorbables natural polymer compatibility such as albumen, hyaluronic acid, proteoglycan, Glucosamine, chondroitin sulfate is good, and
And easy to manufacture goes out the Porous sponge material of high porosity, but processing performance relative mistake, intensity is very weak, it is difficult to make to obtain
It is desirable that form, and in culture or in vivo transplanting after, be easily deformed under compressing.
We have made one kind in view of the shortcomings that above difference experience is pondered, overcomes more than different materials meticulously
New composite material.
The content of the invention
More than solving the problems, such as, the present invention provides a kind of Porous sponge material of definite shape, it has sufficient
High porosity can provide sufficient room for cell culture, while have certain intensity and compatibility, and repopulating cell is trained after making
After supporting, organism transplanting is carried out, fills up organism (cartilage) missing, carries out (cartilage) regeneration.
The compound porous plastid sponge structure material of the present invention forms peripheral skeleton by synthesizing high-molecular porous plastid, internal
The big natural porous polymer plastid of the crosslinking packing ratio periphery porosity, as feature.
The present invention manufactures the compound porous matter sponge material of definite shape, and macromolecule and natural is synthesized by bioresorbable
Macromolecule is kneaded to be formed, and it is peripheral skeleton to synthesize high-molecular porous matter sponge material, supports the shape and structure of entire stent, energy
Bear certain pressure, the big natural porous polymer matter sponge material of this porosity of inner hollow crosslinking packing ratio, as feature.
There is abundant stomata space inside the compound porous matter sponge material of the present invention, by natural organism macromolecule
It forms, density sowing can cultivate cell, such as cartilage cell greatly, composite material periphery skeleton can bear pressure when biology is buried
So as to holding structure shape, stomata ratio and selection material can be adjusted, making is kneaded and synthesizes high-molecular porous matter sponge material, certainly
Surely suitable peripheral intensity and shape, so as to be suitble to different use objects.
Specifically, gabarit skeleton is made with the good bioresorbable synthesis macromolecule of processing performance, central portion has
Cavity, mechanical strength and the porosity are all higher, can adjust thickness and the porosity to adjust the strength of materials by selecting material,
The porous structure body of bioresorbable natural polymer is filled in macroscopic-void, and this structure is further strengthened in crosslinking, so as to
Form the manufacturing method of the compound porous matter sponge material of high intensity and macro porosity.The big intensity of gabarit skeleton makes this compound
Material energy persistence keeps certain mechanical strength, and the pillar or top structure of synthesis high molecular material can be also set in hollow space
Further improve mechanical strength.
Contain hollow bulb in bioresorbable synthesis macromolecule, which is filled with bioresorbable natural polymer
Porous material can also add one or more in Porcine HGF, cell differentiation controlling elements.
The interior hollow section is also provided with pillar and/or top structure, and the pillar and/or top structure are
Bioresorbable synthesizes high molecular material.The pillar and/or top structure can stablize porous plastid sponge structure, improve Porous
Sponge material intensity and bracing force, so whithin a period of time, under definite shape, cartilage cell is adhered on material, culture
Promote hyperplasia differentiation, extracellular organization is promoted to secrete to form biological tissue.
The compound porous matter sponge material or hollow bulb of above-mentioned hollow porous structure have top structure, there is corbeling
Compound porous matter sponge material, hollow bulb are filled with bioresorbable natural polymer, and sertoli cell adhesion promotes hyperplasia
Differentiation promotes extracellular organization secretion.
The interior hollow section can also be filled with natural macromolecular material or derivatives thereof and cell growth factor
Son, cell differentiation controlling elements.
The bioresorbable synthesis high molecular material of described hollow, pillar or top structure include PLA (PDLA or
PLLA), any one in PGA, copolymer PLGA, copolymer PCL.
The bioresorbable synthesis macromolecule porosity of the peripheral skeleton is 10-99%, and aperture is 10-800 μm；It is excellent
Choosing is 50-95% using the porosity, is 20-600 μm it is preferable to use aperture；
The more plastid porositys of natural polymer of the internal crosslinking filling are 10-99.5% μm, aperture 10-1000
μm, it is 60-99% it is preferable to use the porosity, is 20-600 μm it is preferable to use aperture；Interior hollow section can set pillar and/
Or top structure is 1-20, it is preferable to use for 1-3.Porous plastid pore structure is adhered as cell, and multiplication and tissue are again
Place is based oneself upon in life, and pore can connect mutually more preferably.
The thickness of the wall of obtained compound porous matter sponge material is synthesized as 0.1mm~100mm, it is preferable to use wall thickness to be
0.2~50mm；
The thickness at bottom is 0.2~50mm it is preferable to use base thickness in 0.1mm~100mm；
Diameter or width is in 0.1mm~100mm, and preferably diameter or width is in 0.2~50mm；
Depth is between 0.1mm~100mm, and preferred depth is between 0.2~50mm.
The natural macromolecular material includes I-type collagen, hyaluronic acid, chondroitin sulfate, proteoglycan, albumen
Glycan, Glucosamine, the one or more in gelatin；Wherein, concentration can be used in 0.1-3%, hyaluronic acid in collagen
Concentration can be used in 0.05-2% chondroitin sulfates concentration to can be used, and in 0.1-20%, concentration can be used in 0.1- in proteoglycan
20%, concentration can be used in 0.1-20% in proteoglycans, and concentration can be used in Glucosamine, and in 0.1-30%, gelatin can be used dense
Degree is in 0.1-15%.
Porcine HGF, cell differentiation controlling elements include epithelical cell growth factor (EGF), insulin, blood platelet
Outgrowth factor (PDGF), the fibrous bud hyperplasia factor (FGF), hepatocyte proliferation factor (HGF), intravascular cortex outgrowth factor
(VEGF), β characters conversion outgrowth factor (TGF-β), the one or more in the bon e formation factor (BMP)；Concentration is 0.01 μ
G/mL-100 μ g/mL are 0.1 μ g/mL-50 μ g/mL it is preferable to use concentration.
The present invention provides a kind of production method of compound porous matter sponge material, is as follows：
(1) the Porous sponge material that bioresorbable synthesizes high molecular hollow structure is manufactured.
(2) prepare natural polymer containing absorbability, Porcine HGF, a kind of cell differentiation controlling elements or more than one
Solution, and be filled in above-mentioned bioresorbable and synthesize high-molecular porous matter sponge material hollow bulb.
(3) it is freeze-dried, afterwards bridge formation processing is carried out using gaseous state or liquid bridging agent.It is specific as follows：
Above-mentioned operation (1) can use particle liquation process (Particulate-Leaching) to manufacture Porous sponge material
Material.Mixed dissolution bioresorbable synthesizes macromolecule first in solvent, is then filled with above-mentioned appropriately sized solute particles, stirs
After mixing uniformly, the porous material mold of hollow porous structure is inserted, fully after drying, is taken out from mold, passes through washing etc.
Method removes Porous agent, so as to which the hollow porous structure sponge material of above-mentioned operation (1) be made.Bioresorbable synthesizes
Any one dissolving that high molecular material is included in PLA (PDLA or PLLA), PGA, copolymer PLGA, copolymer PCL is above-mentioned
Absorbability synthesis macromolecule, usable solvent such as chloroform-chloroform, carbon tetrachloride, Isosorbide-5-Nitrae-dioxane, dichloromethane,
Ethyl acetate, acetone etc., the particle include water soluble crystallines sugariness particle and the chlorinations such as glucose, sucrose, maltose
The salts particle crystallization such as sodium, sodium sulphate, potassium chloride, sodium tartrate, sodium citrate, ammonium carbonate, sodium carbonate, sodium bicarbonate.It can use
Pure water Jin Stains, which are rinsed, removes above-mentioned crystallization sugariness particle or salt particle crystallization formation Porous sponge material.It is formed above-mentioned porous
A certain size ice pellets can also be used in the hole of matter shape material, and ice pellets can be removed by freeze-dried method,
In above-mentioned operation (2), after bioresorbable synthesis high molecular material is made, it is immersed in and is inhaled filled with biology
Among the solution of the property received natural macromolecular material, solution inner face can add Porcine HGF, cell differentiation controlling elements or this
A little derivatives, solution is added to hollow bulb there are many kinds of method, but infusion process is relatively suitble to.Infusion process is exactly containing one kind
Or two kinds of bioresorbable natural polymers, Porcine HGF, the aqueous solution of cell differentiation controlling elements or these derivatives,
Dipping synthesizes high-molecular porous matter sponge material, by depressurizing degassing process, bioresorbable natural polymer, cell growth factor
Son, cell differentiation controlling elements or the aqueous solution containing these derivatives are filled in bioresorbable synthesis high score with regard to full and uniform
Son hollow porous structure hole in and hollow space.
In above-mentioned operation (3), it is crosslinked using bridging agent and reinforces composite material, make structure more secured, shape is more solid,
Well-known bridging agent can use.Include the aldehyde such as isocyanates, glutaraldehyde, formaldehyde, paraformaldehyde than better suited bridging agent
Class, particularly glutaraldehyde, containing two aldehyde structures, crosslinking is abundant, and effect is relatively good.It is full and uniform for above-mentioned material is made to build bridge,
It can be impregnated, can also be fumigated with gas bridging agent using bridge formation agent solution when specifically used, it is certain density in certain temperature
Under bridging agent, the bridging agent of aqueous solution saturation flashes to steam, above-mentioned bioresorbable natural polymer, Porcine HGF,
Cell differentiation controlling elements and bioresorbable synthesis macromolecule are built bridge.It if is built bridge using gas, it is necessary to which control is built bridge
Temperature, in the range of bridging agent steam can be formed, controlled at 20-50 DEG C, so as to which bioresorbable be allowed to synthesize macromolecule
The sponge material of hollow porous structure cannot dissolve.The bridge formation time is decided by bridging agent species and bridge formation temperature, in not shadow
Under the premise of ringing hydrophily and the bioresorbable of hollow Porous sponge material, when nor affecting on transplanting, the appropriate bridge formation time
When being set in 10 point -12 small.
Nowadays the regenerating bone or cartilage graft materials of international mature, there is animal cartilage source, have other people donations, there is autologous patient
There is tissue engineering bone/cartilage in source, but animal origin (or other people contribute) cartilage has immune refusal, special animal origin
Cartilage also has virus disease risk, and self cartilage is best graft materials, but limited source, therefore tissue engineering artificial cartilage
As hot spot, it is however generally that collagen colloid (or sponge material) compatibility is strong, but fragile easily contraction, how according to organism
Cartilage defects shape, it is big with high molecular material making intensity, while the material of high-affinity is complete as the regeneration place of cell
The heat subject of world research.It the characteristics of high intensity possessed by composite material of the present invention, high-affinity, high void content, can be with
For the regeneration of various tissues and organ, such as cartilage, bone, tendon, ligament etc..
In the technical solution of the application, if without skeleton being difficult to make dimensionally stable only with collagen, structure is tight
Close sponge material, simple collagen protein sponge material can be shunk, and structure is crisp immediately by crosslinking (such as glutaraldehyde)
It is weak, it is implanted into also easily to absorb after human body reluctantly and shrink, composite material strength of the present invention is high, and stiffness (N/mm) ratio is only used
The material that synthesis macromolecule is made doubles, such as this PLLA macromolecules sponge structure (150 μm~150 μm) stiffness
For the composite high-moleculars sponge structure such as 3.91 ± 0.24N/mm (n=7), PLLA- collagens stiffness be 8.15 ±
0.64N/mm (n=7), it is therefore evident that, this strength of materials is very high, can after organism is implanted into, shape will maintain compared with
For a long time until forming biological tissue, it is natural that this PLLA material hollow bulbs are filled with high-affinity and the collagen of high void content etc.
Macromolecule is high void content composite material most effective so far.This composite material central portion after freeze-dried forms aperture
Be connected structure, and biological cell is easily sowed into aperture, and cell quick wall attaching under high-affinity environment adapts to rapidly ring
Border absorbs nutrition and various cytokine profiles, at the same a large amount of secretory cell interstitials (ECM) and form biological tissue.Composite material
Outside joined the natural polymers such as collagen, capillary can be formed above, and metabolic waste is transported in transport nutrition, is promoted
Into cell proliferation, promotion forms biological tissue, while the artificial synthesized macromolecule of these cell disintegrations and natural macromolecular material.Cause
This material composition of the present invention and structure provide a fit closely good environment to regenerating various tissues and organ.
Figure of description
Fig. 1 present invention synthesizes the technological process of high-molecular porous matter sponge material making-natural porous polymer matter solution
Figure.
Fig. 2 is that the bioresorbable of hollow porous structure synthesizes macromolecule sponge material schematic diagram.
Fig. 3 is the graph of the high-molecular porous matter sponge material of hollow synthesis of PLLA in embodiment 1.
Fig. 4 is the high-molecular porous matter sponge material of hollow synthesis of PLLA in embodiment 1 in electron microscope vertical section figure.
Fig. 5 is the graph of compound porous matter sponge material in embodiment 1.
Fig. 6 is the vertical section figure of the place of joining of compound porous matter sponge material in embodiment 1 under an electron microscope.
Specific embodiment
Bioresorbable polymeric hollow porous structure material, this implementation are made by taking artificial synthesized macromolecule PLLA as an example
Method, using multiple material (such as PGA, PLGA, PCL etc.), can use a variety of sodium chloride crystal grains in the case where being suitble to environmental condition
It is attempted in footpath, it is not limited to present implementation.
Embodiment 1
Sodium chloride crystalline particle is made available separately about 90 μm~150 μm grains of diameter with 170 mesh sieve and the sieving of 100 mesh sieve
Son.On the other hand 1g PLLA are dissolved into 5mL chloroforms, modulation obtains synthesis Polymer Solution.The chloroformic solution of dissolving PLLA
Teat glass is put into, the sodium chloride crystalline particle 9g (9 times of PLLA amounts) of 90 μm~150 μm of addition is uniformly mixed.Then equal
The PLLA-NaCl- chloroforms of even mixing insert mold (politef system).Bioresorbable synthesis high score is made using this mold
Molecular hollow Porous sponge structure.To the tightly packed mixture in mold gap, dried 3-4 days in air, then vacuum is done
Dry one day.Solid PLLA- sodium chloride is removed after drying from mold, distillation water retting liquate rinses sodium chloride.It is every 2 it is small when exchange
First water is processed as 4 days.Thus obtain 90 μm~150 μm of aperture, the hollow synthesis for the PLLA that the porosity is 90%
High-molecular porous matter sponge material.
To modulate the compound porous matter sponge materials of bioresorbable macromolecule PLLA, then natural polymer solution, day are made
Right Polymer Solution adds 0.2% hyaluronic acid, the full and uniform stirring system of 2% proteoglycans by 0.5%I- collagen types
Into then the leaching of absorbability macromolecule PLLA compound porous matter sponge materials is placed in (above-mentioned 0.5% among natural polymer solution
I- collagen type solution, 0.2% hyaluronic acid, 2% proteoglycans) make compound porous matter sponge material.Natural polymer
Solution impregnates the PLLA Porous sponge materials in 90 μm~150 μm of the aperture of above-mentioned manufacture, passes through reduced pressure treatment, natural polymer
Mixed aqueous solution is just saturated in the hollow bulb of PLLA Porous sponge framework materials and the hole gap of four peripheral parts.Then PLLA
Porous sponge material -40 DEG C freeze 4 it is small when.When decompression (0.2Torr) freeze-dried 48 is small after freezing, in PLLA Porous
Natural polymer sponge structure, more matter of the natural polymer sponge structure are formed in the hollow bulb and surrounding pore of sponge material
The body porosity is 97.3%, and the material of manufacture is impregnated with the glutaraldehyde water solution of 10wt% or steamed in 25% glutaraldehyde saturation
Under gas, bridge formation is handled when 37 DEG C 4 small, is washed with distilled water 5 times, then with 0.1M glycine solutions impregnate 24 it is small when, remove
After unreacted aldehyde radical, it is washed with distilled water 20 times.Then -30 DEG C freeze again 4 it is small when, it is freeze-dried 48 it is small when, modulation make shape
Into compound PLLA Porous sponge material, hollow bulb is then natural porous polymer matter sponge material, you can is made compound porous
Matter sponge material.The thickness for synthesizing the PLLA walls of obtained compound porous matter sponge material is 1mm；The thickness at bottom is 1mm；Diameter
Or width is 8mm；Depth is 6mm.
Embodiment 2
Sodium chloride crystalline particle is made available separately about 150 μm~250 μm grains of diameter with 100 mesh sieve and the sieving of 60 mesh sieve
Son.On the other hand 1g PLLA are dissolved into 5mL chloroforms, modulation obtains synthesis Polymer Solution.The chloroformic solution of dissolving PLLA
Teat glass is put into, the sodium chloride crystalline particle 9g (9 times of PLLA amounts) for adding 150 μm~250 μm of grain size is uniformly mixed.Then
Mixed uniformly PLLA-NaCl- chloroforms are inserted mold (politef system).Bioresorbable is made using this mold to synthesize
The molecular hollow Porous sponge structure of high score.It is 3-4 days dry in air to the tightly packed mixture in mold gap, then very
It is empty drying for one day.Solid PLLA- sodium chloride is removed after drying from mold, distillation water retting liquate rinses sodium chloride.It is every 2 it is small when
First water is exchanged, is processed as 4 days.Thus obtain 150 μm~250 μm of aperture, in the PLLA that the porosity is 90%
Sky synthesizes high-molecular porous matter sponge structure material.
To modulate the compound porous matter sponge materials of bioresorbable macromolecule PLLA, then natural polymer solution, day are made
Right Polymer Solution adds 0.1% hyaluronic acid, the full and uniform stirring system of 0.5% proteoglycans by 1%I- collagen types
Into the leaching of absorbability macromolecule PLLA compound porous matter sponge materials is then placed in (above-mentioned 1%I- among natural polymer solution
Collagen type solution, 0.1% hyaluronic acid, 0.5% proteoglycans) make compound porous matter sponge material.Natural polymer
Solution impregnates the PLLA Porous sponge materials in 150 μm~250 μm of the aperture of above-mentioned manufacture, passes through reduced pressure treatment, natural polymer
Sub- mixed aqueous solution is just saturated in the hollow bulb of PLLA Porous sponge framework materials and the hole gap of four peripheral parts.Then
PLLA Porous sponge material -40 DEG C freeze 4 it is small when.It is more in PLLA when decompression (0.2Torr) freeze-dried 48 is small after freezing
Natural polymer sponge structure is formed in the hollow bulb and surrounding pore of hole matter sponge material, the natural polymer sponge structure
More plastid porositys are 98.4% μm, and hollow space sets 3 pillars.The glutaraldehyde water solution of the material 10wt% of manufacture
It impregnates or under 25% glutaraldehyde saturated vapor, bridge formation is handled when 37 DEG C 4 small, is washed with distilled water 5 times, is then used 0.1M
When glycine solution immersion 24 is small, after removing unreacted aldehyde radical, it is washed with distilled water 20 times.Then -30 DEG C to freeze 4 again small
When, it is freeze-dried 48 it is small when, modulation make form compound PLLA Porous sponge material, hollow bulb is then natural porous polymer
Matter sponge material, you can compound porous matter sponge material is made.Synthesize the PLLA walls of obtained compound porous matter sponge material
Thickness is 1mm；The thickness at bottom is 1mm；Diameter or width is 5mm；Depth is 4mm
Embodiment 3
Bone morphogenic protein BMP-2 can induce mesenchymal cell and be divided into bone, cartilage, ligament, tendon and nerve fiber rush
Into cartilage joint reparation.Adjust alcium and phosphor metabolization deposition bone calcium, stimulated osteoblastic proliferation, inhibit arthritis inflammatory invade profit and
Fracture surgery swelling pain.This example attempts addition BMP-2 and makes composite material, and growth factor is not limited to BMP.
Sodium chloride crystalline particle is made available separately about 90 μm~150 μm grains of diameter with 170 mesh sieve and the sieving of 100 mesh sieve
Son.On the other hand 1g PLLA are dissolved into 5mL chloroforms, modulation obtains synthesis Polymer Solution.The chloroformic solution of dissolving PLLA
Teat glass is put into, the sodium chloride crystalline particle 9g (9 times of PLLA amounts) of 90 μm~150 μm of addition is uniformly mixed.Then equal
The PLLA-NaCl- chloroforms of even mixing insert mold (politef system).Bioresorbable synthesis high score is made using this mold
Molecular hollow Porous sponge structure.To the tightly packed mixture in mold gap, dried 3-4 days in air, then vacuum is done
Dry one day.Solid PLLA- sodium chloride is removed after drying from mold, distillation water retting liquate rinses sodium chloride.It is every 2 it is small when exchange
First water is processed as 4 days.Thus obtain 90 μm~150 μm of aperture, the hollow synthesis for the PLLA that the porosity is 90%
High-molecular porous matter sponge structure material.
To modulate the compound porous matter sponge materials of bioresorbable macromolecule PLLA, then natural polymer solution, day are made
Right Polymer Solution adds 50 μ g/mL BMP-2,0.1% hyaluronic acid, 0.5% proteoglycans fills by 1%I- collagen types
Point uniform stirring is made, then the compound porous matter sponge material leachings of absorbability macromolecule PLLA be placed in natural polymer solution it
In (above-mentioned 1%I- collagen types solution, 0.1% hyaluronic acid, 0.5% proteoglycans) make compound porous matter sponge material
Material.Natural polymer solution impregnates the PLLA Porous sponge materials in 90 μm~150 μm of the aperture of above-mentioned manufacture, at decompression
Reason, natural polymer mixed aqueous solution are just saturated with the hollow bulb of PLLA Porous sponge framework materials and the hole gap of four peripheral parts
It is interior.Then PLLA Porous sponge material -40 DEG C freeze 4 it is small when.It is small that (0.2Torr) freeze-dried 48 is depressurized after freezing
When, natural polymer sponge structure is formed in the hollow bulb of PLLA Porous sponge materials and surrounding pore.The natural polymer
More plastid porositys of sub- sponge structure are 98.4% μm.The material of manufacture impregnated with the glutaraldehyde water solution of 10wt% or
Under 25% glutaraldehyde saturated vapor, bridge formation is handled when 37 DEG C 4 small, is washed with distilled water 5 times, then water-soluble with 0.1M glycine
When liquid immersion 24 is small, after removing unreacted aldehyde radical, it is washed with distilled water 20 times.Then -30 DEG C freeze again 4 it is small when, it is freeze-dried
48 it is small when, modulation make form compound PLLA Porous sponge material, hollow bulb is then natural porous polymer matter sponge material,
It can be prepared by compound porous matter sponge material.The thickness for synthesizing the PLLA walls of obtained compound porous matter sponge material is 2mm；Bottom
Thickness be 1mm；Diameter or width is 7mm；Depth is 5mm.
Embodiment 4
Crystallization of sucrose particle is made available separately about 90 μm~150 μm particles of diameter with 170 mesh sieve and the sieving of 100 mesh sieve.
On the other hand 1g PLLA are dissolved into 5mL chloroforms, modulation obtains synthesis Polymer Solution.The chloroformic solution of dissolving PLLA is put
Enter teat glass, the crystallization of sucrose particle 9g (9 times of PLLA amounts) of 90 μm~150 μm of addition is uniformly mixed.Then uniformly mixed
PLLA- sucrose-chloroform of conjunction inserts mold (politef system).Bioresorbable synthesis high score subgroup is made using this mold
Into hollow Porous sponge structure.It is 3-4 days dry in air to the tightly packed mixture in mold gap, then it is dried in vacuo one
My god.Solid PLLA- sucrose is removed after drying from mold, distillation water retting liquate rinses sucrose.It is every 2 it is small when exchange single flash
Water is processed as 4 days.Thus obtain 90 μm~150 μm of aperture, the porosity be 90% PLLA hollow synthesis macromolecule it is more
Hole matter sponge material.
To modulate the compound porous matter sponge materials of bioresorbable macromolecule PLLA, then natural polymer solution, day are made
Right Polymer Solution adds 0.2% hyaluronic acid, the full and uniform stirring system of 2% proteoglycans by 0.5%I- collagen types
Into then the leaching of absorbability macromolecule PLLA compound porous matter sponge materials is placed in (above-mentioned 0.5% among natural polymer solution
I- collagen type solution, 0.2% hyaluronic acid, 2% proteoglycans) make compound porous matter sponge material.Natural polymer
Solution impregnates the PLLA Porous sponge materials in 90 μm~150 μm of the aperture of above-mentioned manufacture, passes through reduced pressure treatment, natural polymer
Mixed aqueous solution is just saturated in the hollow bulb of PLLA Porous sponge framework materials and the hole gap of four peripheral parts.Then PLLA
Porous sponge material -40 DEG C freeze 4 it is small when.When decompression (0.2Torr) freeze-dried 48 is small after freezing, in PLLA Porous
Natural polymer sponge structure is formed in the hollow bulb and surrounding pore of sponge material.More matter of the natural polymer sponge structure
The body porosity is 97.3% μm.The material of manufacture is impregnated or with the glutaraldehyde water solution of 10wt% in 25% glutaraldehyde saturation
Under steam, bridge formation is handled when 37 DEG C 4 small, is washed with distilled water 5 times, then with 0.1M glycine solutions impregnate 24 it is small when, remove
After removing unreacted aldehyde radical, it is washed with distilled water 20 times.Then -30 DEG C freeze again 4 it is small when, it is freeze-dried 48 it is small when, modulation make
Compound PLLA Porous sponge material is formed, hollow bulb is then natural porous polymer matter sponge material, you can be made compound more
Hole matter sponge material.The thickness for synthesizing the PLLA walls of obtained compound porous matter sponge material is 1mm；The thickness at bottom is 1mm；Directly
Footpath or width are 7mm；Depth is 5mm.
Claims (10)
1. a kind of compound porous matter sponge material, which is characterized in that
The material synthesizes macromolecule with internal crosslinking filled with bigger than the peripheral skeleton porosity by the bioresorbable of peripheral skeleton
Natural porous polymer plastid be kneaded, the bioresorbable synthesis macromolecule in contains hollow bulb, the hollow bulb filling
There are the one or more in bioresorbable natural porous polymer material, Porcine HGF, cell differentiation controlling elements, in
Empty portion forms aperture and is connected structure；
Pillar and/or top structure 1-20 are provided in the hollow bulb, the pillar and/or top structure are bio-absorbable
Property synthesis high molecular material；
The natural macromolecular material includes I- collagen types, and hyaluronic acid, chondroitin sulfate, proteoglycan, albumen gathers
Sugar, Glucosamine, the one or more in gelatin；Wherein, collagen can be used concentration hyaluronic acid can make in 0.1-3%
Concentration can be used in 0.1-20% in 0.05-2% chondroitin sulfates with concentration, concentration can be used in 0.1-20%, albumen in proteoglycan
Concentration can be used in 0.1-20% in glycan, and concentration can be used in Glucosamine, and in 0.1-30%, concentration can be used in 0.1- in gelatin
15%；
The Porcine HGF, cell differentiation controlling elements, including epithelical cell growth factor (EGF), insulin
（Insulin）, blood platelet outgrowth factor (PDGF), the fibrous bud hyperplasia factor (FGF), hepatocyte proliferation factor (HGF), blood
Endothelial tube layer outgrowth factor (VEGF), β characters conversion outgrowth factor (TGF-β), one kind or more in the bon e formation factor (BMP)
Kind, concentration is 0.01 μ g/mL-100 μ g/mL.
2. compound porous matter sponge material described in claim 1, which is characterized in that described hollow, pillar or top structure
Bioresorbable synthesis high molecular material include polylactic acid PLA, that is, PDLA or PLLA, polyglycolic acid PGA, lactic acid and ethyl alcohol
The copolymer PLGA of acid, any one in polycaprolactone (PCL).
3. compound porous matter sponge material described in claim 1, which is characterized in that
The bioresorbable synthesis macromolecule porosity of the peripheral skeleton is 10-99%, and aperture is 10-800 μm；
The more plastid porositys of natural polymer of the internal crosslinking filling are 10-99.5% μm, and aperture is 10-1000 μm.
4. compound porous matter sponge material described in claim 1, which is characterized in that
The bioresorbable synthesis macromolecule porosity of the peripheral skeleton is 50-95%, and aperture is 20-600 μm；
The more plastid porositys of natural polymer of the internal crosslinking filling are 60-99%, and aperture is 20-600 μm；
Interior hollow section can set pillar and/or top structure as 1-3.
5. compound porous matter sponge material described in claim 1, which is characterized in that the compound porous matter sponge material synthesized
The thickness of the wall of material is 0.1mm~100mm；
The thickness at bottom is in 0.1mm~100mm；
Diameter or width is in 0.1mm~100mm；
Depth is between 0.1mm~100mm.
6. compound porous matter sponge material described in claim 1, which is characterized in that the compound porous matter sponge material synthesized
The thickness of the wall of material is 0.2~50mm；
The thickness at bottom is in 0.2~50mm；
Diameter or width is in 0.2~50mm；
Depth is between 0.2~50mm.
7. compound porous matter sponge material described in claim 1, which is characterized in that Porcine HGF can be wherein added,
Cell differentiation controlling elements, including epithelical cell growth factor (EGF), insulin（Insulin）, blood platelet outgrowth factor
(PDGF), the fibrous bud hyperplasia factor (FGF), hepatocyte proliferation factor (HGF), intravascular cortex outgrowth factor (VEGF), β
Character conversion outgrowth factor (TGF-β), the one or more in the bon e formation factor (BMP)；Concentration is 0.1 μ g/mL-50 μ
g/mL。
8. the preparation method of the compound porous matter sponge material of claim 1-7 any one of them, which is characterized in that including as follows
Step：
(1) bioresorbable synthesizes the preparation of high-molecular porous matter sponge material, and Porous sponge is manufactured using particle liquation process
Material, mixed dissolution bioresorbable synthesizes macromolecule first in solvent, is then filled with crystalline particle, after stirring evenly,
Insert mold in mold, it is 3-4 days dry in air, then be dried in vacuo one day, after fully dry, taken out from mold, washing removing
Crystalline particle is made bioresorbable and synthesizes high-molecular porous matter sponge material, which contains hollow bulb, the crystal grain
Attached bag includes sodium chloride, sodium sulphate, potassium chloride, sodium tartrate, sodium citrate, ammonium carbonate, sodium carbonate, sodium bicarbonate, glucose, sugarcane
Sugar, any one in maltose；
(2) preparation and filling of bioresorbable natural polymer solution, bioresorbable synthesis high molecular material are made
Afterwards, the solution of natural polymer containing absorbability is filled to the hollow bulb of above-mentioned material, and it is naturally high to be immersed in bioresorbable
Among the solution of molecular material, solution inner face can add one or more Porcine HGFs, cell differentiation controlling elements or this
A little derivatives, by depressurizing degassing process, bioresorbable natural polymer, Porcine HGF, cell differentiation controlling elements
Or the full and uniform bioresorbable that is filled in of aqueous solution containing these derivatives synthesizes high molecular hollow porous structure
In hole and hollow space；
(3) it is freeze-dried to will be filled with the high-molecular porous matter sponge material of synthesis of natural polymer solution, then carries out frame
Bridge, after bridging agent aqueous solution or saturation bridge formation agent solution are flashed to steam, by above-mentioned bioresorbable natural polymer, cell
Growth factor, cell differentiation controlling elements, bioresorbable synthesis macromolecule are built bridge, and after the completion of bridge formation, it is sweet to carry out 0.1M
Propylhomoserin impregnates, and is then washed with distilled water 3-6 times, then freezes 3-6h under the conditions of -25 DEG C ~ -35 DEG C again, then freeze-dried
Compound porous matter sponge material is made in 48h.
9. the preparation method of the compound porous matter sponge material described in claim 8, which is characterized in that the solvent includes chlorine
Imitative-chloroform, carbon tetrachloride, Isosorbide-5-Nitrae-dioxane, dichloromethane, ethyl acetate, any one in acetone.
10. the preparation method of the compound porous matter sponge material described in claim 8, which is characterized in that the bridging agent bag
Include isocyanates, glutaraldehyde, formaldehyde, any one in paraformaldehyde.
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