CN107913435A - Compound hard brain (ridge) membrane implant and its preparation method and application - Google Patents

Compound hard brain (ridge) membrane implant and its preparation method and application Download PDF

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CN107913435A
CN107913435A CN201610884151.7A CN201610884151A CN107913435A CN 107913435 A CN107913435 A CN 107913435A CN 201610884151 A CN201610884151 A CN 201610884151A CN 107913435 A CN107913435 A CN 107913435A
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ridge
layer
membrane
hard brain
porous
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CN107913435B (en
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聂洪涛
张凯
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Beijing Bang Technology Co Ltd
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Beijing Bang Technology Co Ltd
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Priority to US16/015,166 priority patent/US10736994B2/en
Priority to US16/907,707 priority patent/US11219704B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • 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
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/32—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Heart & Thoracic Surgery (AREA)
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Abstract

The present invention relates to a kind of compound hard brain (ridge) membrane implant for being used to be implanted into the reparation of hard brain (ridge) membrane defect and regenerate hard brain (ridge) membrane tissue and preparation method thereof, first porous layer of implant promotes bone tissue to be formed as osteoconductive scaffold, second porous layer promotes the reparation and regeneration of hard brain (ridge) membrane as the cytoskeleton of regeneration collagen, and intermediate layer prevents that cerebrospinal fluid is excessive.The present invention compound hard brain (ridge) membrane implant can effectively facilitate hard brain (ridge) membrane regeneration and and bone combination.

Description

Compound hard brain (ridge) membrane implant and its preparation method and application
Technical field
The invention belongs to field of biomedicine technology, is related to one kind and is used for reparation or the hard brain of regeneration of damaged in surgical operation The compound hard brain (ridge) membrane implant of (ridge) membrane tissue.For more precisely, it is made of porous materials the present invention relates to a kind of Compound hard brain (ridge) membrane implant and preparation method thereof and application method.
Background technology
The brain and spinal cord of people is covered by hard brain/spinal meninges (hereinafter referred to as hard brain (ridge) membrane), its integrality Central nervous Normal work it is most important.It is as shown in Figure 1 human brain structure diagram.Hard brain (ridge) membrane is by three layers of overlapped tissue structure Into being respectively from outside to inside：Endocranium, arachnoid and pia mater.Hard brain (ridge) membrane refers between skull and brain, and backbone One layer of dura mater between spinal cord.When people hard brain (ridge) membrane integrality by premeditated or accidental damage when, if hard brain (ridge) film is not timely repaired, and consequence will be very serious.
Clinically, wound, inflammation, tumor operation and birth defect may all cause hard brain (ridge) membrane to be damaged.Neurosurgery Operation is imperfect to hard brain (ridge) membrane suture to cause the complication such as cerebrospinal fluid leakage, infection, meningitis and epilepsy.Hard brain (ridge) Film defect can also cause hernia cerebri, nerve fiber and its overlying tissue adhesion, Pseudomeningocele, cortex scar, leakage of cerebrospinal, with And the various unpredictable consequences such as the parenchymatous wound infection of brain may be threatened.Therefore, having for hard brain (ridge) membrane is repaired Efficacious prescriptions method has huge clinical demand.Over the past decades, a variety of hard brain (ridge) membrane substitutes (implant) are developed And applied to clinic.
Hard brain (ridge) membrane plasty is a kind of surgical plastic or reconstruction operations carried out in hard brain (ridge) membrane.Repair hard brain (ridge) film defect needs a kind of hard brain (ridge) membrane implant (being often referred to hard brain (ridge) membrane sticking patch), such as surgical operation (such as tumour Excision) or wound caused by hard brain (ridge) membrane large defect.In addition, Arnold Chiari deformities, spinal sensory protein, backbone become The birth defects such as shape also need hard brain (ridge) membrane plasty to be treated.
At present, repair impaired hard brain (ridge) membrane concern is primarily with implantable and/or absorbable hard brain (ridge) membrane and to be implanted into Thing, it is transplanted to hard brain (ridge) membrane damaged part, may replace and/or regenerating damaged tissue.Hard brain (ridge) membrane implant is facing Both it had been used for hard brain (ridge) membrane defect caused by regenerating nerve surgical site infections on bed, and had also been used to preventing cerebrospinal fluid excessive and group Knit adhesion.
Hard brain (ridge) membrane implant is usually made of following different materials：(1) autologous or allograft；(2) close Forming material, such as nondegradable expanded PTFE (Gore-Tex) or degradable lactic acid/hydroxyacetic acid copolymerization Body (Vicryl)；(3) biomaterial, such as the collagen from ox/Zhu Deng animal tissues.
There are many problems for current hard brain (ridge) membrane implant.First, autologous and allograft donor is very It is limited.Fascia late and hat shape periosteal tissue are clinically to repair the common autologous material of hard brain (ridge) membrane defect.And it is derived from lyophilized The hard brain (ridge) membrane graft of corpse may then cause Creutzfeldt-Jakob disease (CJD).Due to the propagation risk of CJD, the hard brain of corpse (ridge) Film product is disabled.Nondegradable synthetic material belongs to bio-inert material, it is impossible to organizing good combination；And can The synthetic material of degraded would generally produce acidic by-products, may cause inflammatory reaction.In addition, the degraded of degradation material Speed is difficult to control, and there are drawback.Due to originals such as local organization reaction, scar excessively formed, meninges inflammation or bleeding risks Cause, non-degradable and degradable artificial synthetic material have clinically all been rejected use.It is derived from chitling lower floor mucous membrane and cattle heart The biomaterial of bag also be used to prepare hard brain (ridge) membrane implant.However, this dissimilar material cannot be gradually resorbed, therefore can It can cause the complication such as infection and immunological rejection.Be derived from the degradable collagen matrix material of ox tendon there is also it is certain the problem of, Such as degradation rate is difficult to control, mechanical performance is low and must use the drawbacks such as suture.
The content of the invention
To solve the above-mentioned problems, it is an object of the invention to provide a kind of compound hard brain (ridge) membrane implant, this is hard Hard brain (ridge) membrane can be promoted to regenerate and promote for brain (ridge) film implant and the combination of bone tissue, wherein interbed can also prevent Cerebrospinal fluid is excessive, especially can adapt to the implant in the case where using suture and inapplicable suture.
Another object of the present invention is to provide the preparation method of above-mentioned compound hard brain (ridge) membrane implant.
Third object of the present invention is the application for providing above-mentioned compound hard brain (ridge) membrane implant.
To achieve these goals, the present invention provides a kind of compound hard brain (ridge) membrane implant, including one first porous Layer, is made of non-collagen polymer and the osteoacusis material synthesized；One second porous layer, by the non-collagen polymer and glue synthesized Original composition；One intermediate layer between the first porous layer and the second porous layer, its porosity are less than the first porous layer and second Porous layer, or it is non-porous；When implant is implanted into patient's hard brain (ridge) membrane defect, which is bonded with bone tissue, should Second porous layer is bonded with hard brain (ridge) membrane；The osteoacusis material of implant promotes bone tissue to grow into the first porous layer, and collagen promotees The reparation and regeneration of the second porous layer are organized in into hard brain (ridge) membrane；Intermediate layer reduce or prevent cerebrospinal fluid from the second porous layer and Hard brain (ridge) membrane is overflowed.
When compound hard brain (ridge) membrane implant implantation patient's hard brain (ridge) membrane defect, the first porous layer and bone Tissue fitting, the loose structure of the first porous layer contribute to material after being implanted into be combined with bone tissue, and osteoacusis material therein promotees The first porous layer is grown into bone tissue；Second porous layer is bonded with hard brain (ridge) membrane, and the loose structure of the second porous layer contributes to Material is combined with hard brain (ridge) membrane after implantation, and collagen therein promotes the reparation and regeneration of hard brain (ridge) membrane tissue；Intermediate layer without The material of hole or low porosity then reduces or prevents cerebrospinal fluid from being overflowed from the second porous layer and hard brain (ridge) membrane.
Preferably, the non-collagen polymer of the synthesis is poly(aryl ether ketone) (PEAK), polyethylene (PE), poly terephthalic acid Glycol ester (PET), polymethyl methacrylate (PMMA), expanded PTFE (ePTFE), polylactic acid (PLA), polyethanol Sour (PGA) or Poly(D,L-lactide-co-glycolide (PLGA).
It is highly preferred that poly(aryl ether ketone) (PEAK) is polyether-ether-ketone (PEEK) or polyether ketone ketone (PEKK).The polyethylene (PE) it is ultra-high molecular weight polyethylene (UHMWPE).The collagen is derived from the tissue of ox or pig.
First porous layer is made of the fiber containing non-collagen polymer, and fiber includes the painting with osteoacusis material Layer.
Second porous layer is made of the fiber containing non-collagen polymer, and fiber includes the coating with collagen.
Preferably, the non-collagen polymer of the synthesis is polyether ketone ketone (PEKK) or ultra-high molecular weight polyethylene (UHMWPE)。
Preferably, the porosity of first porous layer and second porous layer is 20-90%；It is it is highly preferred that described Porosity is 30-80%；It is further preferred that the porosity is 40-70%.
Preferably, the aperture of first porous layer and second porous layer is 10-1000 microns；It is highly preferred that institute Aperture is stated as 20-800 microns；It is further preferred that the aperture is 50-500 microns.
Preferably, the porosity in the intermediate layer is 0-10%.
Preferably, the osteoacusis material includes bone-like apatite stone material or calcium phosphate material.
Preferably, the non-collagen polymer in the intermediate layer infiltrates through first in the interface in the first porous layer and intermediate layer The hole of porous layer.
Preferably, the non-collagen polymer in the intermediate layer infiltrates through second in the interface in the second porous layer and intermediate layer The hole of porous layer.
The present invention also provides a kind of preparation method of compound hard brain (ridge) membrane implant, comprise the following steps：
The one side of first porous polymeric nitride layer and third polymer layer is combined closely；
The another side of second porous polymeric nitride layer and third polymer layer is combined closely；
The third polymer layer is sufficiently low for non-porous or its porosity, so as to prevent that cerebrospinal fluid is excessive；With
First porous polymeric nitride layer is impregnated into osteoacusis material, the second porous polymeric nitride layer dipping collagen-based materials.
Wherein, the first porous polymeric nitride layer is with the method that the third polymer layer is combined：Heat described first Porous polymeric nitride layer or the third polymer layer, and apply to the first porous polymeric nitride layer and the third polymer layer Pressure, so that the polymeric material of third polymer layer is infiltrated through in the hole of the first porous polymeric nitride layer.
Wherein, the second porous polymeric nitride layer is with the method that the third polymer layer is combined：Heat described second Porous polymeric nitride layer or the third polymer layer, and apply to the second porous polymeric nitride layer and the third polymer layer Pressure, so that the polymeric material of third polymer layer is infiltrated through in the hole of the second porous polymeric nitride layer.
Wherein, the second porous polymeric nitride layer is impregnated with collagen solution or dispersion liquid.
Specific method is：The second porous polymeric nitride layer is impregnated in collagen solution or dispersion liquid, then using vacuum Second porous polymeric nitride layer described in oven drying.
Preferably, the collagen content of the collagen solution is 0.01-5wt%.
Wherein, the first porous polymeric nitride layer is impregnated with the solution of calcium ions and phosphate anion.
Specific method is：First porous polymeric nitride layer is soaked in containing calcium salt and phosphatic solution, or is successively used Calcium salt soln and phosphate solution immersion.
Wherein, the calcium salt is one or more combinations in calcium chloride, calcirm-fluoride, CaCl2.
Preferably, the concentration of the calcium salt soln is calculated as 0.001-1mol/L with calcium ion.
Preferably, the concentration of the phosphate solution is calculated as 0.001-1mol/L with phosphate radical.
The present invention separately provides a kind of product of compound hard brain (ridge) membrane implant as treatment pachymeninx defect is prepared Application.
Compound hard brain (ridge) membrane implant provided by the invention is implanted into compound hard at patient's hard brain (ridge) membrane defect The method of brain (ridge) film implant：
Compound hard brain (ridge) membrane implant is implanted at patient's brain hard brain (ridge) membrane defect；
Hard brain (ridge) membrane defect and the bottom porous layer of the implant of non-collagen polymer and collagen containing synthesis Contact, collagen promote the reparation and the regeneration of bottom porous layer inner tissue of hard brain (ridge) membrane；
The top porous layer of bone tissue and the implant of non-collagen polymer and the osteoacusis calcium phosphate material containing synthesis Contact, promotes bone growth to enter top porous layer, top porous layer and skull tissue is combined as a whole, and
The intermediate layer of the non-collagen polymer containing synthesis between the porous layer of top and bottom is used to prevent brain ridge Liquid is excessive.
Wherein, implant is sized for implantation site.
Wherein, collagen promotes fibroblast activity and as the cytoskeleton for storing new collagen.
Implant surgery uses or implant can be fixed on affected part without using suture.
The thickness of regenerated bone tissue or bone-conduction structure can reach 1mm or more.
Hard brain (ridge) membrane plasty refers to repair hard brain (ridge) membrane using hard brain (ridge) membrane implant in hard brain (ridge) membrane The surgical plastic or reconstruction operations of defect.Hard brain (ridge) membrane implant can be thin film, and size just covers hard brain (ridge) Film defect.Hard brain (ridge) membrane implant is fixed on by hard brain (ridge) membrane defect by operation of opening cranium.Hard brain (ridge) membrane The purpose of implant is to repair damaged tissues, or the new tissue of regeneration, or both all have.
At present, repair impaired hard brain (ridge) membrane concern is primarily with implantable and/or absorbable hard brain (ridge) membrane and to substitute Thing.Hard brain (ridge) membrane implant clinically not only be used to prevent that the cerebrospinal fluid after neurosurgery is excessive, organize adhesion, but also It is used for regeneration of damaged hard brain (ridge) membrane.
Hard brain (ridge) membrane implant has some following key character：(1) hard brain (ridge) membrane implant must be able to prevent brain ridge Liquid is excessive.Cerebrospinal fluid refers to a kind of limpid colourless body fluid in brain and spinal cord.Cerebrospinal fluid fills whole brain and intraspinal outer Cavum subarachnoidale (hole between arachnoid and pia mater) and ventricular system.(2) hard brain (ridge) membrane implant must have Standby durability, robustness and pliability.Durability refers to postoperative in the preoperative can effectively bear abrasion, pressure and various operations. Pliability or flexibility no less important, because implant must comply with the group at implant-endocranium interface and implant-skull interface Knit surface.(3) hard brain (ridge) membrane implant should also be in endocranium face and skull face and tissue good combination.It is good in endocranium face It is good combine contain by collagen in implant outgrowth so as to promoting regeneration；In skull face, implant should promote bone It is organized in growth in implant.(4) if implant can gradually degrade more preferably with regeneration.(5) hard brain (ridge) membrane is implanted into Thing should be according to there is a good biocompatibility, such as low infection risk, reacts without immune response, foreign.(6) hard brain (ridge) membrane is planted Flexible should be had in surgical procedures by entering thing.It can especially be fitted in the case where using suture and inapplicable suture Should.
A kind of compound hard brain (ridge) membrane implant of the present invention has above section or whole advantages.Especially originally Invention includes a kind of compound hard brain (ridge) membrane implant, its porous material adjacent with skull, which contains osteoconductive scaffold, to be promoted Being grown into bone tissue in implant, its porous material adjacent with hard brain (ridge) membrane contains the stent that can promote collagen regeneration, Wherein interbed can prevent that cerebrospinal fluid is excessive.Bone conduction effect refers to that bone tissue is grown on a certain surface, for example, in porous material Internal pore surface is grown.
The beneficial effects of the present invention are：
The present invention provides a kind of compound hard brain (ridge) membrane implant, which can promote Hard brain (ridge) membrane regenerates, and can promote and the combination of bone tissue, and it is excessive to be also prevented from cerebrospinal fluid, especially in use seam It can be adapted in the case of line and inapplicable suture.
Brief description of the drawings
Fig. 1 is human brain structure diagram.
Fig. 2 is the compound hard brain (ridge) membrane implant elevational cross-section between implantation skull and endocranium provided by the invention Schematic diagram.
Fig. 3 is the enlarged diagram in the compound hard brain (ridge) membrane implant section described in Fig. 2, and it is adjacent to illustrate implant The boundary layer of materials at two layers.
Embodiment
The present invention provides a kind of implantable hard brain (ridge) membrane implant, and comprising trilaminate material, its first porous layer is by closing Into non-collagen polymer and osteoacusis material composition, its second porous layer is made of the non-collagen polymer and collagen synthesized, There is an intermediate layer between first porous layer and the second porous layer.Hard brain (ridge) membrane implant can be that film can also be thin slice Form, multilayer material are combined together the thickness for forming all or part of film or thin slice.
Intermediate layer is non-loose structure, or its porosity is less than the first porous layer and the second porous layer.In the hard brain of patient When (ridge) film defect carries out implant surgery, the first porous layer is contacted with bone tissue or adjacent, the second porous layer and hard brain The contact or adjacent of (ridge) film.
Fig. 2 is compound hard brain (ridge) membrane implant elevational cross-section schematic diagram provided by the invention, its middle section 100 includes First porous layer 102, the second porous layer 104, intermediate layer 106.After implantation, the upper surface 108 of the first porous layer 102 connects with skull Touch, and the lower surface (not shown) of the second porous layer 104 is contacted with hard brain (ridge) membrane.First porous layer 102 is by containing synthesizing The fiber 103 of non-collagen polymer form, the second porous layer 104 is made of the fiber 105 containing the non-collagen polymer synthesized. 103 surface of fiber is osteoacusis material coating, and 105 surface of fiber is collagenic coating.Intermediate layer 106 is non-porous synthesis Non- collagen polymer material.
First porous layer, 102 thickness is T1, and 104 thickness of the second porous layer is T2, and 106 thickness of intermediate layer is T3.T1 is 0.05-3mm, is preferably 0.05-1mm, 1-1.5mm, 1.5-2mm, 2-2.5mm, or 2.5-3mm.T2 is 0.05-3mm, is preferably 0.05-0.5mm, 0.5-1mm, 1-2mm, or 2-3mm.T3 is 0.001-1mm, preferably 0.001-0.01mm, 0.01-0.1mm, 0.1-0.5mm, or 0.5-1mm.
The non-collagen polymer of synthesis account for most of weight and volume of the first porous layer and the second porous layer.Synthesis Non- collagen polymer can be taken as matrix, and collagen or mineral can be in the non-collagen polymers of the synthesis of corresponding porous layer Scattered or distribution.The collagen part by weight of second porous layer can be 0.1-50%, preferably 0.1-1%, 1-5%, 5-10%, 10-20%, 20-30%, 30-40%, or 40-50%.
Mineral promote bone tissue to be grown in the first porous layer hole, and collagen promotes hard brain (ridge) membrane in the second porous layer hole Repair and regenerate in gap.Reduce or prevent that cerebrospinal fluid is excessive from the second porous layer or hard brain (ridge) membrane in intermediate layer.Also may be used in intermediate layer To there is certain hole, but porosity must be sufficiently low to prevent that cerebrospinal fluid is excessive.
Artificial-synthetic copolymer refers to the polymeric material manually prepared, including thermoplastic, thermosetting plastics and bullet Property body etc..Thermoplastic refers at a certain temperature, such as glass transition temperature (Tg), can possess pliability or plasticity, and It can cure after cooling.Thermosetting polymer refers to prepolymer material after irradiating or being heated to certain temperature, cure hard, and This change is irreversible.Elastomer refers to the polymer with viscoelasticity, that is, refers to stickiness and elasticity, molecular force Very weak polymer, compared with other materials, usual Young's modulus is low, and failure strain power is high.
In some embodiments, the non-collagen polymer of synthesis is poly(aryl ether ketone), refers to phenylene ring and passes through oxygen bridge (ehter bond) A kind of plastics being formed by connecting with carbonyl (ketone).Poly aryl ether ketone polymer includes polyether-ether-ketone, polyether ketone ketone, polyether ether ketone ketone and Polyetherketoneetherketoneketone.
Polyether-ether-ketone is the thermoplastic polymer of semicrystalline, high temperature resistant, anticorrosive, good mechanical property.Polyether-ether-ketone Young's modulus is 3-4GPa, tensile strength 90-100MPa.Glass transition temperature (Tg's) and melting temperature (Tm's) are as shown in table 1. The glass transition temperature (Tg) of polyether ketone ketone is 162 DEG C.
In some embodiments, the non-collagen polymer of synthesis is free from the polymer of fluorine.
In other embodiments, the non-collagen polymer of synthesis is polyethylene, ultra-high molecular weight polyethylene (such as：), polyethylene terephthalate, polymethyl methacrylate, and expanded PTFE.
The glass transition temperature and melting temperature for the polymeric material that 1. part of table is adapted to
The non-collagen polymer of synthesis can also be Biostatic polymer, such as poly(aryl ether ketone) or polyethylene.Later Embodiment in, the non-collagen polymer of synthesis is then biological degradation polyalcohol, including but not limited to：It is polylactic acid, left-handed poly- Lactic acid, left-right rotary mixing polylactic acid, poly- acetic acid alcohol, Poly(D,L-lactide-co-glycolide.Biological degradation polyalcohol refers to contacting Hydrolysis or enzymatic degradation reaction can occur after body fluid, or both the polymer that all has of reaction.It is raw in this patent specification Thing degradation polymer and biological absorbable, can biology absorb, can bio-digestion be synonym.And Biostatic polymer is not Can biodegradable polymer.
Mineralogical composition can be bioactivity calcium phosphate compound, such as bone-like apatite stone material.Calcium phosphate material includes But it is not limited to：One-lime phosphate ((Ca (H2PO4)2), Calcium monohydrogen phosphate (aqueous or not aqueous) (CaHPO4.2H2O or CaHPO4)、 Tricalcium phosphate (tri basic calcium phosphate or tricalcium phosphate) (Ca3(PO4)2), hydroxyapatite (Ca5(PO4)3(OH)), apatite (Ca10 (PO4)6(OH,F,Cl,Br)2O), calcium octahate phosphate (Ca8H2(PO4)6.5H2O), biphasic calcium phosphate (tricalcium phosphate and hydroxyapatite Two-phase compound), tetracalcium phosphate (Ca4(PO4)2O), amorphous calcium phosphate, or more compound combination.
Collagen can be derived from the structural proteins of a variety of phoirocyte epimatrixs in animal body.For example, pig or cattle tissue The collagen of middle extraction.
Collagen is triple helix albumen, usually slightly different by two identical chains (α 1) and another chemical constituent Chain (α 2) composition.The amino acid composition of collagen be atypical protein component, especially its high-content hydroxy-proline into Point.The most common die body of amino acid sequence of albumen is Gly-Pro-X and glycine-X- hydroxy-prolines, and wherein X is Any amino acid outside glycine, proline or hydroxy-proline.
In some embodiments, the first porous layer, the second porous layer or upper and lower two layers of non-collagen polymer all by synthesizing Tissue layer made of the fiber or yarn of composition forms.Tissue layer is made by using different method braiding yarns or fiber, Such as through weft knitting, woollen yarn knitting, braiding and electrospinning etc..Electrospinning is a kind of fiber producing processes, is extracted in a polymer solution using electricity Powered fiber, or polymer is melted into the fiber to about 10 nanometers of diameter.Electrospinning has electrospray and traditional dry-spinning fibre The characteristics of dimension.
Medical textile layer can be bought to the Atex Technologies companies of North Carolina.Tissue layer Loose structure comes from the hole between fabric fibre, and the structure in hole can be open-celled structure.
The fabric for referring to use two yarns to interweave composition at a right angle through weft knitting.Include horizontal warp and transverse direction through weft knitting Weft.Latitude and longitude can be the same fiber of identical size or the fiber of obstructed type and size.
Woollen yarn knitting refers to be formed a series of ring using one or a few yarn and formed fabric.Braiding is by three strands or more Stock fiber or yarn, which are interweaved, forms complicated structure or decorative pattern.The usual length of braiding and it is thin, it is overlapped using Z-shaped pigtail method Braiding, per share filament are functionally identical.
Tissue layer can also be non-woven fabrics, broadly be defined as by mechanics, calorifics, chemical mode entanglement fiber or filament Manufactured fabric or net structure.Non-woven fabrics can be smooth porous fabric, be directly prepared into by single fiber, or It is made up of the plastics or plastic film of melting.Non-woven fabrics can be made of fiber orient or random.
Multilayer fabric layer can obtain preferable intensity, elongation percentage and other mechanical performances by be combineding with each other.It can pass through To the different-diameter of fiber, density, direction, and extra mechanical processing realizes the control to porosity.
In some embodiments, the first porous layer contains mineral, without collagen.Alternatively, the first porous layer contains ore deposit at the same time Thing and collagen.
Mineral can be impregnated into top fabric layer, and mineral coating is formed on the surface of fiber.Mineral can equably immerse top Portion's porous layer reaches certain thickness.
Collagen can immerse bottom fabric layer, or bottom and top fabric layer.Using above-mentioned similar method, in fiber table Face forms collagenic coating.Mineral can equably immerse bottom fabric layer and reach certain thickness.When top fabric layer includes mineral and glue When former, mineral coating can cover collagenic coating, and collagenic coating can also cover mineral coating, or form both uniformly or non-uniformly The coating of mixing.
In other examples, the first porous layer, second porous layer or both be all containing hole, passage or both all Some porous polymer foams.Foam of polymers can be prepared by capturing gas in polymeric liquid or solid.For example, can Under supercritical temperature and pressure, using the synthesis of pore-foaming agent filler, extrusion is mixed, porous polyethers ether is extracted with Hou Jingshui Ketone.Porous network structure can be open-celled structure, be connected with each other by hole.
Mineral or collagen can be impregnated into polymer foam layer.In some embodiments, mineral or collagen can be overlying on hole Inner wall, so as to be partially filled with the hole of foam of polymers.In some embodiments, the foam of polymers of the first porous layer can include Collagen and mineral.Collagenic coating can cover mineral, and mineral coating can also cover collagen, or form both and uniformly or non-uniformly mix The coating of conjunction.
Alternatively, mineral, collagen, or both the non-collagen polymer of synthesis all with forming foam of polymers mix comprehensively. Even before foam of polymers formation or when being formed, mineral or collagen can be mixed with the non-collagen polymer of synthesis.Example Such as, the mixture of the non-collagen polymer and collagen of synthesis, or the mixture of the non-collagen polymer and mineral of synthesis can pass through It is prepared by the mode of melting mixing or solution precipitation.The hole of foam can be formed in preparation process or afterwards.
The intermediate layer of compound hard brain (ridge) membrane implant can be also one layer of thin slice or film, its porosity it is very low or It is non-porous.Thin slice or film can be prepared by the method for melting mixing, such as extrusion molding or injection moulding.It is alternatively, middle Layer is the low-down tissue layer of porosity, for example, tissue layer is made of the fiber of close weave.Thin slice or film can also be obstructed Braiding is crossed to be made, such as non-woven fibre.
First porous layer and the second porous layer have porous network structure.Hole may extend over whole porous layer.First is porous The porosity of layer or the second porous layer is 20-90%, is preferably 30-80%, more preferably 40-70%, average pore size 10- 1000 microns, be preferably 50-800 microns, more preferably 50-500 microns.Intermediate layer can be non-porous structure, or its voidage It is extremely low, less than 10%, such as 0.01-0.1%, 0.01%-1%, or 1-10%.
It is hard that the embodiment for the treatment of patient's hard brain (ridge) membrane defect method is included in the implantation of patient's hard brain (ridge) membrane defect Brain (ridge) film implant.Before implantation, a certain proportion of skull tissue around hard brain (ridge) membrane defect need to be removed, makes defect portion Position is exposed.Implant covers hard brain (ridge) membrane defect, and implant is suitable for the tissue around affected part.The non-collagen of synthesis The second porous layer that polymer and collagen are formed is contacted with hard brain (ridge) membrane tissue, and fixation implant can use or without using seam Line.
After implant is fixed, it can be covered with skull tissue.Skull tissue and the non-collagen polymer containing synthesis The first porous layer formed with osteoacusis calcium phosphate material contacts.
The collagen component of second porous layer contributes to the reparation and regeneration of hard brain (ridge) membrane.Collagen is by promoting into fibre Cellular activity reparation and regeneration hard brain (ridge) membrane tissue are tieed up, cytoskeleton is served as and new collagen is stored in hole.Osteoacusis phosphorus Sour calcium material induces bone tissue and is grown in the hole of the first porous layer, and the first porous layer is combined with skull tissue tight. Intermediate layer between first porous layer and the second porous layer also artificial non-collagen polymer, can prevent cerebrospinal fluid from affected part It is excessive.
It should be prepared first in compound hard brain (ridge) membrane implant embodiment more including top porous layer, intermediate layer and bottom Aperture layer it is composite structured, then by material as described above in operating method dipping mineral and collagen.
The preparation method of compound hard brain (ridge) membrane implant has multiple embodiments, including by the first porous polymeric nitride layer with The one side of third polymer layer is combined closely, and the another side of the second porous polymeric nitride layer and third polymer layer is combined closely. First porous polymeric nitride layer is located at the top layer of implant, and the second porous polymeric nitride layer is located at the bottom of implant.
Third polymer layer can be non-porous or its porosity is sufficiently low, so as to prevent that cerebrospinal fluid is excessive.Preparation method Further comprise the first porous polymeric nitride layer will be impregnated to osteoacusis material, the second porous polymeric nitride layer dipping collagen-based materials.
In some embodiments, with reference to the method for usable hot pressing.For example, by the first porous polymeric nitride layer and third polymerization Nitride layer combines, including heating the first porous polymeric nitride layer or third polymer layer, and to the first porous polymeric nitride layer and trimerization Compound layer applies pressure, so that the polymeric material of third polymer layer is infiltrated through in the hole of the first porous polymeric nitride layer. Using similar method, the second porous polymeric nitride layer is combined with third polymer layer, including the second porous polymeric nitride layer of heating Or third polymer layer, and apply pressure to the second porous polymeric nitride layer and third polymer layer, so that third polymer layer Polymeric material infiltrate through in the hole of the second porous polymeric nitride layer.So that third polymer layer is porous poly- with first and second The interface that a polymer interpenetrates respectively is formed between compound layer.
Fig. 3 is the enlarged diagram in compound hard brain (ridge) membrane implant section 100 in Fig. 2, and it is adjacent to illustrate implant The boundary layer of materials at two layers.In Fig. 3, skull, the lower surface of the second porous layer 104 are close in the upper surface 108 of the first porous layer 102 110 are close to hard brain (ridge) membrane, and intermediate layer is 106.First porous layer 102 includes boundary layer or interface zone 102a, and second is porous Layer includes boundary layer or interface zone 104a, and the polymeric material in intermediate layer 106 is scattered in around fiber 103 and 105 respectively.The The outer surface or region of 104 porous layer of one porous layer 102 and the second porous layer have no polymeric material.First porous layer 102 is thick Spending T1 includes the thickness T1a of 102a and the thickness T1b of extraneous surface layer；Second porous layer, 104 thickness T2 includes the thickness T2b of 104a With extraneous surface layer T2b.
The second porous polymeric nitride layer can be impregnated in collagen solution or dispersion liquid by the second porous layer, then using vacuum Second porous polymeric nitride layer described in oven drying obtains.Dipping refers to polymer architecture fully soaking collagen solution, makes porous The surface of layer forms collagen and mineral coating.Alternatively, the second porous layer only is soaked in collagen solution or dispersion liquid, make its surface Form collagenic coating.The collagen content of collagen solution is 0.01-5wt%, 0.05-2wt%, 0.1-1wt%, or 2-10%.
Calcium salt and phosphate solution can be used to impregnate the first porous polymeric nitride layer and obtain for first porous layer.First porous polymeric The dipping of nitride layer can be used containing calcium and phosphate solution immersion.Or successively soaked using the solution containing calcium salt and phosphate solution Bubble rinses.When exposed to 25-110 DEG C of temperature or afterwards, composite construction is toasted.Calcium salt is calcium chloride, calcirm-fluoride, nitridation The combination of calcium or more compound.Phosphate is ammonium phosphate or phosphoric acid.
The concentration of calcium salt is 0.001-1mol/L, 0.001-0.05mol/L or 0.002-0.01mol/L.It is phosphatic dense Spend for 0.001-1mol/L, 0.001-0.05mol/L or 0.001-0.01mol/L.
Unless stated otherwise, the definition of following vocabulary is all as follows：
All quantitative values are all " approximate numbers ", regardless of whether expressing." approximate number " refers to numerical value about, that is, professional Think to be equal with desired value numerical value (such as：Function or result are equal).In many cases, " approximate number " represents to round up Arrive with the immediate value of desired value.
" approximate number " also can refer to above and below a certain quantitative value, including：± 1%, ± 5%, ± 10%, ± 20%.Such as：About 10mm (± 10%) refers to 10mm, from 9mm to 11mm, from 9mm to 10mm, or from 10mm to 11mm.
Specific data interval includes all values in data area both ends and section.
It is professional although disclosing the component for belonging to different, feature and/or appropriate dimension, section and/or the value of specification Personnel can judge whether required dimension, section and/or value are deviated with the value disclosed under the prompting of context.
It typically include " and or " two layers of meaning herein and in claims using "or", unless otherwise indicated.
Embodiment 1
A kind of compound hard brain (ridge) membrane implant being made of three layers of polyether ketone ketone material：The polyether-ketone of first porous layer Ketone fabric face has osteoid apatite coating, porosity 50%, thickness 2mm；The polyether ketone ketone fabric pore rate in intermediate layer is 0, thickness 0.5mm；The polyether ketone ketone fabric face of second porous layer has type i collagen coating, porosity 50%, thickness 1mm.
Embodiment 2
A kind of compound hard brain (ridge) membrane implant being made of three layers of superhigh molecular weight polyethylene material：First porous layer It is DSM N. V.Fabric, its surface are osteoid apatite coating, porosity 60%, thickness 2mm；Intermediate layer is Superhigh molecular weight polyethylene material, porosity 0.1%, thickness 0.5mm；Second porous layer isFabric, its table Face is type i collagen coating, porosity 60%, thickness 1.5mm.
Embodiment 3
A kind of compound hard brain (ridge) membrane implant being made of three layers of polyetheretherketonematerials materials：First porous layer is polyethers ether Ketone fabric, its surface are osteoid apatite coating, porosity 50%, thickness 1.5mm；Intermediate layer is polyetheretherketonematerials materials, hole Rate is 0.05%, thickness 0.5mm；Second porous layer is polyetheretherketonematerials materials, its surface is type i collagen coating, porosity 50%, Thickness 1mm.
Embodiment 4
The compound hard brain (ridge) membrane implant that one kind is made of three strata methyl methacrylate (PMMA) materials：First Porous layer is polymethyl methacrylate fabric, its surface is osteoid apatite coating, porosity 30%, thickness 2.5mm；It is middle Layer is polymethyl methacrylate materials, porosity 0.01%, thickness 0.1mm；Second porous layer is poly-methyl methacrylate Ester fabric, its surface are type i collagen coating, porosity 30%, thickness 0.5mm.
Embodiment 5
The compound hard brain (ridge) membrane implant that one kind is made of three strata ethylene glycol terephthalate (PET) materials： First porous layer is PET fabrics, its surface is osteoid apatite coating, porosity 40%, thickness 1.5mm；Intermediate layer is PET materials Material, porosity 0.08%, thickness 0.5mm；Second porous layer is PET fabrics, its surface is type i collagen coating, porosity 40%, thickness 0.5mm.
The preparation method of the compound hard brain (ridge) membrane implant of embodiment 6
The method for preparing polyether-ether-ketone (PEEK) hard brain (ridge) membrane implant of embodiment 3, comprises the following steps：
Step 1：PEEK fabrics are made in electrospinning PEEK fibers；
Step 2：One layer of densification, the PEEK films of low porosity are added among upper and lower two layers of PEEK fabrics
Step 3：Use more than ultra-sonic welded three layers of PEEK materials, it is ensured that middle PEEK films and upper and lower two-layer fabrics are close With reference to；
Step 4：The sulfuric acid solution that the three layers of PEEK materials immersion concentration combined closely by more than is 80wt% 1 minute；
Step 5：The one side of PEEK materials is soaked in the calcium ion containing 2.0mM and the phosphate anion solution 5 of 1.0mM My god；
Step 6：The another side of PEEK materials is soaked in the solution 1 day containing 5% type i collagen；
Step 7：Clean, is dry, packaging, and the PEEK materials of above step preparation are sterilized using epoxy second ring to obtain the final product.
The preparation method of the compound hard brain (ridge) membrane implant of embodiment 7
Prepare the side of the compound hard brain (ridge) membrane implant of ultra-high molecular weight polyethylene (UHMWPE) material of embodiment 2 Method, comprises the following steps：
Step 1：PurchaseThe commercially available UHMWPE fabrics of fibrage；
Step 2：One layer of densification, the UHMWPE films of low porosity are added among upper and lower two layers of UHMWPE fabrics；
Step 3：Use more than 90 DEG C of high temperature bonds three layers of UHMWPE materials, it is ensured that middle UHMWPE films and upper and lower two layers Fabric tightness combines；
Step 4：By more than three layers of UHMWPE materials combining closely be soaked in the solution 4 containing 10M sodium hydroxides it is small when；
Step 5：Above UHMWPE materials are handled using oxygen plasma 30 minutes；
Step 6：The phosphate anion that the one side of UHMWPE materials is soaked in the calcium ion containing 2.0mM and 1.0mM is molten Liquid 5 days；
Step 7：The another side of UHMWPE materials is soaked in the solution 1 day containing 5% type i collagen；
Step 8：Cleaning, dry, packaging, and using epoxy second ring sterilize more than step played the UHMWPE materials of preparation both.
The present invention is suitable for a variety of modifications, form and specification, its example is shown in figure, and will be explained in detail below State.But its purpose is not limited to various aspects described by above example.On the contrary, its purpose covers the spirit of the present invention And all modifications, equivalent and substitute in category.

Claims (33)

  1. A kind of 1. compound hard brain (ridge) membrane implant, it is characterised in that including：
    One first porous layer, is made of non-collagen polymer and the osteoacusis material synthesized；
    One second porous layer, is made of the non-collagen polymer and collagen that synthesize；
    One intermediate layer between the first porous layer and the second porous layer, is made of, its hole the non-collagen polymer synthesized Rate is less than the first porous layer and the second porous layer, or non-porous；
    When implant is implanted into patient's hard brain (ridge) membrane defect, which is bonded with bone tissue, second porous layer It is bonded with hard brain (ridge) membrane；
    The osteoacusis material of implant promotes bone tissue to grow into the first porous layer, and collagen promotes hard brain (ridge) membrane to be organized in more than second The reparation and regeneration of aperture layer；
    Reduce or prevent cerebrospinal fluid from being overflowed from the second porous layer and hard brain (ridge) membrane in intermediate layer.
  2. 2. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that the non-collagen polymerization of the synthesis Thing is poly(aryl ether ketone), polyethylene, polyethylene terephthalate, polymethyl methacrylate, expanded PTFE, poly- breast Acid, polyglycolic acid or Poly(D,L-lactide-co-glycolide.
  3. 3. compound hard brain (ridge) membrane implant as claimed in claim 2, it is characterised in that the poly(aryl ether ketone) is polyethers ether Ketone or polyether ketone ketone.
  4. 4. compound hard brain (ridge) membrane implant as claimed in claim 2, it is characterised in that the polyethylene is supra polymer Weight northylen.
  5. 5. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that the collagen is derived from ox or pig Tissue.
  6. 6. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that first porous layer is by containing non- The fiber of collagen polymer is formed.
  7. 7. compound hard brain (ridge) membrane implant as claimed in claim 6, it is characterised in that the fiber is included to be passed with bone Lead the coating of material.
  8. 8. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that second porous layer is by containing non- The fiber of collagen polymer is formed.
  9. 9. compound hard brain (ridge) membrane implant as claimed in claim 8, it is characterised in that the fiber includes and carries collagen Coating.
  10. 10. the compound hard brain (ridge) membrane implant as described in claim 6 or 8, it is characterised in that the non-collagen of the synthesis Polymer is polyether ketone ketone.
  11. 11. the compound hard brain (ridge) membrane implant as described in claim 6 or 8, it is characterised in that the non-collagen of the synthesis Polymer is ultra-high molecular weight polyethylene.
  12. 12. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that first porous layer and institute The porosity for stating the second porous layer is 20-90%.
  13. 13. compound hard brain (ridge) membrane implant as claimed in claim 12, it is characterised in that the porosity is 30- 80%.
  14. 14. compound hard brain (ridge) membrane implant as claimed in claim 12, it is characterised in that the porosity is 40- 70%.
  15. 15. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that first porous layer and institute The aperture for stating the second porous layer is 10-1000 microns.
  16. 16. compound hard brain (ridge) membrane implant as claimed in claim 15, it is characterised in that the aperture is micro- for 20-800 Rice.
  17. 17. compound hard brain (ridge) membrane implant as claimed in claim 15, it is characterised in that the aperture is micro- for 50-500 Rice.
  18. 18. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that the porosity in the intermediate layer For 0-10%.
  19. 19. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that the osteoacusis material includes Bone-like apatite stone material or calcium phosphate material.
  20. 20. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that the non-collagen in the intermediate layer Polymer infiltrates through the hole of the first porous layer in the interface in the first porous layer and intermediate layer.
  21. 21. compound hard brain (ridge) membrane implant as claimed in claim 1, it is characterised in that the non-collagen in the intermediate layer Polymer infiltrates through the hole of the second porous layer in the interface in the second porous layer and intermediate layer.
  22. 22. a kind of preparation method of compound hard brain (ridge) membrane implant, it is characterised in that comprise the following steps：
    The one side of first porous polymeric nitride layer and third polymer layer is combined closely；
    The another side of second porous polymeric nitride layer and third polymer layer is combined closely；
    The third polymer layer is sufficiently low for non-porous or its porosity, so as to prevent that cerebrospinal fluid is excessive；With
    First porous polymeric nitride layer is impregnated into osteoacusis material, the second porous polymeric nitride layer dipping collagen-based materials.
  23. 23. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 22, it is characterised in that described first Porous polymeric nitride layer is with the method that the third polymer layer is combined：Heat the first porous polymeric nitride layer or the described 3rd Polymeric layer, and apply pressure to the first porous polymeric nitride layer and the third polymer layer, so that third polymer The polymeric material of layer is infiltrated through in the hole of the first porous polymeric nitride layer.
  24. 24. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 22, it is characterised in that described second Porous polymeric nitride layer is with the method that the third polymer layer is combined：Heat the second porous polymeric nitride layer or the described 3rd Polymeric layer, and apply pressure to the second porous polymeric nitride layer and the third polymer layer, so that third polymer The polymeric material of layer is infiltrated through in the hole of the second porous polymeric nitride layer.
  25. 25. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 22, it is characterised in that described second Porous polymeric nitride layer is impregnated with collagen solution or dispersion liquid.
  26. 26. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 25, it is characterised in that by described the Two porous polymeric nitride layer are impregnated in collagen solution or dispersion liquid, then dry second porous polymer using vacuum drying oven Layer.
  27. 27. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 25, it is characterised in that the collagen The collagen content of solution is 0.01-5wt%.
  28. 28. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 22, it is characterised in that described first Porous polymeric nitride layer is impregnated with the solution of calcium ions and phosphate anion.
  29. 29. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 28, it is characterised in that more than first Pore polymer layer is soaked in containing calcium salt and phosphatic solution, or is successively soaked using calcium salt soln and phosphate solution.
  30. 30. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 29, it is characterised in that the calcium salt For one or more combinations in calcium chloride, calcirm-fluoride, CaCl2.
  31. 31. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 29, it is characterised in that the calcium salt The concentration of solution is calculated as 0.001-1mol/L with calcium ion.
  32. 32. the preparation method of compound hard brain (ridge) membrane implant as claimed in claim 29, it is characterised in that the phosphoric acid The concentration of salting liquid is calculated as 0.001-1mol/L with phosphate radical.
  33. A kind of 33. application of compound hard brain (ridge) membrane implant as the product for preparing treatment hard brain (ridge) membrane defect.
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