CN108837184A - A kind of composite membrane and preparation method thereof for Guided Bone Regeneration - Google Patents
A kind of composite membrane and preparation method thereof for Guided Bone Regeneration Download PDFInfo
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- CN108837184A CN108837184A CN201810446632.9A CN201810446632A CN108837184A CN 108837184 A CN108837184 A CN 108837184A CN 201810446632 A CN201810446632 A CN 201810446632A CN 108837184 A CN108837184 A CN 108837184A
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- 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
- A61L27/3604—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 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
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Abstract
The present invention discloses a kind of composite membrane and preparation method thereof for Guided Bone Regeneration.The preparation method of the composite membrane includes following operating procedure：Pig jejunum handles to obtain submucous layer of small intestine through mechanical means, and multilayer transverse and longitudinal is superimposed to obtain compacted zone after the processes such as acid, detergent and alkali process, by the collagen solution of preparation be coated uniformly on compacted zone it is compound after through vacuum freeze drying obtain composite membrane.There is excellent biocompatibility and bioactivity with composite membrane prepared by this method, easily it is absorbed by tissue, the compacted zone property of can choose in structure prevents soft tissue to bone defect region, weaker zone is loose and porous structure, bioactie agent or drug can be combined, it supports new regeneration, promotes wound healing.The combination of the composite membrane makes it obtain excellent mechanical performance, can be in the stabilization of certain time holding regenerative space.
Description
Technical field
The present invention relates to Guided Bone Regeneration films of biomedical materials field and preparation method thereof.More specifically, this draws
It leads osteanagenesis film and belongs to natural composite membrane, the reparation for bone tissue and periodontium.
Background technique
Inducting osseous tissue regeneration art is at present clinically to the optimal selection of Repair of tissue defect, and principle is to pass through regeneration
The effects of physical barriers of film, prevents soft tissue from entering bone uptake area, is that the new bone growth in bone defect region reserves regenerative space,
And skeletonization class cell is guided to grow into new bone in bone defect area, to achieve the purpose that bony union.
Early stage is with polytetrafluoroethylene (PTFE) for the 1st generation regeneration membrane material of Guided Bone Regeneration（e-PTFE）For representative can not
Degradable material, such material is easy to operate and good biocompatibility, clinical effectiveness are good.But due to that cannot be absorbed by tissue, place 4
It needs second operation to take out after ~ 6 weeks, increases the chance of wound, operation may cause to damage to periodontium again, and to new
Attachment generates destruction.
Biodegradable material is that current Guided Bone Regeneration film studies more a kind of material.Due to such material biofacies
Capacitive is good, and catabolite is nontoxic, easy to form and processing, has certain intensity with space needed for maintaining hyperblastosis,
After regeneration, material is degradable or is absorbed by tissue, and is a kind of material with favourable prospects.Biodegradable material
It is divided into artificial synthesized high molecular material and natural macromolecular material.Wherein with the artificial synthesized macromolecule material of polylactic acid-based equal representatives
Material has excellent mechanical property and biocompatibility, 201010105573.2 He of Chinese Patent Application No.
201310586143.0 preparing guide tissue regeneration film with polylactic acid material.But due to making after the fracture of polylactic acid hydrolysis of ester bonds with
Carboxyl, which appears increase, causes local ph to decline, and easily leads to patient and aseptic inflammation reaction occurs.Using collagen as the natural of representative
Macromolecule regeneration membrane has antigenic low, good biocompatibility, and has hemoglutination, may participate in tissue healing process, degradation speed
The advantages that rate can be adjusted as needed is current most commonly used guide tissue regeneration film both at home and abroad, as the country has listed
Bio-Gide collagem membrane, sea oral restoration film difficult to understand, rich special medical collagen membrane etc..But the simple of current wide clinical application comes from
The collagen of pig collagen, ox-hide or beef tendon has the following defects as guide tissue regeneration film：First is that degradation time in vivo is short；
Second is that the requirement relative to regeneration membrane, the tension stress of collagem membrane is smaller, is easy to happen in application process and collapses and lose space
Maintenance ability；Third is that collagem membrane is easy to cause local chronic inflammatory to react.Before studies have shown that being exposed to intraoral collagen
Film（Bio-Gide collagem membrane and Hai Ao oral restoration film）Meeting accelerated degradation, increases the risk of infection.（Bai Peng, Ye Ping, Wu Run
Hair, two kinds of collagem membranes of Dai Yongzhong are exposed to the comparative study China oral implantology magazine of degradation in oral environment,
2011,16(01):56-57.）Glue can be reduced by different crosslinking technologicals and processing technology in the preparation process of collagem membrane
Former antigenicity improves biocompatibility and adjusts its degradation speed, increases its mechanical strength.Rich spy's medical collagen repair membrane is just
The white plates porous membrane being processed into is crosslinked for aldehydes.Chinese patent CN201710126662.7 and
CN201710124188.4 is all made of glutaraldehyde as cross linker to reach the effect for improving mechanical performance and reducing degradation speed, but
The introducing of the introducing of crosslinking agent, especially aldehyde crosslinking agent can generate potential toxic side effect to human body and find in the long run
It is a kind of without add crosslinking agent and be able to satisfy clinical demand guide tissue regeneration film it is imperative.
In addition, the guide tissue regeneration film reported at present is designed to the form of duplicature or multilayer film mostly, but it is easy
Appearance is layered and tears problem.In order to avoid multilayer film bonding is not close, the complicated procedures of forming such as mechanical press are needed, and are affected again
The microcosmic result and repairing effect of filming.Multilayer complex films room machine intensity is inhomogenous simultaneously, and the structure of MULTILAYER COMPOSITE to plant
There is foreign body sensation after entering, and clinical application effect is bad.A kind of periosteum described in Chinese Patent Application No. CN201710126698.5
Preparation method, although can overcome disadvantages mentioned above, its cumbersome preparation process is unfavorable for actual production from now on very much.
Therefore, clinically it is badly in need of a kind of good biocompatibility, can induce regeneration, the good degradable guidance of mechanical strength
Bone tissue regeneration film, and the production method of this kind of film should be suitble to industrialization production.
Summary of the invention
A kind of it is an object of the invention to overcome the deficiencies of the prior art and provide biocompatibilities and mechanical strength good, energy
Degradation in vivo, while the bioactivity regeneration membrane and preparation method thereof for being able to guide regeneration.The regeneration membrane is natural material
Compound guiding regeneration membrane, compacted zone can prevent unwanted soft tissue from growing into defect area, and weaker zone is loose and porous structure,
New regeneration can be supported in conjunction with bioactie agent or drug, promote wound healing.The combination of the composite membrane, obtains it
Excellent mechanical performance is obtained, it can be in the stabilization of certain time holding regenerative space.
A kind of above-mentioned composite membrane and preparation method thereof for Guided Bone Regeneration, specific step is as follows：
（1）The preparation of compacted zone trees-Osima jacoti, Osima excavata
Pig jejunum is cleaned up, the tissues such as removal mucous layer, muscle layer, placenta percreta is mechanically struck off, obtains mucous membrane of small intestine
Lower layer splits the submucosa of tubulose, is cleaned with purified water to no dirt；
Submucous layer of small intestine is placed in the hydrochloric acid or peracetic acid soln that volumetric concentration is 0.5 ~ 5% to impregnate 1 ~ 2 hour and is disappeared
Then poison is cleaned 2 ~ 3 times with purified water；
Submucous layer of small intestine is placed in detergent solution, temperature controlled ultrasonic 15-40min, is then cleaned 3 times with purified water.Its
Middle detergent can be any one or several mixed containing Triton X-100/200, NaTDC or lauryl sodium sulfate
Solution is closed, concentration is 0.01% ~ 0.1%（w/v）；
Submucous layer of small intestine is soaked in aqueous slkali, 10 ~ 30 min are impregnated at 2 ~ 8 DEG C and carry out de- cell processing, are then used again
Equivalent purifies water process 2 ~ 3 hours, so recycles 1 ~ 3 time, until purification of aqueous solutions pH to 7.0-7.4.The aqueous slkali is hydrogen
Sodium oxide molybdena, potassium hydroxide or calcium hydroxide aqueous solution, solution concentration are 0.01 ~ 0.1M.By alkaline solution treatment, it is more thorough to take off cell
Bottom, and repeatedly circular treatment can reduce DNA residual；
By de- cell treated single layer trees-Osima jacoti, Osima excavata drawout, 2 ~ 10 are superimposed according to horizontal and vertical alternate mode
Layer is laid on freeze-drying mold.
（2）The preparation of collagen solution
With organic acid dissolution collagen, collagen solution is formed；The mass volume ratio concentration range of collagen solution is 0.05 ~ 8%, viscosity
Coefficient is 1000 ~ 4000cp.The good collagen solution of stirring and dissolving, standing and defoaming processing；
Selectively, 0.1 ~ 20 mg/mL of the concentration of drug is added in collagen solution；
Selectively, the content that growth factor is added in collagen solution is 2 ~ 10 μ g/mL.
（3）The preparation of composite membrane
It will（1）Obtained densification is placed in mold, will（2）The collagen solution even application prepared is on compacted zone, then
It is demoulded after vacuum freeze drying.
Wherein, step（3）The uniform coating, can use vacuum rotating technology for coating, by revolving speed and time come
Control the thickness of collagen layer.
Wherein, step（3）Using vacuum freeze drying, after can be pre-freeze 8 at -20 DEG C ~ -80 DEG C ~ for 24 hours, it is transferred to cold
It is lyophilized in lyophilizer, drying condition can be dry 24 ~ 48h at -50 DEG C ~ -60 DEG C.
Compared with prior art, the present invention has following remarkable advantage and beneficial effect：
1. the present invention selects natural degradable material to prepare Guided Bone Regeneration film, have excellent biocompatibility and biology living
Property, and be easily absorbed by tissue, it is not required to secondary taking-up；
2. the present invention is in the structure of regeneration membrane, using structure of composite membrane, compacted zone is trees-Osima jacoti, Osima excavata, the property of can choose
Prevent soft tissue to bone defect region growing；Weaker zone is type i collagen, and loose porous structure is conducive to the regeneration of new bone；System
Preparation Method is that collagen solution is coated on multilayer trees-Osima jacoti, Osima excavata, and after freeze-drying, the two has excellent bond strength
And mechanical strength, while the composite membrane has preferable adhesion and flexibility, and it is not tearable broken, it is conducive to surgical procedure；
3. guide tissue regeneration film preparation method of the invention is simple, easily controllable, it is readily produced, while different pharmaceutical can be added
Or growth factor obtains preferably bone tissue regeneration effect.
Detailed description of the invention
Fig. 1 is the electron scanning micrograph of trees-Osima jacoti, Osima excavata of the present invention.
Fig. 2 is the electron scanning micrograph of collagen layer of the present invention.
Fig. 3 is the scanning result of zoopery Micro CT.
Fig. 4 is zoopery defective region bone rege-neration diaphysis fraction（BV/TV）It indicates.
Fig. 5 is the antibacterial effect figure of the composite regenerated film of the present invention
Specific embodiment
Below by specific embodiment, technical scheme is described further, but these specific embodiments are not
The protection scope limiting the invention in any way.
Embodiment 1：
A kind of composite regenerated film for bone tissue regeneration, prepares as follows：
（1）The preparation of compacted zone trees-Osima jacoti, Osima excavata
Pig jejunum is cleaned up, the tissues such as removal mucous layer, muscle layer, placenta percreta is mechanically struck off, obtains mucous membrane of small intestine
Lower layer splits the submucosa of tubulose, is cleaned with purified water to no dirt；
Submucous layer of small intestine is placed in the peracetic acid soln that volumetric concentration is 2% to impregnate 1.5 hours and is carried out disinfection, is then used
Purified water is cleaned 3 times；
Submucous layer of small intestine is placed in the sodium dodecyl sulfate solution of 0.05% (w/v), temperature controlled ultrasonic 20min, then with pure
Change water to clean 3 times；
Submucous layer of small intestine is soaked in the sodium hydroxide solution of 0.05M, 30 min are impregnated at 4 DEG C and carry out de- cell processing,
Then purified water process 3 hours with equivalent again, so circulation 2 times, until purification of aqueous solutions pH to 7.0-7.4；
By de- cell treated single layer trees-Osima jacoti, Osima excavata drawout, 6 layers are superimposed according to horizontal and vertical alternate mode,
It is laid on freeze-drying mold；
（2）The preparation of collagen solution
With acetate dissolution collagen, collagen solution is formed, viscosity coefficient is 1800 cp.Bones morphology is added in collagen solution
Protein growth factors, content are 5.0 μ g/mL, after mixing standing and defoaming；
（3）The preparation of composite membrane
It will（1）The compacted zone of acquisition is cut into rectangular die size, is placed in mold, will（2）The collagen solution prepared is equal
It is even to be coated on compacted zone, at -40 DEG C after 8 h of pre-freeze, dry 48h is transferred in freeze drier at -50 DEG C.Demoulding
Obtain the composite regenerated film of inducting osseous tissue regeneration；
（4）The preparation of lyophilized collagen
It will（2）The solution of preparation at -40 DEG C after 8 h of pre-freeze, is transferred in freeze drier at -50 DEG C dry 48h.Demoulding
It can be obtained the lyophilized collagen of the growth factor containing bone morphogenetic protein；
（5）Zoopery
Method：Using（1）The fine and close sticking patch layer of acquisition,（4）The lyophilized collagen of acquisition and（3）The composite membrane of acquisition is respectively used to
The repairing research in the dog mandibular defect area Beagle covering oral cavity；
After implantation 3 months, Micro CT scanning result is shown in attached drawing 3, defective region bone rege-neration diaphysis fraction（BV/TV）
Attached drawing 4 is shown in expression, the results show that the complex repairation effect of composite membrane is well very more than single fine and close sticking patch layer or lyophilized collagen layer
It is more.
Embodiment 2：Composite regenerated film for paradenlal tissue regeneration
（1）The preparation of compacted zone trees-Osima jacoti, Osima excavata
Pig jejunum is cleaned up, the tissues such as removal mucous layer, muscle layer, placenta percreta is mechanically struck off, obtains mucous membrane of small intestine
Lower layer splits the submucosa of tubulose, is cleaned with purified water to no dirt；
Submucous layer of small intestine is placed in the hydrochloric acid solution that volumetric concentration is 1.5% to impregnate 1 hour and is carried out disinfection, then with purifying
Water cleans 3 times；
Submucous layer of small intestine is placed in the sodium deoxycholate solution of 0.08% (w/v), then temperature controlled ultrasonic 30min uses purified water
Cleaning 3 times；
Submucous layer of small intestine is soaked in the sodium hydroxide solution of 0.05M, 20 min are impregnated at 4 DEG C and carry out de- cell processing,
Then purified water process 3 hours with equivalent again, so circulation 3 times, until purification of aqueous solutions pH to 7.0-7.4；
By de- cell treated single layer trees-Osima jacoti, Osima excavata drawout, 4 layers are superimposed according to horizontal and vertical alternate mode,
The compacted zone of Guided bone regeneration film is obtained after drying；
（2）The preparation of collagen solution
With acetate dissolution collagen, the collagen solution of 0.5% mass volume ratio is formed.Metronidazole is added in collagen solution, concentration is
1.0 mg/mL, after mixing standing and defoaming；
（3）The preparation of composite membrane
It will（1）The compacted zone of acquisition is cut into rectangular die size, is placed in mold, will（2）The collagen solution prepared is equal
It is even to be coated on compacted zone, at -20 DEG C after 20 h of pre-freeze, it is transferred in freeze drier at -54 DEG C and dries for 24 hours.Demoulding is
It can get the composite regenerated film of Guide Periodontal Tissue Regeneration.
It is slender using periodontitis the main pathogenic fungi-porphyromonas by the composite regenerated film containing metronidazole of above-mentioned acquisition
Born of the same parents bacterium carries out antibacterial activity in vitro experiment, as a result can verify that the antibacterial effect of composite regenerated film, sees attached drawing 5.Wherein Fig. 5（It is left）It is aobvious
Show be growth the unicellular bacterium bacterium colony of porphyromonas,（In）Display is the unicellular bacterium of porphyromonas being killed,（It is right）It is aobvious
What is shown is the unicellular bacterium of all porphyromonas.It can thus be seen that the composite regenerated film of the invention containing metronidazole, Ke Yibao
The drug effect for holding metronidazole has the function that obviously to inhibit the unicellular bacterium growth of porphyromonas.
The above embodiment of the present invention is the description of the invention and cannot be used for the limitation present invention, with right of the invention
Any change in the comparable meaning and scope of claim, is all considered as being included within the scope of the claims.
Claims (7)
1. a kind of composite membrane for Guided Bone Regeneration, it is characterised in that：Including compacted zone and weaker zone, the compacted zone by
Trees-Osima jacoti, Osima excavata is constituted, and weaker zone is made of collagem membrane.
2. composite membrane according to claim 1, it is characterised in that：The compacted zone passes through more for trees-Osima jacoti, Osima excavata
Layer transverse and longitudinal direction is alternately formed by stacking, and compacted zone is uniform-distribution with mutual perforative hole, and 30 μm of aperture <, wherein being laterally and pig
The vertical direction of small intestine enteron aisle is longitudinally the direction parallel with chitterlings enteron aisle, lateral, longitudinal alternately 2 ~ 10 layers of superposition, thickness
100~600μm。
3. composite membrane according to claim 1, it is characterised in that：The weaker zone is collagen solution vacuum freeze drying shape
At 300 ~ 500 μm of thickness, wherein collagen is type i collagen.
4. composite membrane according to claim 1 or 3, it is characterised in that：Drug and/or biology can be added in the weaker zone
Active factors, drug can be taxol, adriamycin, gentamicin, acetyl spiramycin, Amoxicillin, metronidazole, Fourth Ring
One of element, azithromycin, penicillin etc. or multiple combinations, growth factor can spread out for bone morphogenetic protein, blood platelet
Raw growth factor, the one or more of fibroblast growth factor.
5. a kind of compound membrane preparation method for Guided Bone Regeneration according to claim 1, it is characterised in that including with
Lower step：
（1）The preparation of compacted zone trees-Osima jacoti, Osima excavata
Pig jejunum is cleaned up, the tissues such as removal mucous layer, muscle layer, placenta percreta is mechanically struck off, obtains mucous membrane of small intestine
Lower layer splits the submucosa of tubulose, is cleaned with purified water to no dirt；
Submucous layer of small intestine is placed in the hydrochloric acid or peracetic acid soln that volumetric concentration is 0.5 ~ 5% to impregnate 1 ~ 2 hour and is disappeared
Then poison is cleaned 2 ~ 3 times with purified water；
Submucous layer of small intestine is placed in detergent solution, temperature controlled ultrasonic 15-40min, is then cleaned 3 times with purified water；Its
Middle detergent can be any one or several mixed containing Triton X-100/200, NaTDC or lauryl sodium sulfate
Solution is closed, concentration is 0.01% ~ 0.1%（w/v）；
Submucous layer of small intestine is soaked in aqueous slkali, 10 ~ 30 min are impregnated at 2 ~ 8 DEG C and carry out de- cell processing, are then used again
Equivalent purifies water process 2 ~ 3 hours, so recycles 1 ~ 3 time, until purification of aqueous solutions pH to 7.0-7.4；
The aqueous slkali is sodium hydroxide, potassium hydroxide or calcium hydroxide aqueous solution, and solution concentration is 0.01 ~ 0.1M；
By alkaline solution treatment, it is more thorough to take off cell, and repeatedly circular treatment can reduce DNA residual；
By de- cell treated single layer trees-Osima jacoti, Osima excavata drawout, 2 ~ 10 are superimposed according to horizontal and vertical alternate mode
Layer is laid on freeze-drying mold；
（2）The preparation of collagen solution
With organic acid dissolution collagen, collagen solution is formed；The mass volume ratio concentration range of collagen solution is 0.05 ~ 8%, viscosity
Coefficient is 1000 ~ 4000cp；The good collagen solution of stirring and dissolving, standing and defoaming processing；
Selectively, the concentration that drug is added in collagen solution is 0.1 ~ 20 mg/mL；
Selectively, the content that growth factor is added in collagen solution is 2 ~ 10 μ g/mL；
（3）The preparation of composite membrane
Step（1）After obtained densification is placed in mold, by step（2）The collagen solution even application prepared is in compacted zone
On, then demoulded after vacuum freeze drying.
6. compound membrane preparation method according to claim 5, it is characterised in that：The step（3）Described in uniform painting
The thickness of collagen layer can be controlled by revolving speed and time using vacuum rotating technology for coating by covering.
7. compound membrane preparation method according to claim 5, it is characterised in that：The step（3）It is middle to use vacuum refrigeration
It is dry, after can be pre-freeze 8 at -20 DEG C ~ -80 DEG C ~ for 24 hours, it is transferred in freeze drier and is lyophilized, drying condition can be -50
DEG C ~ -60 DEG C at dry 24 ~ 48h.
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| CN2017105650989 | 2017-07-12 | ||
| CN201710565098.9A CN107281552A (en) | 2017-07-12 | 2017-07-12 | It is a kind of for composite membrane of Guided Bone Regeneration and preparation method thereof |
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| CN201810446632.9A Withdrawn CN108837184A (en) | 2017-07-12 | 2018-05-11 | A kind of composite membrane and preparation method thereof for Guided Bone Regeneration |
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| CN111330080A (en) * | 2020-03-31 | 2020-06-26 | 江苏白衣缘生物工程有限公司 | Biomembrane for guiding regeneration of oral cavity bone and preparation method thereof |
| CN113425904A (en) * | 2020-03-23 | 2021-09-24 | 成都中科奥格生物科技有限公司 | Oral cavity patch material and preparation method and application thereof |
| CN115006597A (en) * | 2022-06-02 | 2022-09-06 | 上海威高医疗技术发展有限公司 | Oral cavity repairing film and preparation method thereof |
| CN115429939A (en) * | 2022-09-23 | 2022-12-06 | 博纳格科技(天津)有限公司 | Preparation method of oral biomembrane with controllable product performance |
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| CN107281552A (en) | 2017-10-24 |
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