CN102526808B - Artificial skin and preparation method thereof - Google Patents
Artificial skin and preparation method thereof Download PDFInfo
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- CN102526808B CN102526808B CN201110458812.7A CN201110458812A CN102526808B CN 102526808 B CN102526808 B CN 102526808B CN 201110458812 A CN201110458812 A CN 201110458812A CN 102526808 B CN102526808 B CN 102526808B
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Abstract
The invention relates to artificial skin, which is formed by compounding a microporous membrane epidermal layer with piezoelectric conducting performance and a natural high polymer bionic skin corium, wherein the microporous membrane epidermal layer mainly comprises polyvinylidene fluoride and/or a polymer thereof, i.e., polyvinylidene fluoride-trichloroethylene; and the skin corium is a collagen membrane. The preparation method mainly comprises the following steps of: preparing the microporous membrane epidermal layer; polarizing the epidermal layer; and compounding a dermal scaffold and preparing double-layer artificial skin. In the use process of the artificial skin, electric stimulation of which the strength is similar to that of bioelectricity can be generated after binding and extruding, so that healing of a skin wound is facilitated. Meanwhile, the epidermal layer of the artificial skin has a microporous structure of which the size is smaller than those of pathogenic bacteria, so that pathogenic bacteria can be isolated effectively, and infection is prevented; and meanwhile, evaporation of wound moisture can be controlled effectively, and high air permeability and flexibility are achieved.
Description
Technical field
The invention belongs to bioactive materials field, refer in particular to a kind of artificial skin that possesses piezoelectricity conductive performance and preparation method thereof.
Background technology
Bio electricity is a kind of universal phenomenon in organism, and the various vital movements in organism are all accompanied by electrical phenomena, and closely related with the metabolism of body.In organism, the generation of electrical phenomena is because transcellular ion flow can produce across cell electromotive force, when cellular layer occurs damagedly, or intercellular tight junction resistance is while reducing, and cell electromotive force just drive current flows out from these regions, form electric field, this is the basic feature of cell activities.At present research shows that various kinds of cell can produce reaction to endogenous or additional electric field, and research shows to have Endogenous Electrical Fields near district of tissue injury, and cell variation biology such as can divide a word with a hyphen at the end of a line under electric field action.Electric field in organism, in cell proliferation, differentiation and migration, plays an important role in the Regeneration and Repair process that especially promotes to organize.
Along with progressively going deep into of research, people have found piezoelectric effect in the tissues such as bone, blood vessel, muscle, Peterlin etc. find research in 1967 that Kynoar (PVDF) thin film has that piezoelectric property is strong, flexible, degree of accuracy is high, frequency response is wide, response speed is fast, elastic energy density is high, indefatigability and stable performance, easily the good combination property such as processing preparation.Particularly its acoustic impedance and air, water and biological tissue are very approaching.Therefore PVDF and copolymer p VDF-TrFE (Kynoar-trifluoro-ethylene) thereof are widely used in many technical fields.Importantly such material has good water resistance, and water absorption rate is low, nontoxic, implants in animal body and finds no any untoward reaction, more approaching with the various biological piezoelectric effect in human body.
Skin, as human organ, has the moisture of maintenance, breathes freely and prevent the functions such as bacteria attack.Be subject to the infringements such as wound, burn, inflammation when skin, especially, in the time that large-area skin is subject to grievous injury, wound should be protected immediately.If the shallow-layer or the small size that are only skin are impaired, new skin can autologously be regenerated.If the large area skin of deep layer is subject to wound, skin just can not be realized selfreparing, conventionally must carry out auto-skin grafting, as methods such as stamp skin-grafting, mesh graft, embedding skins.Therefore, how to realize clinically skin regeneration induction, also have very large challenge.
Summary of the invention
Technical problem to be solved by this invention is: a kind of double-layered artificial skin that possesses piezoelectricity conductive performance is provided, solves the technical problem such as the repairing effect of skin and the regeneration of skin histology in prior art.
The present invention takes following technical scheme: a kind of preparation method of artificial skin comprises the following steps:
Step 1, prepares the membranaceous epidermal area of micropore;
Step 2, carries out the polarization processing of epidermal area;
Step 3, be compounded to form double-layered artificial skin: epidermal area prepared by step 2 is put into mould, on film surface, apply the pre-prepd natural polymer solution of one deck, then lyophilization, crosslinked, clean, on the membranaceous epidermal area of micropore, form the natural polymer bionic dermis layer as dermis scaffold effect, thereby be compounded to form double-layered artificial skin.
Prepared artificial skin, comprises that the membranaceous epidermal area composite natral of the micropore macromolecule bionic dermis layer with piezoelectricity conductive performance forms; The membranaceous epidermal area of described micropore is mainly made up of Kynoar and/or its copolymer polyvinylidene fluoride-trifluoro-ethylene.Described skin corium is collagem membrane.
The membranaceous epidermal area thickness of described micropore is 50 ~ 500 μ m, and pore size scope is 0.05 ~ 0.45 μ m, can effectively control the evaporation of moisture, the intrusion that prevents antibacterial and infection.
Collagen in described collagem membrane is type i collagen albumen, or in type i collagen albumen, is mixed with a small amount of collagen-based composite that in III Collagen Type VI, chondroitin sulfate, hyaluronic acid, glycosaminoglycans, one or more components are mixed to form that is selected from.
In described the 1st step, use certain organic solvent dissolution PVDF, PVDF and/or PVDF-TrFE, be enclosed in the container that is full of protective gas, be placed in the baking oven of uniform temperature and fully dissolve, then pyrosol poured out, be placed on thin plate, natural cooling or quenching, PVDF and/or PVDF-TrFE can be separated with solvent, crystallization, film forming; Then film is repeatedly cleaned and removes organic solvent, drying prepares the membranaceous epidermal area of micropore.Organic solvent used is selected from the double solvents of one or more formations in benzophenone and dimethyl phthalate, diethyl phthalate, DMF, N,N-dimethylacetamide, dimethyl sulfoxide; PVDF or PVDF-TrFE, or the two mass volume ratio concentration after dissolving of PVDF and PVDF-TrFE is 5 ~ 40%; Noble gas can be selected from nitrogen, argon and helium a kind of; Oven temperature can be 180 ~ 250 ℃.
In described step 2, be that the membranaceous epidermal area of micropore that step 1 is prepared is placed in the silicone oil of uniform temperature, the upper and lower surface of epidermal area is covered with electrode, the processing that polarizes, and polarization is cleaned and is removed silicone oil after processing, and drying prepares the membranaceous epidermal area of micropore; Silicone oil temperature is in the scope of 100 ~ 130 ℃, and polarizing voltage is 5 ~ 20 MV/m.The electrode that upper and lower surface covers of epidermal area is silver electrode, and polarization keeps voltage again until room temperature after handling.
In described step 3, previously prepared natural polymer solution is collagen solution, is dissolved in spirit of vinegar or is dissolved in the water to form by collagen solute, and the mass volume ratio concentration of collagen solute is 0.1 ~ 2%; Described collagen solute refers to type i collagen albumen, or one or more the collagen solutes that are mixed to form in III Collagen Type VI, chondroitin sulfate, hyaluronic acid, glycosaminoglycans that are selected from of type i collagen albumen and a small amount of (accounting for solute total mass ratio content is 0 ~ 5%); Described cryodesiccated temperature range is-60 ~-40 ℃; Cross-linking method is chemical crosslinking, and cross-linking agent is selected from one or more in glutaraldehyde, genipin, carbodiimides, and the mass volume ratio concentration of cross-linking agent in cross-linking system is 0.1 ~ 1%.Crosslinking time 12 ~ 24h.
Mould therefor is that corrosion resistant plate processes, and plate central authorities are that the length and width of groove, groove are respectively in the scope of 10 ~ 50cm.
The invention has the beneficial effects as follows: the present invention be based on bio electricity promote to play an important role in the Regeneration and Repair process of tissue and PVDF and PVDF-TrFE piezoelectric effect basis on a kind of double-layered artificial skin that possesses piezoelectricity conduction effect of developing.Be proven, artificial skin in the process using, the wrapping that is subject to extruding, the electricity irritation that can produce similar bio electricity intensity, thus promote the healing of skin wound.Meanwhile, the epidermal area of this artificial skin is microcellular structure, and the size of pore structure is less than the size of pathogenic bacteria, can effectively isolates pathogenic bacteria, protects from infection; And can effectively control the evaporation of wound moisture, possess good breathability and compliance.
The specific embodiment
Double-layered artificial skin of the present invention, comprises the epidermal area of being prepared by Kynoar (PVDF) or its copolymer p VDF-TrFE (Kynoar-trifluoro-ethylene), and the bionic dermis layer of being made up of natural polymer.Be a kind of double-layered artificial skin that possesses piezoelectricity conductive performance, can effectively improve the repairing effect of skin, especially induce the regeneration of skin histology.
The membranaceous epidermal area thickness of this micropore is 50 ~ 500 μ m, and pore size scope is 0.05 ~ 0.45 μ m, can effectively control the evaporation of moisture, the intrusion that prevents antibacterial and infection.The bionic dermis layer of this natural polymer is collagem membrane.Described collagen refers to type i collagen albumen, or type i collagen albumen with a small amount of (as, in collagen gross mass, content is lower than 5%) III Collagen Type VI, chondroitin sulfate, hyaluronic acid, glycosaminoglycans in one or more collagen-based composites that are mixed to form.
The present invention possesses the preparation method of the double-layered artificial skin of piezoelectricity conductive performance, mainly comprises the following steps:
Step 1, prepare the membranaceous epidermal area of micropore: use certain organic solvent dissolution PVDF, PVDF and/or PVDF-TrFE, be enclosed in the container that is full of protective gas, be placed in the baking oven of uniform temperature and fully dissolve, then pyrosol poured out, be placed on the stainless steel metal thin plate or sheets of glass of same high temperature, natural cooling or quenching, PVDF and/or PVDF-TrFE can be separated with solvent, crystallization, film forming; Then film is repeatedly cleaned and removes organic solvent, drying prepares the membranaceous epidermal area of micropore.
Step 2, carries out the polarization processing of epidermal area: the membranaceous epidermal area of micropore that step 1 is prepared is placed in the silicone oil of uniform temperature, and the upper and lower surface of epidermal area is covered with silver electrode, the processing that polarizes, then keep voltage until room temperature.Then with silicone oil abluent and ethanol, film is repeatedly cleaned and removes silicone oil, drying prepares the membranaceous epidermal area of micropore that possesses piezoelectricity conductive performance.
Step 3: the bionic dermis layer that compound one deck natural polymer is made on epidermal area, prepare double-layered artificial skin: epidermal area prepared by step 2 is put into special or non-particular manufacturing craft, on film surface, apply the pre-prepd natural polymer solution of one deck, then lyophilization, crosslinked, clean, on the membranaceous epidermal area of micropore, form dermis scaffold (the bionic dermis layer of also making for natural polymer), thereby prepare double-layered artificial skin.
In the 1st step, organic solvent is selected from benzophenone and dimethyl phthalate, diethyl phthalate, N, dinethylformamide, N, the double solvents of one or both formations in N-dimethyl acetylamide, dimethyl sulfoxide, and be (8 ~ 10) by solvent and solute volume ratio: 1 dissolves.PVDF or PVDF-TrFE, or the two mass volume ratio concentration after dissolving of PVDF and PVDF-TrFE is 5 ~ 40%.Noble gas is selected from nitrogen, argon and helium a kind of; Oven temperature is 180 ~ 250 ℃, first cleans with ether and then clean with ethanol when cleaning; Preparing the membranaceous epidermal area thickness of micropore is 50 ~ 500 μ m, and pore size scope is 0.05 ~ 0.45 μ m, can effectively control the evaporation of moisture, the intrusion that prevents antibacterial and infection.
In described step 2, silicone oil temperature is in the scope of 100 ~ 130 ℃, and polarizing voltage is 5 ~ 20 MV/m.
In described step 3, particular manufacturing craft is that the medical grade corrosion resistant plate that 5mm is thick processes, and plate central authorities are that the degree of depth of groove and groove is 3mm, and the length and width of groove are respectively in the scope of 10 ~ 50cm; Natural polymer solution is collagen solution, and solute is collagen, and solvent is spirit of vinegar or water.Described collagen solute is type i collagen albumen, or type i collagen albumen and a small amount of (as, in collagen, shared quality percentage composition is less than 5%) one or more are mixed to form collagen-based composite in III Collagen Type VI, chondroitin sulfate, hyaluronic acid, glycosaminoglycans.In collagen solution, the mass volume ratio concentration of collagen solute is 0.1 ~ 2%.Cryodesiccated temperature range is-60 ~-40 ℃; Cross-linking method is chemical crosslinking, and cross-linking agent is selected from the one in glutaraldehyde, genipin, carbodiimides.In the cross-linking system of cross-linking agent and duplicature formation, the mass volume ratio concentration of cross-linking agent is 0.1 ~ 1%, crosslinking time 12 ~ 24h.Be appreciated that indication particular manufacturing craft in step 3, also can carry out according to specific needs structural design or adjustment, other mould that also can choice for use prior art.
Further illustrate double-layered artificial skin of the present invention below in conjunction with example, but not as restriction of the present invention.
example 1
The described double-layered artificial skin that possesses piezoelectricity conductive performance, specifically comprises the following steps:
(1) use benzophenone and dimethyl phthalate double solvents (volume ratio 8:1) to dissolve PVDF, mass volume ratio concentration after dissolving is 40%, be enclosed in the container that is full of helium, be placed in 200 ℃ of baking ovens and fully dissolve,, then pyrosol is poured out, stainless steel metal thin plate, quenching, PVDF and the solvent that is placed in same high temperature is separated, crystallization, film forming; Then film is repeatedly cleaned and removes organic solvent, drying prepares the membranaceous epidermal area of micropore.Then first clean, clean repeatedly to clean again remove organic solvent with ethanol with ether, drying prepares the membranaceous epidermal area of micropore.
(2) carry out the polarization processing of epidermal area, the membranaceous epidermal area of micropore preparing by step (1) is placed in the silicone oil of 120 ℃, and the upper and lower surface of epidermal area is covered with silver electrode, and processing polarizes, polarizing voltage is 5 ~ 20 MV/m, keeps voltage until room temperature.Then with silicone oil abluent and ethanol, film is repeatedly cleaned and removes silicone oil, drying prepares the membranaceous epidermal area of micropore.
(3) epidermal area of then being prepared by step (2) is put into particular manufacturing craft, on film surface, applying the pre-prepd mass volume ratio concentration of one deck is 1% collagen solution, then lyophilization under-40 ℃ of conditions, to add mass volume ratio concentration be that 0.1% genipin is cross-linked 24h, then deionized water repeatedly cleans, on the membranaceous epidermal area of micropore, forms dermis scaffold, prepares double-layered artificial skin.
example 2
The described double-layered artificial skin that possesses piezoelectricity conductive performance, specifically comprises the following steps:
(1) use benzophenone and dimethyl phthalate double solvents (9:1) to dissolve PVDF and PVDF-TrFE(mass ratio 4:1), after dissolving, the mass volume ratio concentration of solute is 30%, be enclosed in the container that is full of helium, be placed in 240 ℃ of baking ovens and fully dissolve,, then pyrosol is poured out, be placed in stainless steel metal thin plate, quenching, solute PVDF and the PVDF-TrFE of same high temperature and solvent is separated, crystallization, film forming; Then film is repeatedly cleaned and removes organic solvent, drying prepares the membranaceous epidermal area of micropore.Then first clean, clean repeatedly to clean again remove organic solvent with ethanol with ether, drying prepares the membranaceous epidermal area of micropore.
(2) then carry out the polarization processing of epidermal area, the membranaceous epidermal area of micropore preparing by step (1) is placed in the silicone oil of 130 ℃, and the upper and lower surface of epidermal area is covered with silver electrode, and processing polarizes, polarizing voltage is 5 ~ 20 MV/m, keeps voltage until room temperature.Then with silicone oil abluent and ethanol, film is repeatedly cleaned and removes silicone oil, drying prepares the membranaceous epidermal area of micropore.
(3) epidermal area of being prepared by step (2) is put into particular manufacturing craft, on film surface, applying the pre-prepd mass volume ratio concentration of one deck is 1% collagen solution, then lyophilization under-40 ℃ of conditions, to add mass volume ratio concentration be that 1% glutaraldehyde is cross-linked 12h, repeatedly clean, on the membranaceous epidermal area of micropore, form dermis scaffold with deionized water again, prepare double-layered artificial skin.
Patent of the present invention be based on bio electricity promote to play an important role in the Regeneration and Repair process of tissue and PVDF and PVDF-TrFE piezoelectric effect basis on a kind of double-layered artificial skin that possesses piezoelectricity conduction effect of developing.Be proven, artificial skin, in the process using, is subject to the electricity irritation that wrapping extruding can produce similar bio electricity intensity, thereby promotes the healing of skin wound.Meanwhile, the epidermal area of this artificial skin is microcellular structure, and the size of pore structure is less than the size of pathogenic bacteria, can effectively isolates pathogenic bacteria, protects from infection; Meanwhile, can effectively control the evaporation of wound moisture, possess good breathability and compliance.
Claims (8)
1. a preparation method for artificial skin, comprises the following steps:
Step 1, prepare the membranaceous epidermal area of micropore: with organic solvent dissolution PVDF and/or PVDF-TrFE, be enclosed in the container that is full of protective gas, be placed in the baking oven of uniform temperature and fully dissolve, then pyrosol poured out, be placed on thin plate, natural cooling or quenching, PVDF and/or PVDF-TrFE and solvent is separated, crystallization, film forming; Then film is cleaned and removes organic solvent, drying makes the membranaceous epidermal area of micropore;
Step 2, carries out the polarization processing of epidermal area;
Step 3, be compounded to form double-layered artificial skin: epidermal area prepared by step 2 is put into mould, on film surface, apply the pre-prepd natural polymer solution of one deck, then lyophilization, crosslinked, clean, thereby form the natural polymer bionic dermis layer as dermis scaffold function on the membranaceous epidermal area of micropore;
Prepared artificial skin, comprises the membranaceous epidermal area of micropore and one deck natural polymer bionic dermis layer with piezoelectricity conductive performance; The membranaceous epidermal area of described micropore is mainly made up of Kynoar and/or its copolymer polyvinylidene fluoride-trifluoro-ethylene, and described natural polymer bionic dermis layer is collagen rete.
2. the preparation method of artificial skin as claimed in claim 1, is characterized in that: the membranaceous epidermal area thickness of described micropore is 50 ~ 500 μ m, and pore size scope is 0.05 ~ 0.45 μ m, can effectively control the evaporation of moisture, the intrusion that prevents antibacterial and infection.
3. the preparation method of artificial skin as claimed in claim 1, it is characterized in that: the collagen in described collagem membrane is type i collagen albumen, or in type i collagen albumen, be mixed with a small amount of collagen-based composite that in III Collagen Type VI, chondroitin sulfate, hyaluronic acid, glycosaminoglycans, one or more components are mixed to form that is selected from.
4. the preparation method of artificial skin as claimed in claim 1, it is characterized in that: in described the 1st step, organic solvent is selected from benzophenone and dimethyl phthalate, diethyl phthalate, N, the double solvents of one or more compositions in dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide; Mass volume ratio concentration after PVDF and/or PVDF-TrFE dissolve is 5 ~ 40%.
5. the preparation method of artificial skin as claimed in claim 1, it is characterized in that: in described step 2, that the membranaceous epidermal area of micropore that step 1 is prepared is placed in the silicone oil of uniform temperature, the upper and lower surface of epidermal area is covered with electrode, processing polarizes, polarization is cleaned and is removed silicone oil after processing, and drying prepares the membranaceous epidermal area of micropore with piezoelectricity conductive performance.
6. the preparation method of artificial skin as claimed in claim 5, is characterized in that: in described step 2, silicone oil temperature is in the scope of 100 ~ 130 ℃, and polarizing voltage is 5 ~ 20 MV/m; The electrode that upper and lower surface covers of epidermal area is silver electrode, and polarization keeps voltage again until room temperature after handling.
7. the preparation method of artificial skin as claimed in claim 1, it is characterized in that: in described step 3, previously prepared natural polymer solution is collagen solution, be dissolved in spirit of vinegar or be dissolved in the water by collagen solute and form, the mass volume ratio concentration of collagen solute is 0.1 ~ 2%; Described collagen solute refers to type i collagen albumen, or type i collagen albumen and one or more the collagen solutes that are mixed to form in III Collagen Type VI, chondroitin sulfate, hyaluronic acid, glycosaminoglycans that are selected from that to account for collagen solute quality be 0 ~ 5% than content; Described cryodesiccated temperature range is-60 ~-40 ℃; Cross-linking method is chemical crosslinking, and cross-linking agent is selected from one or more in glutaraldehyde, genipin, carbodiimides, and the mass volume ratio concentration of cross-linking agent in cross-linking system is 0.1 ~ 1%.
8. the preparation method of the artificial skin as described in any one in claim 1-7, mould therefor is to be processed by corrosion resistant plate, plate central authorities are that the length and width of groove, groove are respectively in the scope of 10 ~ 50cm.
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| CN102861355A (en) * | 2012-10-12 | 2013-01-09 | 中国人民解放军第三军医大学 | Functional wound dressing capable of accelerating wound healing and preparation method thereof |
| CN104068945B (en) * | 2014-06-27 | 2016-11-16 | 深圳齐康医疗器械有限公司 | A kind of artificial skin and preparation method thereof |
| CN104984407B (en) * | 2015-07-01 | 2017-11-24 | 北京湃生生物科技有限公司 | A kind of tissue engineering artificial skin and preparation method thereof |
| CN105031740B (en) * | 2015-07-01 | 2017-10-13 | 北京湃生生物科技有限公司 | A kind of biomimetic prosthetic skin with waterproof and breathable function and preparation method thereof |
| CN106492278A (en) * | 2016-12-27 | 2017-03-15 | 广东泰宝医疗器械技术研究院有限公司 | A kind of artificial skin and preparation method thereof |
| CN107261205A (en) * | 2017-06-13 | 2017-10-20 | 北京大学口腔医学院 | A kind of powered tissue repair film and preparation method thereof that prevents adhesion |
| CN113663134B (en) * | 2021-08-27 | 2023-02-28 | 苏州诺普再生医学有限公司 | Bionic skin stent and preparation method thereof |
| CN115444974B (en) * | 2022-10-25 | 2024-01-30 | 中国地质大学（北京） | Electroactive composite patch for treating scalds and preparation method and application thereof |
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| JPH04135563A (en) * | 1990-09-28 | 1992-05-11 | Terumo Corp | Artificial skin |
| US20060041318A1 (en) * | 2004-08-19 | 2006-02-23 | Shannon Donald T | Laminar skin-bone fixation transcutaneous implant and method for use thereof |
| EP2962704A1 (en) * | 2008-10-07 | 2016-01-06 | Nanonerve, Inc. | Multilayer fibrous polymer scaffolds, methods of production and methods of use |
| US10406346B2 (en) * | 2009-02-11 | 2019-09-10 | United States Of America As Represented By The Administrator Of Nasa | Device and method for healing wounds |
| CN101716375B (en) * | 2009-11-20 | 2014-10-22 | 深圳齐康医疗器械有限公司 | Artificial skin prepared from purely natural materials and having gradient hole structure and property |
| CN101716376B (en) * | 2009-11-20 | 2014-10-22 | 深圳齐康医疗器械有限公司 | Growth factor slow-release type double-layered artificial skin |
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