CN116942908B - Absorbable biological isolation composite membrane material and preparation method thereof - Google Patents
Absorbable biological isolation composite membrane material and preparation method thereof Download PDFInfo
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- CN116942908B CN116942908B CN202310947290.XA CN202310947290A CN116942908B CN 116942908 B CN116942908 B CN 116942908B CN 202310947290 A CN202310947290 A CN 202310947290A CN 116942908 B CN116942908 B CN 116942908B
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- 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
- 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
- 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
- A61L27/58—Materials at least partially resorbable by the body
-
- 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
- A61L2430/32—Materials or treatment for tissue regeneration for nerve reconstruction
Abstract
The invention provides an absorbable biological isolation composite membrane material and a preparation method thereof; the method comprises the following steps: taking bovine Achilles tendon tissue, and carrying out protease treatment and virus inactivation procedures to obtain a collagen solution with the mass fraction of 0.5% -5%; spreading collagen solution in a mould, and drying to obtain a main bracket; mixing the waterproof bonding material with water to obtain a bonding layer solution with the concentration of 1% -25%; after freezing treatment, cleaning the adhesive layer solution to obtain adhesive microspheres with diameters of 0.1-5 mu m; spraying the adhesive microspheres on the surface of the main support, and drying to obtain a composite support; and carrying out vacuum dry-heat crosslinking or ultraviolet crosslinking on the composite stent to obtain the absorbable biological isolation composite membrane material. The absorbable biological isolation composite membrane material prepared by the invention has excellent mechanical property, anti-seepage property and water resistance; short production period, low cost and large-scale production.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to an absorbable biological isolation composite membrane material and a preparation method thereof.
Background
In the operations of thoracic cavity, abdominal cavity and pelvic cavity organs, related organs include but are not limited to heart, lung, esophagus, stomach, duodenum, liver, spleen, gall bladder, small intestine, colon, bladder, ovary, uterus and the like, the independence and the integrity of the organs are often required to be recovered in the operation, the operation suturing or anastomosis strength of the organs is enhanced, the leakage of the content of the organs is prevented, the adhesion of the organs and surrounding tissues is prevented, and the repair and the growth of the self tissues of the organs are promoted. Most operations need to be sutured and repaired by surgical suture, but leakage easily occurs between each needle suture position of an anastomotic orifice, the suture position is unsmooth, and tissue adhesion easily occurs; tissue growth at the suture requires that the biological scaffold material induce self-tissue to grow in a given direction. At the same time, the repairing material can be tightly combined with the surgical suture, and the visceral surface has self-adhesive property, thereby achieving the aim of compression hemostasis. The material is preferably capable of being finally absorbed by the human body without causing foreign matter to remain in the human body. Such isolated repair materials are currently lacking.
Vascular anastomosis surgery is currently mainly performed by a doctor using an operation needle and a suture to anastomose a broken end of a blood vessel. However, because the blood has a certain pressure in the blood vessel, extravascular leakage of the blood easily occurs between the sutures, which results in failure of the operation; too dense suturing is easy to cause tissue ischemia and tissue necrosis of the anastomotic stoma, and the operation fails. Clinically, an adhesive isolating membrane material is needed, which is used for strengthening and isolating after suturing at the vascular anastomosis, preventing blood leakage and preventing adhesion between the anastomosis and surrounding tissues.
If the peripheral nerve anastomosis operation is performed, if the self-adhesive isolating membrane material is provided, the labor intensity of a doctor for anastomosis of nerves can be greatly reduced, the operation time is shortened, the self-repair of nerve tissues is induced, the adhesion of the nerves and the peripheral tissues is prevented, and the success rate of nerve anastomosis is improved.
Before dental implant, bone powder is often filled in alveolar bone, but the bone powder is easy to fall off, and collagen films are covered at the filling part of more bone powder in the past. However, collagen membrane is easy to fall off, which leads to bone powder overflow and affects the operation effect. There is a need for a single-sided self-adhesive, absorbable bio-barrier composite film.
Neurosurgery craniotomy and intrathecal surgery often involve repair of dura mater or dura mater. The dura mater (spinal) is a tough membranous tissue that clings between the inside of the skull and the brain tissue, and is a natural barrier that protects the brain tissue. Factors such as open skull injury, tumor erosion, surgical operation and the like can lead to the defect of the dura mater, and further can cause the occurrence of cerebrospinal fluid leakage. If not treated, it can cause intracranial infection, causing arachnoiditis or meningitis, and even developing a series of life-threatening complications such as brain abscess and intracranial hemorrhage.
The repair of dura mater (dura mater) is classified into autologous tissue suture repair, artificial dura mater simple attachment repair and the like. Suture repair often requires a high skill and considerable time for suturing by the physician to prevent leakage of cerebrospinal fluid. The existing adhesive dura mater repairing material has no self-adhesive property, and the leakage of cerebrospinal fluid cannot be prevented by simple adhesion. The product can be used as a supplement for suture repair or as a simple attachment, can improve the effect of preventing cerebrospinal fluid leakage, reduce the labor intensity of doctors, reduce the requirements on the surgical skills of the doctors, reduce the surgical time, save medical resources, improve the surgical effect and reduce complications. The medical cost is reduced as a whole.
The main means for repairing the dura mater defect clinically at present are biological patches obtained from tissues such as acellular allogenic or animal-derived dermis, bovine or porcine pericardium and the like, or nondegradable polymer fiber patches such as polyurethane, expanded polytetrafluoroethylene and the like.
However, the above-mentioned Dura mater substitute materials have problems, such as that a doctor performs retrospective analysis on a patient using bovine pericardium artificial meninges (Dura-Guard), that the Dura mater repair material uses a heterogeneous biological material treated by antigen removal, such as bovine pericardium products treated by glutaraldehyde crosslinking, that a small amount of aldehyde groups are introduced while removing antigenicity of heterogeneous proteins, that residual toxicity is present, and that the membrane crosslinked by glutaraldehyde is unfavorable for invasion of fibroblasts into an implanted tissue, that cells have difficulty in migration and differentiation, and that they are difficult to be metabolized by the body, that it is difficult to reconstruct into a new Dura mater tissue, and that chronic inflammatory reactions inevitably exist.
The Chinese application (publication No. CN 218792626U) uses polypropylene/polyester fiber as a main substrate, which cannot be compared with the bioactivity of collagen and cannot bring nutrition to surrounding tissue cells after degradation. A representative polyurethane material is the Neuro-Patch produced by Below, germany, and the artificial dura mater Patch is made of polyurethane, is a microporous, velvet-shaped non-woven material, and is taken as an inert material and cannot be decomposed and absorbed by human bodies. There were doctor visits back, 132 patients with craniocerebral injury underwent flap decompression, 50 of which had been enlarged with this patch of material to repair the dura mater, and the results showed that this patch increased the risk of formation of epidural or subdural hematomas at the site of decompression, and increased the risk of intracranial infection.
In recent years, in the improvement of the dura mater repair material, more and more attention is focused on materials with bioactivity such as collagen, and populus euphratica et al prepare the dura mater repair material by extracting collagen from pig skin serving as a raw material by adopting an in-situ spinning technology (publication number CN 103263694A). Compared with the traditional solvent spinning, the method has the advantages of friendly process, reduced toxic and side effects and retaining the three-strand spiral structure of collagen, but the method has extremely complicated process, high production cost and incapability of large-scale production. Although the Chinese application (publication No. CN 111359018A) adopts recombinant collagen as a base material, the design method is that after the collagen and chitosan are mixed according to a certain proportion, the process route is that the collagen is dried to form a film, the surface is particularly compact, and the other layer has a perforation design (serving as cerebrospinal fluid diversion effect), but the porosity is far insufficient to meet the requirements of migration and proliferation of autologous dural cells on the material, so that defective tissues cannot heal for a long time. Ruiguo et al (publication No. CN 107551324A) devised a seamable sponge material made from collagen, which has mechanical properties, either in dry or wet form, that are far superior to those of the prior art.
Li Ya et al (publication No. CN 114225113A) prepared by recombinant collagen and an adhesive, freeze-dried to obtain a meninges repair material, which is referred to herein as preventing leakage of cerebrospinal fluid, but does not provide substantial anti-leakage test data in the whole text, and in mechanical properties, since the autologous dura mater is defective, the intracranial pressure and vascular pressure of the human body generate certain pressure on the repair material, the repair material needs to have mechanical properties not limited to tensile strength and elongation at break, and the repair material also needs to have proper bursting strength.
Biological artificial dura mater, the isolating membrane DuraGen, is a product of Integra, U.S.A., which is prepared by special treatment using bovine Achilles tendon type I collagen as a carrier. The tissue structure is stable, can be completely absorbed by tissues, has good tissue compatibility, is convenient to repair, and does not need to be sutured. However, the surface tackiness is poor, and in the defect of dura mater and spinal film, the product is difficult to fix in the operation, and the displacement phenomenon is generated, so that the operation is inconvenient. The adhesive layer of the Chinese application patent (publication No. CN 209437423U) adopts the a-butyl cyanoacrylate, although the adhesive layer still has certain pungent smell at a lower content, the brittleness is higher, the water resistance is poor, and the adhesive effect can not be achieved under the condition that a large amount of bleeding or effusion exists in the brain.
At present, clinical researches agree that ideal dura mater, dura mater substitutes, nerve sheath repair materials and other viscera isolating membrane materials have the following characteristics (1) excellent biocompatibility and no immunogenicity; (2) does not cause acute and chronic inflammatory reactions; (3) the safety is good, the toxicity and the carcinogenesis are avoided, and the disease is not transmitted; (4) the ceramic material has certain compactness and can prevent tissue fluid from leaking; (5) can play a role of a bracket, promote the formation of a new fibrous tissue and prevent adhesion with an autologous tissue; (6) absorbable, the replacement barrier film should be gradually absorbed while the new tissue is formed; (7) the operation is simple and convenient, and the waiting time of the doctor in the operation is reduced; (8) the materials are easy to obtain and have wide sources.
Disclosure of Invention
In order to solve the problems, the invention provides a method for producing high-purity type I collagen by utilizing bovine Achilles tendon tissue through enzymolysis treatment and virus inactivation treatment, wherein a vacuum freeze-drying technology is adopted to obtain a sponge or cold air for drying to obtain a collagen film, and the collagen film is used as an absorbable biological isolation composite film material bracket, has no immunogenicity, is simple in process and is suitable for large-scale production.
On the basis, microspheres prepared by emulsifying and freezing composite cellulose and protein adhesives are combined with a sponge bracket or a collagen film to form an absorbable biological isolation composite film repair material. The collagen has excellent biocompatibility, the sponge structure has a certain porosity and a rough surface, and can give cells a space for migration, proliferation and differentiation and gradually form an autologous membrane tissue. Meanwhile, the adhesive microsphere is compounded on the collagen transparent film, the diameter of the microsphere is about 0.1-5 mu m when observed under an electron microscope, the surface of the microsphere is rough, the environment for growing the fiber cells can be provided, the degradation period of the adhesive microsphere material is longer than that of collagen, and the tissue growth period of the autologous membrane can be effectively matched. The collagen is prepared and freeze-dried to obtain compact sponge through concentration, and the collagen film after being dried by cold air has excellent antiseep performance, so that the conditions of cerebrospinal fluid leakage, blood extravasation in vascular surgery and the like are prevented to the greatest extent. And physical crosslinking is adopted, so that the safety problems such as chemical reagent residues and the like are avoided, the adhesive has good mechanical properties (tensile strength, bursting strength, elongation at break and the like), flexibility and adhesiveness, and meanwhile, the adhesive microspheres can effectively avoid the occurrence of the situations such as product displacement and the like in operation, and the overall operation time is shortened.
The application discloses a preparation method of an absorbable biological isolation composite membrane material, which specifically comprises the following steps:
s1, collagen preparation: taking bovine Achilles tendon tissue, and carrying out protease treatment and virus inactivation procedures to obtain a collagen solution with the mass fraction of 0.5% -5%;
s2, preparing a main support: spreading the collagen solution obtained in the step S1 in a mould, and drying to obtain a main bracket;
s3, preparation of an adhesive layer: mixing the waterproof bonding material with water to obtain a bonding layer solution with the concentration of 1% -25%; after freezing treatment, cleaning the adhesive layer solution to obtain adhesive microspheres with diameters of 0.1-5 mu m;
s4, preparing a composite bracket: spraying the adhesive microspheres in the step S3 on the surface of the main support in the step S2, and drying to obtain a composite support;
s5, performing S5; and (3) carrying out vacuum dry-heat crosslinking or ultraviolet crosslinking on the composite scaffold obtained in the step (S4) to obtain the absorbable biological isolation composite membrane material.
Preferably, the protease in step S1 is pepsin or ficin.
Preferably, in the step S1, the ratio of the protease to the bovine Achilles tendon tissue is 1:0.01-1:0.2, and the enzymolysis time is 2-96 hours.
Preferably, the virus inactivation step in step S1 is specifically performed as follows: bovine Achilles tendon tissue and 0.5% -30% saline solution are mixed according to 1g:5ml to 1g: mixing in a proportion of 100ml, wherein the treatment time is 24-48 hours; the salt solution is one or more of ammonium sulfate, sodium sulfate, potassium hydroxide, sodium nitrate, potassium nitrate and sodium phosphate.
Preferably, the collagen solution is spread in the mold in the step S2 to a thickness of 0.3mm to 5mm.
Preferably, the drying mode in the step S2 is cold air drying or freeze drying; the temperature of the cold air drying is 2-12 ℃; the pre-freezing temperature of freeze drying is-60 ℃ to-18 ℃ for 4-48 hours, the freezing temperature is-60 ℃ to-2 ℃ and the pre-freezing time is 24-96 hours.
Preferably, the water-proof adhesive in step S3 is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, silk fibroin, mussel protein, glycerol, polylactic acid, polyethylene glycol, and polyvinyl alcohol.
Preferably, the drying mode in the step S4 is cold air drying or freeze drying; the temperature of the cold air drying is 2-12 ℃; the pre-freezing temperature of freeze drying is-60 ℃ to-18 ℃ for 4-48 hours, the freezing temperature is-60 ℃ to-2 ℃ and the pre-freezing time is 24-96 hours.
Preferably, the temperature of vacuum dry-thermal crosslinking in the step S5 is 80-125 ℃ and the time is 18-48 h; the ultraviolet crosslinking temperature is 4-8 ℃, the wavelength is 254nm, and the time is 2-4 hours.
The invention also discloses an absorbable biological isolation composite membrane material, which is prepared by adopting the preparation method of the absorbable biological isolation composite membrane material.
The invention has the beneficial effects that:
the absorbable biological isolation composite membrane material disclosed by the invention is prepared from bovine Achilles tendon tissue rich in collagen components through enzyme treatment and virus inactivation treatment, so that high-purity low-immunogenicity type I collagen is obtained, the cost is low, the yield is high, and mass industrialized production can be realized; the mechanical property of the main bracket manufactured by the method is better than that of protein powder/protein peptide directly purchased in the market;
after the collagen scaffold prepared by the method is subjected to physical crosslinking, the problem of chemical crosslinking agent residue is avoided;
in the freeze-drying process, pores are regulated and controlled at a deep low temperature on the surface of the sponge, so that the anti-seepage performance is good, and migration, proliferation and differentiation of the fiber cells on the material are facilitated;
collagen has excellent biocompatibility, and can provide nutrients for cells after degradation, so as to accelerate the formation of autologous dura mater;
the collagen membrane scaffold obtained by cold air drying has better anti-seepage performance due to compactness, and has obvious benefits in repairing dura mater or nerve sheath and vascular leakage;
the adhesive microsphere sprayed on the surface of the collagen scaffold is a cellulose and protein adhesive, has no toxic or side effect on human cells, has excellent viscosity and water resistance, and can effectively reduce the probability of infirm adhesion and displacement of materials and human tissues in the use process, thereby achieving the purpose of shortening the operation time. Meanwhile, the degradation period of the adhesive microsphere is longer than that of collagen, and the adhesive microsphere can be better suitable for repairing human body autologous tissues. The features and advantages of the present invention will be described in detail by way of example with reference to the accompanying drawings.
Drawings
FIG. 1 is a schematic representation of an adhesive microsphere of the present invention;
FIG. 2 is a graph showing the comparison of the performance indexes of the invention in example 6 and comparative example 1;
Detailed Description
The present invention will be further described in detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the detailed description and specific examples, while indicating the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the present invention.
The embodiment of the invention provides a preparation method of an absorbable biological isolation composite membrane material, which comprises the following steps:
s1, collagen preparation: taking bovine Achilles tendon tissue, and carrying out protease treatment and virus inactivation procedures to obtain a collagen solution with the mass fraction of 0.5% -5%;
specifically, the protease is pepsin or ficin; the ratio of the bovine Achilles tendon tissue to the protease in the protease treatment is 1:0.01-1:0.2, and the enzymolysis time is 2-96 hours.
The virus inactivation procedure is specifically operated as follows: bovine Achilles tendon tissue and 0.5% -30% saline solution are mixed according to 1g:5ml to 1g: mixing in a proportion of 100ml, wherein the treatment time is 24-48 hours; the salt solution is one or more of ammonium sulfate, sodium sulfate, potassium hydroxide, sodium nitrate, potassium nitrate and sodium phosphate.
S2, preparing a main support: spreading the collagen solution obtained in the step S1 in a mould, and drying to obtain a main bracket; specifically, the collagen solution is paved in a die to a thickness of 0.3 mm-5 mm.
The drying mode is cold air drying or freeze drying; the temperature of the cold air drying is 2-12 ℃; the pre-freezing temperature of freeze drying is-60 ℃ to-18 ℃ for 4-48 hours, the freezing temperature is-60 ℃ to-2 ℃ and the pre-freezing time is 24-96 hours.
S3, preparation of an adhesive layer: mixing the waterproof bonding material with water to obtain a bonding layer solution with the concentration of 1% -25%; after freezing treatment, cleaning the adhesive layer solution to obtain adhesive microspheres with diameters of 0.1-5 mu m; as shown in fig. 1, the smaller diameter of the adhesive microsphere, when morphologically compounded with the dense membrane, can compensate for the problem that cells cannot migrate on the dense membrane due to too dense of the dense membrane;
specifically, the waterproof adhesive substance is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, silk fibroin, mussel protein, glycerol, polylactic acid, polyethylene glycol and polyvinyl alcohol.
S4, preparing a composite bracket: spraying the adhesive microspheres in the step S3 on the surface of the main support in the step S2, and drying to obtain a composite support;
specifically, the drying mode is cold air drying or freeze drying; the temperature of the cold air drying is 2-12 ℃; the pre-freezing temperature of freeze drying is-60 ℃ to-18 ℃ for 4-48 hours, the freezing temperature is-60 ℃ to-2 ℃ and the pre-freezing time is 24-96 hours.
S5, performing S5; and (3) carrying out vacuum dry-heat crosslinking or ultraviolet crosslinking on the composite scaffold obtained in the step (S4) to obtain the absorbable biological isolation composite membrane material. Specifically, the temperature of vacuum dry-thermal crosslinking is 80-125 ℃ and the time is 18-48 h; the ultraviolet crosslinking temperature is 4-8 ℃, the wavelength is 254nm, and the time is 2-4 hours.
Example 1:
s1, taking bovine Achilles tendon to remove fascia, crushing by using a tissue masher, filtering, selecting tissues with diameters of 0-500 mu m, soaking for 24 hours by using 5% sodium chloride solution, and washing for 5 times;
s11, protease treatment: the ficin is selected to carry out enzymolysis treatment in a weak acid environment with the pH value of 5.5, and the mass ratio of the tissue to the protease is 1:0.02, the dosage ratio of tissue to enzymolysis liquid is 1g:20ml, treatment time 3h. After the end, washing with water for 3 times;
s12, virus inactivation: a 1.6M sodium hydroxide was mixed with 1.4M ammonium sulfate to form a salt solution to organize and salt solution at 1g: inactivating viruses in a proportion of 100ml, wherein the treatment time is 36 hours;
s13, after virus inactivation treatment is finished, washing the tissues with deionized water for 6 times to obtain a collagen solution with the mass fraction of 0.5%;
s2, spreading the collagen solution in a Teflon mold, wherein the thickness is 0.3mm, and placing the collagen solution in a cold air drying oven at the temperature of 5 ℃ for 24 hours;
s3, preparing an adhesive layer: the hydroxyethyl cellulose and sodium alginate, and the silk fibroin are dissolved into 10.0% solution at 80 ℃, and the mass ratio of the hydroxyethyl cellulose to the sodium alginate to the silk fibroin is 4:2:4, a step of; freezing for 24 hours, thawing and washing for 3 times by using deionized water to obtain adhesive layer microspheres, wherein the average size of the microspheres is 0.1 mu m;
s4, spraying the adhesive layer microsphere on the collagen film according to the ratio of 0.008g/cm 2 Spraying, and continuously carrying out cold air drying at the temperature of 2 ℃ for 6 hours;
s5, carrying out ultraviolet crosslinking on the composite bracket after cold air drying, wherein the crosslinking temperature is 4-8 ℃, the wavelength is 254nm, and the time is 4 hours; the collagen composite membrane sample is subjected to irradiation sterilization to obtain an absorbable biological isolation composite membrane material;
example 1 the test conditions were as follows:
the dry tensile strength is 57.4Mpa by using an electronic tensile machine;
after soaking in physiological saline for 1min, the wet strength of the steel is measured to be 14.6Mpa;
using a bursting force test model, a bursting collagen membrane center was measured with an average test force value of 11.3N, sufficient to withstand intracranial, vascular, and other visceral pressures;
the wet elongation at break is 21.6%, and the flexibility is good;
3cm multiplied by 4cm samples are used for testing the water resistance, the samples are soaked in purified water for 18-24 hours, at the end of the time, the samples are taken out of the beaker, the liquid left on the surface of the membrane is sucked by filter paper, and after standing for 2h at room temperature, the samples are observed, and the conditions of wrinkling, bubbling, falling off, obvious swelling and the like are avoided;
cutting the sample into 2X 3cm, attaching the sample to the wall of a wet beaker, slightly applying vertical external force to enable the sample to adhere, continuously adding water until the sample completely falls out, and shaking the beaker for 6-8 every 30 minutes in the early stage, wherein the continuous bonding time of the sample is 75+/-2 hours, which indicates that the bonding microsphere can still maintain good water resistance in enough water without displacement.
And (3) preparing Phosphate Buffer Solution (PBS), adding protease XIV with the concentration of 0.5mg/mL, placing 6 groups of pure collagen scaffolds into the buffer solution, simultaneously placing 6 groups of composite collagen films containing the adhesive layer microspheres into the solution with the same concentration, carrying out enzymolysis observation in an environment with consistent temperature and humidity, and drying and weighing every 12 hours. The final pure collagen scaffold lost 50% weight at 52 hours and degraded completely on average at 71 hours; the microsphere sets containing the adhesive layer averaged 129 hours and were completely degraded. The degradation period of the adhesive microsphere is longer than that of collagen, and the adhesive microsphere can be better suitable for repairing human body autologous tissues.
Example 2:
s1, taking bovine Achilles tendon to remove fascia, crushing by using a tissue masher, filtering, selecting tissues with diameters of 0-500 mu m, soaking for 18 hours by using a 3% sodium chloride solution, and washing for 5 times;
s11, protease treatment: the ficin is subjected to enzymolysis treatment in a weak acid environment with the pH of 6.0, and the mass ratio of the tissue to the protease is 1:0.15, the dosage ratio of tissue to enzymolysis liquid is 1g:40ml, treatment time 4h. After the end, washing with water for 3 times;
s12, virus inactivation: a 1.2M sodium hydroxide was mixed with 1.4M potassium nitrate to form a salt solution to organize and salt solution at 1g: inactivating the virus in a proportion of 45ml for 48 hours;
s13, after virus inactivation treatment is finished, washing the tissues with deionized water for 5 times to obtain a collagen solution with the mass fraction of 3.5%;
s2, spreading the collagen solution in a Teflon mold, wherein the thickness is 5mm, and placing the collagen solution in a cold air drying oven at the temperature of 5 ℃ for 24 hours;
s3, preparing an adhesive layer: the hydroxyethyl cellulose and polylactic acid are dissolved into 25.0% solution at 70 ℃, and the mass ratio of the hydroxyethyl cellulose to the polylactic acid to the silk fibroin is 3:4:4. freezing for 18h, thawing and washing with deionized water for 3 times to obtain microspheres with an adhesive layer, wherein the average size is 1.5 mu m;
s4, spraying the adhesive layer microsphere on the collagen film according to the ratio of 0.01g/cm 2 Spraying, and continuously carrying out cold air drying at the temperature of 2 ℃ for 8 hours;
s5, carrying out ultraviolet crosslinking on the composite bracket after cold air drying, wherein the crosslinking temperature is 4-8 ℃, the wavelength is 254nm, and the time is 2 hours; the collagen composite membrane sample is subjected to irradiation sterilization to obtain an absorbable biological isolation composite membrane material;
example 2 the test conditions were as follows:
the dry tensile strength is 66.5Mpa by using an electronic tensile machine;
after soaking in physiological saline for 1min, the wet strength of the material is 15.8Mpa;
using a bursting force test model, measuring the center of the bursting collagen membrane, wherein the average testing force value is 12.9N, and the bursting force test model is also enough to resist the pressure of intracranial, vascular and other viscera;
the wet elongation at break is 20.9%, and the flexibility is good;
3cm multiplied by 4cm samples are used for testing the water resistance, the samples are soaked in purified water for 18-24 hours, at the end of the time, the samples are taken out of the beaker, the liquid left on the surface of the membrane is sucked by filter paper, and after standing for 2h at room temperature, the samples are observed, and the conditions of wrinkling, bubbling, falling off, obvious swelling and the like are avoided;
the sample was cut to 2X 3cm and attached to the wall of a wet beaker cup for a sample duration of 80.+ -.1 hours, indicating that the adhesive microspheres still maintained good water resistance in sufficient water without displacement.
Example 3:
s1, taking bovine achilles tendon to remove fascia, crushing by using a tissue triturator, filtering, selecting a tissue with the diameter of 0-500 mu m, soaking for 18h by using a 2% sodium chloride solution, washing for 3 times, soaking for 24h by using 75% alcohol, and washing for 3 times;
s11, protease treatment: the ficin is subjected to enzymolysis treatment in a weak acid environment with pH of 6.0, and the mass ratio of the tissue to the protease is 1:0.05, and the dosage ratio of the enzyme hydrolysis liquid is 1g:15ml, treatment time 2h. After the end, washing with water for 3 times;
s12, virus inactivation: a 1.6M potassium hydroxide was mixed with 1.5M sodium nitrate to form a salt solution to organize and salt solution at 1g: inactivating the virus in a proportion of 10ml, wherein the treatment time is 24 hours;
s13, after virus inactivation treatment is finished, washing the treated tissue with deionized water for 5 times to obtain a collagen solution with the mass fraction of 3%;
s2, spreading the collagen solution in a Teflon mold, wherein the thickness is 2.5mm, placing in a low-temperature refrigerator, and pre-freezing for 4 hours at the temperature of minus 60 ℃. Freeze-drying at-15deg.C for 60 hr;
s3, preparing an adhesive layer: the hydroxypropyl methylcellulose, the polyethylene glycol and the silk fibroin are dissolved into a 1.0% solution at 60 ℃, and the mass ratio of the hydroxypropyl methylcellulose to the polyethylene glycol to the silk fibroin is 1:2:7. freezing for 18h, thawing and washing for 5 times by using deionized water to obtain adhesive layer microspheres, wherein the average size of the microspheres is 3 mu m;
s4, spraying the adhesive layer microsphere on the sponge bracket, spraying according to 0.006g/cm < 2 >, and continuing to freeze-dry at-60 ℃ for 4 hours;
s5, carrying out vacuum dry-heat crosslinking on the composite sponge, wherein the crosslinking temperature is 125 ℃ and the time is 24 hours; the double-layer sponge sample is subjected to irradiation sterilization to obtain an absorbable biological isolation composite membrane material;
example 3 the test conditions were as follows:
porosity test, with an average value of 69.2%;
the electronic tensile machine has the dry tensile strength of 7.93Mpa, the wet strength of 1.44Mpa, the bursting strength of 5.7N, the wet elongation at break of 45.9 percent and good flexibility;
cutting a sponge with the thickness of 7.5cm multiplied by 7.5cm to test leakage performance, spreading the sponge above a glassware by using a clamp, continuously adding 18-20 mL of purified water, and keeping no leakage in 30 min;
and cutting the sample into 2X 3cm, attaching the sample to the wall of a wet beaker, slightly adhering the sample by vertical external force, adding water until the sample completely falls out, and shaking the beaker for 6-8 hours every 30 minutes in the early stage, wherein the continuous bonding time of the sample is 56+/-2 hours, and the water resistance of the bonding layer is good.
Example 4:
s1, removing fascia from bovine achilles tendon, crushing by using a tissue triturator, filtering, selecting a tissue with the diameter of 0-500 mu m, soaking for 24 hours by using a 5% sodium chloride solution, and washing for 3 times;
s11, enzyme treatment: the pepsin is used for enzymolysis treatment in an acidic environment with the pH value of 2.5, and the mass ratio of the tissue to the protease is 1:0.2, the dosage ratio of tissue to enzymolysis liquid is 1g:50ml, treatment time 96h. After the end, washing with water for 3 times;
s12, virus inactivation: a 1.6M sodium hydroxide was mixed with 0.9M sodium phosphate to form a saline solution to organize and salt the solution at 1g: inactivating viruses in a proportion of 5ml, wherein the treatment time is 48 hours;
s13, after virus inactivation treatment is finished, washing the tissues with deionized water for 3 times to obtain a collagen solution with the mass fraction of 5%;
s2, spreading the collagen solution in a Teflon mold, wherein the thickness is 4.0mm, and placing the collagen solution in a low-temperature refrigerator, wherein the temperature is minus 40 ℃, and pre-freezing for 48 hours. Freeze-drying at-2deg.C for 48 hr;
s3, preparing an adhesive layer: the mussel protein, the polyvinyl alcohol and the polyethylene glycol are dissolved into a 5% solution at 60 ℃, and the mass ratio of the mussel protein to the polyvinyl alcohol to the polyethylene glycol is 4:0.2:0.8. freezing for 48 hours, thawing and washing for 5 times by using deionized water to obtain adhesive layer microspheres, wherein the average size of the adhesive layer microspheres is 5.0 mu m;
s4, spraying the adhesive layer microsphere on the sponge bracket according to the ratio of 0.006g/cm 2 Spraying, and freeze drying at-2deg.C for 24 hr;
s5, carrying out vacuum dry-heat crosslinking on the freeze-dried sponge, wherein the temperature is 105 ℃ and the time is 24 hours; the double-layer sponge sample is subjected to irradiation sterilization to obtain an absorbable biological isolation composite membrane material;
example 4 the test conditions were as follows:
porosity test, average value of 77.4%;
the electronic tensile machine has the dry tensile strength of 8.66Mpa, the wet strength of 1.09Mpa, the bursting strength value of 5.9N, the wet elongation at break of 44.7 percent, and good flexibility;
cutting a sponge with the thickness of 7.5cm multiplied by 7.5cm to test leakage performance, spreading the sponge above a glassware by using a clamp, continuously adding 18-20 mL of purified water, and keeping no leakage in 30 min;
and cutting the sample into 2X 3cm, attaching the sample to the wall of a wet beaker, slightly adhering the sample by vertical external force, adding water until the sample completely falls out, and shaking the beaker for 6-8 hours every 30 minutes in the early stage, wherein the continuous bonding time of the sample is 77+/-4 hours, and the water resistance of the bonding layer is good.
Example 5:
s1, taking bovine achilles tendon to remove fascia, crushing by using a tissue triturator, filtering, selecting a tissue with the diameter of 0-500 mu m, soaking for 18h by using a 2% sodium chloride solution, washing for 3 times, soaking for 24h by using 75% alcohol, and washing for 3 times;
s11, protease treatment: the ficin is subjected to enzymolysis treatment in a weak acid environment with pH of 6.0, and the mass ratio of the tissue to the protease is 1:0.1, the dosage ratio of the enzyme hydrolysis liquid is 1g:10ml, treatment time 3h. After the end, washing with water for 3 times;
s12, virus inactivation: a 1.6M potassium hydroxide was mixed with 1.5M potassium nitrate to form a salt solution to organize and salt solution at 1g: inactivating viruses in a proportion of 5ml, wherein the treatment time is 40 hours;
s13, after virus inactivation treatment is finished, washing the treated tissue with deionized water for 5 times to obtain a collagen solution with the mass fraction of 5%;
s2, spreading the collagen solution in a Teflon mold, wherein the thickness is 3mm, and placing the collagen solution in a low-temperature refrigerator, wherein the temperature is-18 ℃, and pre-freezing for 4 hours. Freeze-drying at-15deg.C for 60 hr;
s3, preparing an adhesive layer: carboxymethyl cellulose, polylactic acid and silk fibroin are dissolved into 5.0% solution at 60 ℃, and the mass ratio of the carboxymethyl cellulose to the polylactic acid to the silk fibroin is 1.5:2.5:6. freezing for 18h, thawing and washing for 5 times by using deionized water to obtain adhesive layer microspheres with average size of 2.5 mu m;
s4, spraying the adhesive layer microsphere on the sponge bracket according to the ratio of 0.01g/cm 2 Spraying, and freeze drying at-2deg.C for 15 hr;
s5, carrying out vacuum dry-heat crosslinking on the composite sponge, wherein the crosslinking temperature is 110 ℃ and the time is 18 hours; the double-layer sponge sample is subjected to irradiation sterilization to obtain an absorbable biological isolation composite membrane material;
example 5 the test cases were carried out,
porosity test, average value of 70.6%;
the dry tensile strength of the electronic tensile machine is 7.81Mpa, the wet strength of the electronic tensile machine is 1.20Mpa, the bursting strength of the electronic tensile machine is 4.9N, and the wet breaking elongation of the electronic tensile machine is 39.3%;
has good flexibility. Cutting a sponge with the thickness of 7.5cm multiplied by 7.5cm to test leakage performance, spreading the sponge above a glassware by using a clamp, continuously adding 18-20 mL of purified water, and keeping no leakage in 30 min;
and cutting the sample into 2X 3cm, attaching the sample to the wall of a wet beaker, slightly adhering the sample by vertical external force, adding water until the sample completely falls out, and shaking the beaker for 6-8 hours every 30 minutes in the early stage, wherein the continuous bonding time of the sample is 75+/-3 hours, and the water resistance of the bonding layer is good.
Example 6:
s1, taking bovine Achilles tendon to remove fascia, crushing by using a tissue triturator, filtering, selecting tissues with diameters of 0-500 mu m, soaking for 24 hours by using a 2% sodium chloride solution, and washing for 3 times. Soaking in 75% alcohol for 18h, washing with water, and performing the next step;
s11, protease treatment: the ficin is used for enzymolysis treatment in a weak acid environment with the pH value of 5.5, and the mass ratio of the tissue to the protease is 1:0.03, the dosage ratio of tissue to enzymolysis liquid is 1g:12ml, treatment time 4h. After the end, washing with water for 3 times;
s12, virus inactivation: a 1.6M sodium hydroxide was mixed with 1.4M sodium sulfate to form a salt solution to organize and salt solution at 1g: inactivating viruses in a proportion of 8ml, wherein the treatment time is 40 hours;
s13, after virus inactivation treatment is finished, washing the tissue with deionized water for 6-8 times to obtain a collagen solution with a mass fraction of 3.0%;
s2, spreading the collagen solution in a Teflon mold, wherein the thickness is 2.5mm, placing the collagen solution in a low-temperature refrigerator, pre-freezing for 6-8 hours at the temperature of-35 ℃, and freezing at the temperature of-10 ℃ for 60 hours;
s3, preparing an adhesive layer: silk fibroin, glycerol and polyethylene glycol are dissolved into a 6.5% solution, and the mass ratio of the silk fibroin to the glycerol to the polyethylene glycol is 3:1:1. freezing for 18h, thawing, and cleaning for 3-5 times by using deionized water to obtain adhesive layer microspheres with average size of 1.5 mu m;
s4, spraying the adhesive layer microsphere on the sponge supportOn a shelf, according to 0.01g/cm 2 Spraying, and freeze drying at-2deg.C for 5 hr;
s5, carrying out vacuum dry-heat crosslinking on the freeze-dried sponge, wherein the temperature is 80 ℃ and the time is 48 hours; the double-layer sponge sample is subjected to irradiation sterilization to obtain an absorbable biological isolation composite membrane material;
example 6 the test conditions were as follows:
the average value of the porous material is 73.9% after the porosity test;
the electronic tensile machine tests that the dry tensile strength is 8.12Mpa, the wet strength is 1.46Mpa, the bursting strength is 5.2N, and the wet breaking elongation is 43.0%;
cutting a sponge with the thickness of 7.5cm multiplied by 7.5cm to test leakage performance, spreading the sponge above a glassware by using a clamp, continuously adding 18-20 mL of purified water, and keeping no leakage in 30 min;
and cutting the sample into 2X 3cm, attaching the sample to the wall of a wet beaker, slightly adhering the sample by vertical external force, adding water until the sample completely falls out, and shaking the beaker for 6-8 hours every 30 minutes in the early stage, wherein the continuous bonding time of the sample is 87+/-3 hours, and the water resistance of the bonding layer is good.
The main test item parameters in the 6 examples described above are collated in Table 1 below.
TABLE 1
Comparative example 1:
the bovine achilles tendon material in example 6 was changed to pigskin:
s1, removing surface hair from pigskin, cutting into small pieces, crushing by using a tissue triturator, filtering, selecting tissues with diameters of 0-500 mu m, soaking for 24 hours by using 2% sodium chloride solution, and washing for 3 times. Soaking in 75% alcohol for 18h, washing with water for 3 times, and performing the next step.
S11, enzyme treatment: the ficin is used for enzymolysis treatment in a weak acid environment with the pH value of 5.5, and the mass ratio of the tissue to the protease is 1:0.03, the mass ratio of the tissue to the enzymolysis liquid is 1g:12ml, treatment time 4h. After the end, washing with water for 3 times;
s12, virus inactivation: a 1.6M sodium hydroxide was mixed with 1.4M sodium sulfate to form a salt solution to organize and salt solution at 1g: inactivating viruses in a proportion of 8ml, wherein the treatment time is 40 hours;
s13, after virus inactivation treatment is finished, washing the tissue with deionized water for 6-8 times to obtain a collagen solution with a mass fraction of 3.0%;
s2, spreading the collagen solution in a Teflon mold, wherein the thickness is 2.5mm, placing the collagen solution in a low-temperature refrigerator, pre-freezing for 6-8 hours at the temperature of-35 ℃, and freezing at the temperature of-10 ℃ for 60 hours;
s3, preparation of an adhesive layer: silk fibroin, glycerol and polyethylene glycol are dissolved into a 6.5% solution, and the mass ratio of the silk fibroin to the glycerol to the polyethylene glycol is 3:1:1. freezing for 18h, thawing, and cleaning for 3-5 times by using deionized water to obtain adhesive layer microspheres with average size of 1.5 mu m;
s4, spraying the adhesive layer microsphere on the sponge bracket according to the ratio of 0.01g/cm 2 Spraying, and freeze drying at-2deg.C for 5 hr;
s5, carrying out vacuum dry-heat crosslinking on the freeze-dried sponge, wherein the temperature is 80 ℃ and the time is 48 hours; the double-layer sponge sample is subjected to irradiation sterilization to obtain an absorbable biological isolation composite membrane material;
comparative example 1 the test conditions were as follows:
the average value of the porous material is 54.9% after the porosity test;
the electronic tensile machine tests that the dry tensile strength is 5.51Mpa, the wet strength is 0.72Mpa, the bursting strength is 3.1N, and the wet breaking elongation is 32.1%;
cutting a sponge with the thickness of 7.5cm multiplied by 7.5cm to test leakage performance, spreading the sponge above a glassware by using a clamp, continuously adding 18-20 mL of purified water, and weighing water with the water content of 2.73g when leakage occurs within 30 min;
cutting a sample into 2X 3cm, attaching the sample to the wall of a wet beaker, slightly applying vertical external force to enable the sample to adhere, adding water until the sample completely falls out, and shaking the beaker for 6-8 hours every 30 minutes in the early stage, wherein the continuous bonding time of the sample is 73+/-3 hours;
after the bovine Achilles tendon is replaced by pigskin, the performance pairs are as shown in figure 2: the collagen content in the pigskin is not as rich as that of the bovine achilles tendon, the components are relatively miscellaneous, the extracted collagen is less I-type collagen, the fiber length is generally shorter, so that the mechanical properties of a collagen finished product such as dry tensile strength, wet tensile strength, bursting strength and the like are lower than those of a sample prepared by using the bovine achilles tendon, meanwhile, the collagen fiber is shorter, the vacuum dry-heat crosslinking under the same condition is caused, the condensation polymerization reaction degree of carboxyl and primary amine side groups is different, the branched chain crosslinking is low, the product leakage resistance is poor, and the leakage condition occurs.
Comparative example 2:
changing the adhesive layer of example 1, step S3, to a medical pressure-sensitive adhesive;
s1, removing fascia from bovine achilles tendon, crushing by using a tissue masher, filtering, selecting a tissue with the diameter of 0-500 mu m, soaking for 24 hours by using a 5% sodium chloride solution, and washing for 5 times;
s11, enzyme treatment: the ficin is subjected to enzymolysis treatment in a weak acid environment with the pH of 5.5, and the mass ratio of the tissue to the protease is 1:0.02, the dosage ratio of tissue to enzymolysis liquid is 1g:20ml, treatment time 3h. After the end, water was washed 3 times.
S12, virus inactivation: a 1.6M sodium hydroxide was mixed with 1.4M ammonium sulfate to form a salt solution to organize and salt solution at 1g: the virus inactivation was performed at a rate of 100ml for 36h.
And S13, after the virus inactivation treatment is finished, washing the tissues with deionized water for 6 times to obtain a collagen solution with the mass fraction of 0.5%.
S2, spreading the collagen solution in a Teflon mold, wherein the thickness is 0.3mm, and placing the collagen solution in a cold air drying oven, wherein the temperature is 5 ℃ and the time is 24 hours.
S3, preparing an adhesive layer: after dissolving the medical pressure-sensitive adhesive, an adhesive layer with the concentration of 5.0% is prepared.
S4, spraying the adhesive layer on the collagen film according to the ratio of 0.008g/cm 2 Spraying, and continuously carrying out cold air drying at the temperature of 2 ℃ for 6 hours;
s5, carrying out ultraviolet crosslinking on the composite bracket after cold air drying, wherein the crosslinking temperature is 4-8 ℃, the wavelength is 254nm, and the time is 4 hours; the collagen composite membrane sample is subjected to irradiation sterilization to obtain an absorbable biological isolation composite membrane material;
comparative example 2 the test conditions were as follows:
the dry tensile strength is only 37.1Mpa by using an electronic tensile machine;
after soaking in physiological saline for 1min, the wet strength of the material is measured to be reduced to 9.2Mpa;
using a bursting force test model to measure the center of the bursting collagen membrane, wherein the average testing force value is 4.3N;
elongation at break in wet state 18.4%;
3cm multiplied by 4cm samples are used for testing the water resistance, the samples are soaked in purified water for 18-24 hours, at the end of the time, the samples are taken out from the beaker, the liquid left on the surface of the membrane is sucked by filter paper, the surface adhesive has the phenomena of foaming, falling and the like after standing for 2h at room temperature;
and cutting the sample into 2X 3cm, attaching the sample to the wall of a wet beaker, slightly adhering the sample by vertical external force, continuously adding water until the sample completely falls out, and shaking the beaker for 6-8 hours every 30 minutes in the early stage, wherein the sample falls off after lasting for about 3 hours, and has poor water resistance.
From the test cases of the comparative example 2 and the example 1, the cellulose and protein adhesive is adopted, so that the adhesive has excellent viscosity and water resistance, and the probability of infirm adhesion and displacement of materials and human tissues can be effectively reduced in the using process, thereby achieving the purpose of shortening the operation time.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (9)
1. The preparation method of the absorbable biological isolation composite membrane material is characterized by comprising the following steps of:
s1, collagen preparation: taking bovine Achilles tendon tissue, and carrying out protease treatment and virus inactivation procedures to obtain a collagen solution with the mass fraction of 0.5% -5%;
s2, preparing a main support: spreading the collagen solution obtained in the step S1 in a mould, and drying to obtain a main bracket;
s3, preparation of an adhesive layer: mixing the waterproof bonding material with water to obtain a bonding layer solution with the concentration of 1% -25%; after freezing treatment, cleaning the adhesive layer solution to obtain adhesive microspheres with diameters of 0.1-5 mu m; in the step S3, the waterproof bonding substance is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, silk fibroin, mussel protein, glycerol, polylactic acid, polyethylene glycol and polyvinyl alcohol;
s4, preparing a composite bracket: spraying the adhesive microspheres in the step S3 on the surface of the main support in the step S2, and drying to obtain a composite support;
s5, performing S5; and (3) carrying out vacuum dry-heat crosslinking or ultraviolet crosslinking on the composite scaffold obtained in the step (S4) to obtain the absorbable biological isolation composite membrane material.
2. The method for preparing the absorbable biological isolating composite membrane material as claimed in claim 1, wherein the method comprises the following steps: the protease in the step S1 is pepsin or ficin.
3. The method for preparing the absorbable biological isolating composite membrane material as claimed in claim 1, wherein the method comprises the following steps: in the step S1, the ratio of the protease to the bovine Achilles tendon tissue is 1:0.01-1:0.2, and the enzymolysis time is 2-96 h.
4. The method for preparing the absorbable biological isolating composite membrane material as claimed in claim 1, wherein the method comprises the following steps: the virus inactivation step in step S1 specifically comprises: bovine Achilles tendon tissue and 0.5% -30% saline solution are mixed according to 1g:5ml to 1g: mixing in a proportion of 100ml, wherein the treatment time is 24-48 hours; the salt solution is one or more of ammonium sulfate, sodium sulfate, potassium hydroxide, sodium nitrate, potassium nitrate and sodium phosphate.
5. The method for preparing the absorbable biological isolating composite membrane material as claimed in claim 1, wherein the method comprises the following steps: and in the step S2, the collagen solution is paved in a die to be 0.3 mm-5 mm thick.
6. The method for preparing the absorbable biological isolating composite membrane material as claimed in claim 1, wherein the method comprises the following steps: the drying mode in the step S2 is cold air drying or freeze drying; the temperature of the cold air drying is 2-12 ℃; the pre-freezing temperature of freeze drying is-60 ℃ to-18 ℃ for 4-48 hours, the freezing temperature is-60 ℃ to-2 ℃ and the pre-freezing time is 24-96 hours.
7. The method for preparing the absorbable biological isolating composite membrane material as claimed in claim 1, wherein the method comprises the following steps: the drying mode in the step S4 is cold air drying or freeze drying; the temperature of the cold air drying is 2-12 ℃; the pre-freezing temperature of freeze drying is-60 ℃ to-18 ℃ for 4-48 hours, the freezing temperature is-60 ℃ to-2 ℃ and the pre-freezing time is 24-96 hours.
8. The method for preparing the absorbable biological isolating composite membrane material as claimed in claim 1, wherein the method comprises the following steps: in the step S5, the temperature of vacuum dry-heat crosslinking is 80-125 ℃ and the time is 18-48 h; the ultraviolet crosslinking temperature is 4-8 ℃, the wavelength is 254nm, and the time is 2-4 hours.
9. An absorbable biological isolating composite membrane material, which is characterized in that: the biological isolation composite membrane material is prepared by adopting the preparation method of the absorbable biological isolation composite membrane material as claimed in any one of claims 1-8.
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