CN103405811A - Anti-adhesion biological membrane and preparation method thereof - Google Patents
Anti-adhesion biological membrane and preparation method thereof Download PDFInfo
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Images
Abstract
The invention provides an anti-adhesion biological membrane and a preparation method thereof. The anti-adhesion biological membrane is a dry membrane which is formed by SIS (styrene isoprene styrene block copolymer) as a support material, compound hyaluronic acid, functional proteins and anti-inflammotary medicines. The anti-adhesion biological membrane is semi-transparent from light white to faint yellow. The thickness of the anti-adhesion biological membrane is 0.01-0.5mm. Compared with the prior art, the anti-adhesion biological membrane has very good biocompatibility, good physical barrier anti-adhesion effect and the effects of resisting inflammatory, stopping bleeding and promoting fiber degradation. The effects of the anti-adhesion biological membrane are obviously superior to those of existing anti-adhesion biological membrane products. Animal experiments prove that the effective rate of the anti-adhesion biological membrane prepared by the method for preventing the adhesion after abdominal surgery reaches above 90%, the effective rate for preventing the adhesion after pelvic cavity surgery reaches above 80%, and the effective rate for preventing the adhesion after tendon surgery reaches above 70%.
Description
Technical field
The invention belongs to tissue engineering biomaterial for medical purpose technical field, be specifically related to a kind of anti blocking biomembrane and preparation method thereof.
Background technology
Tissue adhesion is a kind of common postoperative complication, common patient more than 90% phenomenon that all can stick together after the surgery operation on tendon, after the abdomen operation on pelvis, almost there is the patient more than 70% that adhesion complication in various degree occurs, adhesion may cause the forfeiture of postoperative normal physiological function, cause intestinal obstruction, chronic abdominal pain, chronic pelvic pain and serious ill symptoms, the even threat to life such as infertile.
The material that is applied at present anti research has many, and the collagen extracted as polylactic acid, hyaluronic acid, cellulose, chitosan, silica gel, resin and tendon etc., expect that they can provide temporary physical barriers for the healing of tissue.Above-mentioned material is applied after adopting the method for high-voltage electrostatic spinning technology, Freeze Drying Technique or cross-linked polymeric to be prepared into membranaceous or gel, during the raw materials such as employing polylactic acid, silica gel and resin, normally in solution, add plasticizer, antiseptic and antioxidant etc. and carry out polyreaction, these compositions may bring potential harm to human body; Anti blocking biomembrane prepared as raw material by the collagen that hyaluronic acid, cellulose, chitosan and tendon extract of take, its preventing adhesiving effect not yet reaches clinical approval.It is reported, the Seprafilm hyaluronic acid membrane that domestic and international widely used U.S. Genzyme Corp. (Genzyme Biosurgery) produces, in order to prevent tissue adhesion, its result shows efficiency and only is 47%(Qiqiang Zeng, et, al. World J Surg (2007) 31:2125 – 2131), this product is to be formed by single natural polysaccharide Polymer materialspreparation, can only play preliminary physical barriers effect, can't reach inflammation-inhibiting, suppress fibrosis, promote the effect of healing.
Summary of the invention
Defect for prior art, the purpose of this invention is to provide a kind of anti blocking biomembrane and preparation method thereof, this biomembrane can temporary alternative damaged tissues film, suppress post-operation inflammatory and fibrosis, prevent the tissue adhesion of operative site, have good biocompatibility, without rejection, easy for operation.
Anti blocking biomembrane proposed by the invention, it is characterized in that, to take off trees-Osima jacoti, Osima excavata substrate (the small intestinal submucosa that cell removes antigen, be called for short SIS) be timbering material, composite transparent matter acid, functional protein and anti-inflammatory medicaments and the dry film that forms, dry film is shallow white to faint yellow translucent, and thickness is 0.01～0.5mm.
The preparation method of the anti blocking biomembrane that the present invention proposes, be to take SIS to be timbering material, adopts that sterilization, de-cell remove antigen, composite transparent matter is sour, sterilizing and modification; Concrete steps comprise:
Step 1, disinfect: lamellar SIS is cleaned to without dirt by purified water, and the aqueous slkali that is placed in concentration and is 0.5～5 mol/L soaked 0.5～2.5 hour, then by purified water, cleaned the neutrality to pH; Described aqueous slkali is any of sodium hydroxide solution or potassium hydroxide solution or aqua calcis;
Aqueous slkali has good inactivation of virus and the ability of kill bacteria, guarantees that in the SIS raw material, the load of microorganisms such as virus and antibacterial is reduced to acceptable level, is conducive to follow-up operation; Simultaneously can dissolve water-solubility protein in SIS, retain the three-dimensional rack structure of SIS collagen.
Step 2, de-cell go antigen to process: it is that the trypsin solution of 1～5 mg/mL soaked 0.5～4 hour that the SIS after disinfecting is placed in concentration, after by purified water, cleaning again, be placed in the enzyme liquid that contains 10～25 U/mL concentration DNA hydrolytic enzyme and 30～40 U/mL concentration alpha-galactosidases and soaked 0.5～4 hour, finally by purified water, clean;
Adopt trypsin treatment can the heterogenous cell in SIS be digested, and can carry out appropriateness digestion to SIS collagen scaffold structure, make it more be conducive to fast degradation in vivo; Simultaneously, adopted enzyme liquid to process to reduce to greatest extent the content of the residual and alpha-galactoside of DNA in SIS, thereby guaranteed that resulting SIS has good biocompatibility and extremely low immunogenicity.
Step 3, the acid of composite transparent matter: the SIS cutting on demand after step 2 is processed, the hyaluronic acid solution that is placed in concentration and is 5～20 mg/mL soaked 0.5～2 hour, took out the final vacuum lyophilizing and obtained being compounded with hyaluronic SIS diaphragm;
At the standby one-tenth of SIS composite transparent matter processed with acid diaphragm, can effectively improve the water absorbing capacity of SIS diaphragm, hyaluronic acid can be pasted to rapidly moistening operative site when being applied to clinical operation, avoid the displacement that comes off of anti blocking biomembrane, effective flap coverage, bring into play the effect of anti blocking biomembrane for a long time.
Step 4, sterilization treatment: after being compounded with hyaluronic SIS diaphragm packing, adopt irradiation sterilization, irradiation dose is the gamma ray of 15～40kGy;
The employing radiated by gamma-ray is sterilizing, both guaranteed that the SIS membrane products reached aseptic level, also can cause the support of SIS diaphragm internal structure appropriateness to destroy, to control its degradation rate in vivo, make it before degraded, bring into play good physical barriers effect, avoid too fastly can't effectively bringing into play the anti effect because degrading, or caused slowly multiple complications to occur owing to degrading.
Step 5, modification: the aseptic SIS diaphragm that will obtain was soaked in aseptic modified solution after 10～60 seconds under room temperature, took out and dried under gnotobasis, and aseptic packaging, obtain anti blocking biomembrane, described aseptic modified solution is to contain in normal saline solution: the TGF-beta antagonists (as decorin) of 0.05～0.2 μ g/mL, 5000～25000AXaICU/mL(is equivalent to have in every milliliter of heparin solution the activity of 5000～25000IU anticoagulin Xa) low molecular weight heparin, 0.1 the nonsteroidal anti-inflammatory disease drug of the plasminogen activator of～0.5 mg/mL and 0.1～1 mg/mL is (as aspirin, acetaminophen, indomethacin, naproxen, Nabumetone, diclofenac, ibuprofen, nimesulide, any of rofecoxib or celecoxib).
This step is carried out modification to the SIS diaphragm, interpolation can suppress functional protein such as TGF-beta antagonists and the plasminogen activator etc. that fibrosis forms, and add can inflammation-inhibiting, reduce hemorrhage anti medicine (as low molecular weight heparin, nonsteroidal anti-inflammatory disease drug etc.), make to be compounded with hyaluronic SIS diaphragm and can be used as physiologic barrier and reduce as far as possible damaged tissues is subject in the healing regenerative process traumatic infection impact and disturb, thereby play the effect that promotes the damaged tissues healing.The final mode of drying that adopts of this step prepares anti blocking biomembrane, and the diaphragm structure that can effectively avoid vacuum drying to cause is loose, produce a large amount of pore structures and affect the effect of biomembrane anti.
Anti blocking biomembrane prepared by the present invention, thin film for thickness 0.01～0.5mm, main component is SIS, hyaluronic acid, functional protein and anti-inflammatory medicaments, wherein SIS can be effectively as compound other compositions of three-dimensional rack, maintain membranaceous physical aspect, keep the basic boom of physical barriers in the anti blocking biomembrane body; What hyaluronic acid can effectively absorb operative site organizes sepage and hemorrhage, while making anti blocking biomembrane stick to surgical wound surface, can be rapidly semisolid semigel state thin film, difficult drop-off; Functional protein in anti blocking biomembrane and anti-inflammatory medicaments can effectively play inflammation-inhibiting, promote the effect of fiber degradation.Anti blocking biomembrane prepared by the present invention, be applicable to prevent the operative site tissue adhesion after all kinds of operations such as abdominal cavity, pelvic cavity, nerve, orthopaedics, otorhinolaryngology, has fabulous preventing adhesiving effect.
Compared with prior art, the biocompatibility of anti blocking biomembrane of the present invention is fabulous, the good physical barrier anti effect that had both had at present existing anti blocking biomembrane, has again the anti-inflammatory effect that contains anti-inflammatory factor type anti blocking biomembrane (as bioamnion), also have the effect of the unexistent hemostasis of prior art, promotion fiber degradation, its successful is better than existing all kinds of anti blocking biomembrane product.Adopt the zoopery of rat abdominal cavity anti to prove the present invention, the effective percentage that prepared anti blocking biomembrane prevention Postoperative Adhesion of Abdominal Cavity Surgery occurs reaches more than 90%, the effective percentage that prevention pelvic cavity tissue adhesion occurs reaches more than 80%, and the effective percentage that prevention operation on tendon tissue adhesion occurs reaches more than 70%.
Below by Analysis on Mechanism, the beneficial effect of technical solution of the present invention is described.
(1) due to preparation method of the present invention, effectively retained the three-dimensional collagen scaffold structure of SIS, and digested by appropriateness the degradation rate of controlling SIS with appropriate radiation treatment, make to bring into play effective physical barriers effect before the anti blocking biomembrane degradation in vivo; Its degradable absorption in vivo, avoided the complication such as foreign body reaction that the non-degradable material causes in vivo, long-term chronic inflammation.
(2) due to the inventive method in the acid of SIS diaphragm composite transparent matter, utilized hyaluronic acid to absorb the strong characteristic of moisture ability, make anti blocking biomembrane when the operation application, can effectively be attached at rapidly various surgical wound surfaces, play the effect that physics sticks hemostasis, easy to use, simple to operate, avoided the not good problem of the preventing adhesiving effect caused because coming off.
(3) anti blocking biomembrane of the present invention is when degraded, can disengage several functions albumen and anti-inflammatory medicaments, for damaged tissues regeneration provides the good hemorrhage physiological environment of inhibition fibrosis, inflammation-inhibiting, reduction, thereby has the effect that promotes healing, before damaged part regeneration, can be used as good tissue film's substitute, prevent that effectively adhesion from occurring.
(4) because the present invention adopts aqueous slkali to take off cell, process, be easy to clean and remove, and do not adopt the organic chemical reagents such as any additive, cross-linking agent, fixative, can not cause the residual of harmful reagent, avoided toxicity or the immunoreation that may cause.
(5) because adopting aseptic modification liquid, the present invention processes, in the time of can avoiding sterilizing on the impact of all kinds of activated proteins, anti-inflammatory medicaments activity, at utmost bring into play the inhibition fibrosis of anti blocking biomembrane, the action effect of inflammation-inhibiting, guarantee the anti of anti blocking biomembrane, the ability of promotion healing.
(6) because the present invention adopts, dry processing, to have avoided the short texture that vacuum lyophilization causes diaphragm, the shortcoming that produces pore structure, can effectively keep anti blocking biomembrane without the aperture structure characteristics, to keep good physical barriers function.
The accompanying drawing explanation
Histological section's coloration result photo of SIS diaphragm prepared for the present invention by accompanying drawing 1 can find out that the main component of SIS is collagen, and the SIS diaphragm maintains good three-dimensional rack structure, is conducive to follow-up modification.
Anti blocking biomembrane prepared for the present invention by accompanying drawing 2 is applied to the effect photo of wound surface after 5 seconds, can obviously see, anti blocking biomembrane absorbs rapidly moisture and effectively is attached at wound surface, in 30～60 seconds, can be organized sepage and soak into fully, is difficult for coming off with separate tissue.
Accompanying drawing 3 carries out animal effectiveness experimental result photo for the anti blocking biomembrane that adopts the present invention to prepare; Wherein A, for anti blocking biomembrane being wrapped up to the photo as a result in 2 weeks after injury of liver, can obviously find out, liver parcel place and intraperitoneal intestinal and internal organs do not stick together, and the liver degree of freedom is good, and the parcel place has the part material to remain; B is for wrapping up anti blocking biomembrane in the photo as a result in 4 weeks after Intestine in Rabbits, and small intestinal is not with intestinal and internal organs stick together on every side; C is for wrapping up anti blocking biomembrane in the photo as a result after 8 weeks of rabbit heel string suture site, and tendon and surrounding tissue do not stick together, and healing process of tendons is all right; D is for adopting the as a result photo of anti blocking biomembrane parcel rat sciatic nerve after 8 weeks, and neural healing position does not stick together with muscular tissue on every side, and neural healing state is good.
The specific embodiment
The specific embodiment and effect below in conjunction with example explanation technical solution of the present invention.In example, trees-Osima jacoti, Osima excavata derives from the Surgisis product that Cook Medical company produces; Decorin is purchased from Sino Biological, product article No. 10189-H08H; Low molecular weight heparin is purchased from the Shandong pharmacy, the accurate word H20000095 of traditional Chinese medicines; Plasminogen activator is purchased to German Boehringer Ingelheim Pharma GmbH & Co. KG, registration certificate S20110051.
Embodiment 1,
Step 1, disinfect: the lamellar SIS that will remove mucous layer, lymph node cleans to without dirt by purified water, and the sodium hydrate aqueous solution that is placed in concentration and is 0.5mol/L soaks half an hour, then by purified water, cleans the neutrality to pH;
Step 2, de-cell go antigen to process: it is that the trypsin solution of 1 mg/mL soaks half an hour that the SIS after disinfecting is placed in concentration, after by purified water, cleaning again, the enzyme liquid that is placed in the alpha-galactosidase of the DNA hydrolytic enzyme that contains 25 U/mL and 40 U/mL soaked 4 hours, finally by purified water, cleaned 10 times;
Step 3, the acid of composite transparent matter: the SIS after step 2 is processed is cut to 3 * 4cm, and the hyaluronic acid solution that is placed in concentration and is 20 mg/mL soaked 2 hours, took out the final vacuum lyophilizing and obtained being compounded with hyaluronic SIS diaphragm;
Step 4, sterilization treatment: adopt the radiated by gamma-ray of 15kGy sterilizing after being compounded with hyaluronic SIS diaphragm packing;
Step 5, modification: the aseptic SIS diaphragm that will obtain at room temperature was soaked in aseptic modified solution after 1 minute, took out and dried under gnotobasis, and aseptic packaging, obtain anti blocking biomembrane; Described aseptic modified solution is to contain in normal saline solution: the decorin of 0.05 μ g/mL, the low molecular weight heparin of 5000AXaICU/mL, the aspirin of the plasminogen activator of 0.1mg/mL and 0.1 mg/mL.
The prepared anti blocking biomembrane of this example adopts slighter alkali treatment, the hyaluronic acid composite concentration is higher, the diaphragm obtained thicker (0.2～0.5mm), and sterilizing dose is lower, make this diaphragm degraded slower, be applicable to need the positions such as tendon, nerve of long period isolation, can play the effect of prevention of postoperative adhesion.Referring to C and D in accompanying drawing 3, this anti blocking biomembrane is applied to tendon, nerve suture position, can play good physical isolation effect, inflammation-inhibiting effectively, postoperative 8 all tendons are good with neural healing, tendon or neural necrosis do not occur, rupture, occur without any adhesion with surrounding tissue.
Embodiment 2,
Step 1, disinfect: the lamellar SIS that will remove mucous layer, lymph node cleans to without dirt by purified water, and the sodium hydrate aqueous solution that is placed in concentration and is 3 mol/L soaked 2.5 hours, then by purified water, cleaned the neutrality to pH;
Step 2, de-cell go antigen to process: it is that the 1mg/mL trypsin solution soaks half an hour that the SIS after disinfecting is placed in concentration, by purified water, clean in the enzyme liquid of the alpha-galactosidase be placed on the DNA hydrolytic enzyme that contains 10U/mL and 30U/mL and soak half an hour again, finally by purified water, clean 5 times;
Step 3, the acid of composite transparent matter: the SIS after step 2 is processed is cut to 4 * 6cm, and the hyaluronic acid solution that is placed in concentration and is 5 mg/mL soaks half an hour, takes out and obtains being compounded with hyaluronic SIS diaphragm by vacuum freeze-drying;
Step 4, sterilization treatment: after being compounded with hyaluronic SIS diaphragm packing, carry out irradiation sterilization, irradiation dose is the gamma ray of 25kGy;
Step 5, modification: the aseptic SIS diaphragm that will obtain at room temperature was soaked in aseptic modified solution after 10 seconds, took out and dried under gnotobasis, and aseptic packaging, obtain anti blocking biomembrane; Described aseptic modified solution is to contain in normal saline solution: the decorin of 0.2 μ g/mL, the low molecular weight heparin of 25000AXaICU/mL, the ibuprofen of the plasminogen activator of 0.5 mg/mL and 1 mg/mL.
Anti blocking biomembrane prepared by this example adopts stronger alkali treatment, the hyaluronic acid composite concentration is lower, the diaphragm obtained thinner (0.02～0.1mm), and sterilizing dose is higher, thereby make this diaphragm degraded very fast, the position such as abdominal cavity, pelvic cavity faster that is applicable to degrade, can play the effect of prevention of postoperative adhesion.Referring in accompanying drawing 3 shown in A and B, after this anti blocking biomembrane is applied to abdominal cavity liver, operation on intestine position, good physical isolation effect be can play, internal organs, intestinal adhesion effectively prevented, postoperative 2 all liver degree of freedom are good, and postoperative 4 all small intestinals are not with intestinal, internal organs stick together on every side.
Embodiment 3,
Step 1, disinfect: the lamellar SIS that will remove mucous layer, lymph node cleans to without dirt by purified water, and the potassium hydroxide aqueous solution that is placed in concentration and is 1 mol/L soaked 1 hour, then by purified water, cleaned the neutrality to pH;
Step 2, de-cell go antigen to process: it is that the 3mg/mL trypsin solution soaked 2 hours that the SIS after disinfecting is placed in concentration, by purified water, clean in the enzyme liquid of the alpha-galactosidase be placed on the DNA hydrolytic enzyme that contains 15U/mL and 35U/mL and soaked 2 hours again, finally by purified water, clean 7 times;
Step 3, the acid of composite transparent matter: the SIS after step 2 is processed is cut to 5 * 5cm, and the hyaluronic acid solution that is placed in concentration and is 10mg/mL soaked 1 hour, took out and obtained being compounded with hyaluronic SIS diaphragm by vacuum freeze-drying;
Step 4, sterilization treatment: after being compounded with hyaluronic SIS diaphragm packing, carry out irradiation sterilization, irradiation dose is the gamma ray of 20kGy;
Step 5, modification: the aseptic SIS diaphragm that will obtain was soaked in aseptic modified solution after 30 seconds, took out and dried under gnotobasis, and aseptic packaging, obtain anti blocking biomembrane; Described aseptic modified solution is to contain in normal saline solution: the decorin of 0.1 μ g/mL, the low molecular weight heparin of 10000AXaICU/mL, the acetaminophen of the plasminogen activator of 0.3 mg/mL and 0.5 mg/mL.
Anti blocking biomembrane prepared by this example, with alkali treatment, effectively remove cell component, adopt trypsin, DNA enzyme and alpha-galactosidase to process and can effectively remove the antigenic component that can cause immunologic rejection in SIS, while in zoopery, being applied to the operative site Film with Preventing Adhesion such as nerve, tendon, abdominal cavity, pelvic cavity, has good biocompatibility, rejection seldom appears, the surrounding tissue healing of anti blocking biomembrane application site is good, without oncogenicity, avirulence, body temperature is without abnormal rising, and the every physiological activity of animal is normal.
Embodiment 4,
Step 1, disinfect: will remove mucous layer, the lamellar SIS of lymph node cleans to without dirt by purified water, and the calcium hydroxide aqueous solution that is placed in concentration and is 2 mol/L soaked 2 hours, then by purified water, cleaned the neutrality to pH;
Step 2, de-cell go antigen to process: it is that 2 mg/mL trypsin solutions soaked 3 hours that the SIS after disinfecting is placed in concentration, by purified water, clean in the enzyme liquid of the alpha-galactosidase be placed on the DNA hydrolytic enzyme that contains 20U/mL and 32U/mL and soaked 3 hours again, finally by purified water, clean 8 times;
Step 3, the acid of composite transparent matter: the SIS after step 2 is processed is cut to 4 * 4cm, and the hyaluronic acid solution that is placed in concentration and is 15 mg/mL soaked 1.5 hours, took out and obtained being compounded with hyaluronic SIS diaphragm by vacuum freeze-drying;
Step 4, sterilization treatment: after being compounded with hyaluronic SIS diaphragm packing, carry out irradiation sterilization, irradiation dose is the gamma ray of 40kGy;
Step 5, modification: the aseptic SIS diaphragm that will obtain at room temperature was soaked in aseptic modified solution after 15 seconds, took out and dried under gnotobasis, and aseptic packaging, obtain anti blocking biomembrane; Described aseptic modified solution is to contain in normal saline solution: the decorin of 0.15 μ g/mL, the low molecular weight heparin of 15000AXaICU/mL, the nonsteroidal anti-inflammatory disease drug naproxen of the plasminogen activator of 0.2 mg/mL and 0.8 mg/mL.
Anti blocking biomembrane prepared by this example, by compound with hyaluronic acid, can effectively utilize the extremely strong absorption of hyaluronic acid to keep the ability of moisture, make anti blocking biomembrane effectively absorb the sepage of organizing of operative site, be pasted to the wound surface difficult drop-off, operation technique is convenient, uses simply, as shown in Figure 2.This anti blocking biomembrane passes through modification, while being applied to the animal surgery position, have the fibrosis of inhibition, inflammation-inhibiting, the hemorrhage effect of reduction, can prevent effectively that adhesion from occurring, the experimental group of application anti blocking biomembrane is compared with blank group, have obvious excellent effect result, the anti effective percentage is higher than blank group 30～50%.
Claims (2)
1. an anti blocking biomembrane, is characterized in that, be to take SIS to be timbering material, and the acid of composite transparent matter, functional protein and anti-inflammatory medicaments and the dry film that forms, dry film is shallow white to faint yellow translucent, and thickness is 0.01～0.5mm.
2. prepare the method for anti blocking biomembrane claimed in claim 1, concrete steps comprise:
Step 1, disinfect: lamellar SIS is cleaned to without dirt by purified water, and the aqueous slkali that is placed in concentration and is 0.5～5 mol/L soaked 0.5～2.5 hour, then by purified water, cleaned the neutrality to pH;
Step 2, de-cell go antigen to process: the trypsin solution that the SIS after disinfecting is placed in concentration 1～5 mg/mL soaked 0.5～4 hour, after by purified water, cleaning again, be placed in the enzyme liquid that contains 10～25 U/mL concentration DNA hydrolytic enzyme and 30～40 U/mL concentration alpha-galactosidases and soaked 0.5～4 hour, finally by purified water, clean;
Step 3, the acid of composite transparent matter: the SIS cutting on demand after step 2 is processed, the hyaluronic acid solution that is placed in concentration and is 5～20 mg/mL soaked 0.5～2 hour, took out and obtained being compounded with hyaluronic SIS diaphragm by vacuum freeze-drying;
Step 4, sterilization treatment: after being compounded with hyaluronic SIS diaphragm packing, adopt irradiation sterilization, irradiation dose is the gamma ray of 15～40kGy;
Step 5, modification: the aseptic SIS diaphragm that will obtain was soaked in aseptic modified solution after 10～60 seconds, took out and dried under gnotobasis, and aseptic packaging, obtain anti blocking biomembrane; Described aseptic modified solution is to contain in normal saline solution: the TGF-beta antagonists of 0.05～0.2 μ g/mL, the low molecular weight heparin of 5000～25000AXaICU/mL, the nonsteroidal anti-inflammatory disease drug of the plasminogen activator of 0.1～0.5 mg/mL and 0.1～1 mg/mL.
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