CN106178063B - A kind of no immunological rejection adhesive bandage - Google Patents

Abstract

A kind of no immunological rejection adhesive bandage, it is characterised in that: adhesive bandage includes fibrous base layer, adhesive layer and wound repair dressing layer.

Description

A non-immune rejection Band-Aid

technical field

The invention relates to a non-immune rejection band-aid, which belongs to the field of medical rescue.

Background technique

Wound is the damage of normal skin (tissue) caused by external injury factors such as surgery, external force, heat, electric current, chemical substances, low temperature, and internal factors such as local blood supply disturbance. Often accompanied by disruption of skin integrity and loss of a certain amount of normal tissue, at the same time, the normal function of the skin is impaired. Also called a wound or wound. Wound repair is both wound repair. Wound repair is one of the most important and basic problems faced by trauma and burn surgery and even the whole medical field. However, it has been regarded as an independent subject for systematic and in-depth research, which has attracted people's attention in the past 20 years. attention. On the one hand, many basic problems of wound repair have not been really solved in the past. On the other hand, the development of modern medicine, especially molecular biology, has raised many new problems for wound repair, and even some important concepts are constantly evolving. update and develop. For example, the traditional dressing (gauze) only plays the role of simply covering the wound surface, but now, the concept of dressing has undergone fundamental changes, that is, the dressing should not only cover the wound surface, but also have the function of promoting tissue repair, which is the so-called "active dressing". ’ or ‘Revolutionary Dressing’. Secondly, with the improvement of people's living standards, the requirements for quality of life are also getting higher and higher, so people pay more and more attention to the prevention and treatment of chronic body ulcers and scars, which were not paid much attention in the past. Therefore, it is not only an academic need to pay more attention to wound repair research, but also a new requirement for medicine and biology after social development reaches a certain stage.

Foreign countries attach great importance to wound repair, and its basic research has penetrated to the level of cells, molecules and genes. Since the 1970s, due to the ability to effectively obtain a large number of cytokines and use them in animal experiments, the research on tissue repair based on the relationship between growth factors and wound repair has been at the forefront abroad, and has thus led to the development of the entire wound repair. After nearly 20 years of hard work, he has researched the cytology of tissue repair, extracellular matrix and collagen metabolism, the mechanism of growth factors promoting (inhibiting) wound repair, the pathophysiological characteristics of chronic refractory ulcers and the methods of promoting healing, and the causes of hypertrophic scars. Remarkable progress has been made in areas such as control, active dressing, and gene therapy, and many basic research results have begun to be applied clinically.

The research on wound repair in our country has been continuous, and gratifying achievements have been made in the fields of burn wound repair and so on. But in general, my country's overall research in this field still lags behind western developed countries, and basic research lags behind clinical treatment. Since wound repair is a systematic project, it involves many medical fields such as surgery, trauma surgery, burns, and plastic surgery, and has extensive connections with many basic and applied sciences such as biochemistry, biology, molecular biology, biomechanics, and biomaterials. . Therefore, if it is not regarded as a major subject for interdisciplinary and interdisciplinary research, it is obviously difficult to make breakthroughs. Professor Sheng Zhiyong, an academician of the famous Chinese Academy of Engineering, and Professor Fu Xiaobing of Beijing 304 Hospital, etc., have published a large number of papers or monographs as early as 2003, and proposed that "to make full use of the achievements of modern high-tech biotechnology, from cells Explore the mysteries of normal and out-of-control tissue repair at the molecular and genetic levels, find reliable methods to promote repair, and accelerate the development and application of new products." Viewpoint. At present, the skin wound coverings that have been commercially used in clinic include: epidermal cell membrane, acellular dermal matrix, collagen sponge membrane, collagen gel membrane, etc. ①Epidermal cell membrane: The disadvantage of this membrane (KC) is that the patient’s skin biopsy specimen must be taken, which requires 2-3 weeks of preparation time, lacks dermal components, and the membrane is thin and fragile [O'ConnerNE, Malliken JB, Bankaclilegcls, et al al. Grafting of burns with cultured epitheliunt prepared from autologous epidermal cells [J]. Lancet, 1981, 1: 75-78]. ② Acellular dermal matrix: Its disadvantages are that it may contain unclean antigenic substances, which may cause the risk of virus infection, and the material has poor pore penetration. ③ Collagen sponge membrane: such as Chinese patents 94118836.1 and 01134743.0, its disadvantage is that the material does not contain cell growth factors, and its mechanical properties are poor, and it cannot resist infection; Chinese patent 200510022581. Microsphere slow-release technology, growth factors are easy to lose biological activity. ④ Collagen gel: such as Chinese patents CN02117585.3 and CN03130382.X, the disadvantage is that the production process is complicated, the collagen gel will shrink by about 80%, the ability to resist collagenase degradation is poor, it is easy to be infected by viruses and immune rejection, and it is very brittle , The operation is difficult.

Contents of the invention

The invention aims at the deficiency of the prior art and provides a band-aid with no immune rejection or very low immune rejection effect, wide application range and excellent wound repairing effect. The present invention achieves the above object through the following technical solutions.

A non-immune rejection band-aid is characterized in that the band-aid comprises a fibrous base layer, an adhesive layer and a wound repairing dressing layer. It is characterized in that comprising the steps of:

(1) Manufacture of three-dimensional fiber-based materials

The first step: disperse the biodegradable fiber in water or ethanol to form a homogeneous suspension; in the suspension, the mass fraction of the fiber is 1-10%; the second step: the suspension Carry out aging treatment at 15-36°C for 8-15 hours to make the suspension liquid form a coagulated block; the third step: remove the coagulated water or ethanol in the coagulated block by supercritical drying method to form a fiber interlaced material; Four steps: subject the fiber interlaced material to thermal cross-linking treatment for 1-5 hours to obtain a three-dimensional fiber-based material bonded and fixed at fiber interlaced points;

Biodegradable fibers are selected from the group consisting of polylactic acid, polycaprolactone, polyglycolide, polyurethane, polyvinyl alcohol, or silk protein, elastin-mimicking peptide polymers, and fibers made of one or more substances of alginic acid .

(2) Perform porous treatment

The three-dimensional fiber-based material obtained in step (1) is soaked in water, and then the porous composition is added, the treatment temperature is 20-60°C, and the treatment time is 10-60 minutes.

The porogenic composition is: magnesium carbonate, a foaming agent and a biocompatible adhesive, wherein the foaming agent comprises phosphate and hydrogen phosphate present in the composition in a molar ratio of 1:3 to 1:15, the composition reacts when hydrated to produce carbon dioxide as a gas component, wherein release of the gas component from the composition creates at least 8% porosity in the composition Rate;

(3) Impregnated collagen

The three-dimensional fiber-based material after porous treatment is impregnated with collagen hydrosol containing cell growth factors, and then dried, the content of cell growth factors is 1-10wt%, and the content of collagen is 130-1500IU/mL;

(4) Cross-linking and curing

Carry out cross-linking solidification after drying, wherein, the cross-linking agent is selected from 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, glutaraldehyde, dialdehyde starch, ethylene glycol Any one of alcohol glycidyl ether, glycerol glycidyl ether, bayberry extract, vitex bark extract, and 1,6-hexamethylene diisocyanate; after cross-linking and curing, a wound repair dressing is obtained;

(5) Make Band-Aids

Bond the wound repair dressing to the fibrous base layer.

Wherein the concentration of the cross-linking agent in the cross-linking agent solution is preferably 0.01-0.05 mol/L, more preferably 0.03 mol/L; the time for cross-linking and curing is preferably 5-12 hours, more preferably 8-9 hours .

The cytokines are factors that act on cell homing or chemotaxis or cell differentiation, and these factors can be selected from directional cell migration factor (SDF-1), epidermal growth factor (EGF), fibroblast growth factor (FGF ), interleukin IL-3, angiopoietin-binding factor (ECM), transforming growth factor-α (TGF-α), platelet-derived growth factor (PDGF) or directed cell migration factor, insulin growth factor, bone morphogenetic protein, Bone morphogenetic protein-2, vascular endothelial growth factor, connective tissue growth factor, basic fibroblast growth factor, osteopontin, growth hormones (such as somatotropin) and other cell attraction and adhesion factors

Also included in the biocompatible adhesive are: nucleic acids, carbohydrates, proteins, polypeptides, poly(alpha-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters) ), poly(anhydride-CO-imide), poly(orthocarbonate), poly(α-hydroxyalkanoate), poly(phosphate), poly(L-lactide) (PLLA), poly( D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-CO-glycolide) (PLGA), poly(L-lactide-CO-D,L- lactide), poly(D,L-lactide-CO-propylene carbonate), polyhydroxybutyrate (PHB), polycarboxylic acid, poly(allylamine hydrochloride), poly(chlorinated diene Propyldimethylammonium), poly(ethyleneimine), polytrimethylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethyl methacrylate, carbon fiber, polyethylene glycol, poly Oxyethanol, poly(vinyl alcohol), poly(vinylpyrrolidone), ethylene oxide-CO-propylene oxide block copolymer, poly(ethylene terephthalate), polyamide, and their copolymer.

The biocompatible binder is selected from the group consisting of alginic acid, arabic acid, guar gum, xanthan gum, gelatin, chitin, chitosan, acetic acid chitosan, lactic acid chitosan, chondroitin sulfate , N,O-carboxymethyl chitosan, dextran, fibrin glue, glycerin, hyaluronic acid, sodium hyaluronate, cellulose, glucosamine, proteoglycans, starch, lactic acid, ethylene oxide Propylene oxide copolymer, sodium glycerophosphate, collagen, glycogen, keratin, silk, and mixtures thereof.

Compared with the prior art, the present invention has the following beneficial effects:

(1) The introduction of the porogenic composition makes the dressing have higher and more uniform pores than the conventional wound dressing, which enhances the air permeability of the dressing during use;

(2) Compared with the electrospinning technology of the traditional wound mask, the manufacturing method of the three-dimensional fiber base is simpler and easier to control. Both raw material and process costs are lower, and it has better air and moisture permeability;

(3) The wound dressing produced by the present invention can promote the growth of skin fibroblasts and accelerate the healing of damaged skin. Compared with medical gauze, the days required for animal skin to heal completely are reduced by about half, and there will be no wound redness and swelling and scar contractures.

Detailed ways

Example 1:

(1) Manufacture of three-dimensional fiber-based materials

The first step: disperse the polyvinyl alcohol fiber in water to form a homogeneous suspension; in the suspension, the mass fraction of the fiber is 7%; the second step: carry out the suspension at 15°C Aging treatment for 8 hours to make the suspension form a solidified block; the third step: remove the solidified water or ethanol in the solidified block by supercritical drying method to form a fiber interlaced material; the fourth step: dry the fiber interlaced material for 5 hours Thermal cross-linking treatment to obtain a three-dimensional fiber-based material bonded and fixed at interlaced points of fibers;

(2) Perform porous treatment

The three-dimensional fiber-based material obtained in step (1) was soaked in water, and then the porosity composition was added. The treatment temperature was 25° C. and the treatment time was 18 minutes.

The porogenic composition is: magnesium carbonate, a foaming agent and a biocompatible adhesive, wherein the foaming agent comprises phosphate and hydrogen phosphate present in the composition having a molar ratio of 1:7, the composition reacts when hydrated to produce carbon dioxide as a gas component, wherein release of the gas component from the composition results in a porosity of at least 8% in the composition;

(3) Impregnated collagen

The three-dimensional fiber-based material after porous treatment is impregnated with collagen hydrosol containing cell growth factors, and then dried, the content of cell growth factors is 5wt%, and the content of collagen is 1300IU/mL;

(4) Cross-linking and curing

After drying, carry out cross-linking and curing, wherein the cross-linking agent is ethylene glycol glycidyl ether, and after cross-linking and curing, a wound repair dressing is obtained.

Bond the wound repair dressing to the fibrous base layer.

Example 2:

(1) Manufacture of three-dimensional fiber-based materials

The first step: disperse the silk protein fibers in water or ethanol to form a homogeneous suspension; in the suspension, the mass fraction of fibers is 7%; the second step: put the suspension at 15°C Carry out the aging treatment for 8 hours at the same time to make the suspension liquid form a coagulated block; the third step: remove the coagulated water or ethanol in the coagulated block by supercritical drying method to form a fiber interlaced material; the fourth step: the fiber interlaced material Carry out 2h thermal cross-linking treatment to obtain a three-dimensional fiber-based material bonded and fixed at interlaced points of fibers;

(2) Perform porous treatment

The three-dimensional fiber-based material obtained in step (1) was soaked in water, and then the porous composition was added. The treatment temperature was 20° C. and the treatment time was 50 minutes.

The porogenic composition is: magnesium carbonate, a foaming agent and a biocompatible adhesive, wherein the foaming agent comprises phosphate and hydrogen phosphate present in the composition having a molar ratio of 1:6, the composition reacts when hydrated to produce carbon dioxide as a gas component, wherein release of the gas component from said composition results in a porosity of at least 8% in the composition;

(3) Impregnated collagen

The three-dimensional fiber-based material after the porous treatment is impregnated with collagen hydrosol containing basic fibroblast growth factor, and then dried, the content of basic fibroblast growth factor is 8wt%, and the content of collagen is 130IU/mL;

(4) Cross-linking and curing

After drying, carry out cross-linking and curing, wherein the cross-linking agent is dialdehyde starch, and after cross-linking and curing, a wound repair dressing is obtained. Wherein the content concentration of the cross-linking agent in the cross-linking agent solution is 0.03mol/L; the time for the cross-linking and curing is 8-9h.

Bond the wound repair dressing to the fibrous base layer.

Comparative example 1:

1) Preparation of RGD recombinant spidroin-polyvinyl alcohol composite fiber membrane

Dissolve RGD recombinant spidroin protein (provided by Jinan University) and polyvinyl alcohol (average degree of polymerization is 2400～2500) in 98wt% formic acid solution, prepare to contain 5wt% RGD recombinant spidroin protein and 5wt% polyvinyl alcohol spinning solution. Inhale the spinning solution into a 2mL syringe, and use electrospinning technology to spin the spinning solution under the conditions of 80kV (voltage strength), 20cm (syringe needle distance from the surface of the collecting screen), 5ml/h (spinning solution flow rate), and 45°C. The silk solution was prepared into RGD recombinant spidroin-polyvinyl alcohol composite fiber membrane.

2) Preparation of bFGF-collagen solution

Collagen (provided by Shijiazhuang Xuermei Biotechnology Co., Ltd.) was dissolved in sterile water to prepare a 2wt% collagen solution, and bFGF (provided by Beijing Kexin Biotechnology Co., Ltd.) was added at 500IU/ml to obtain bFGF-collagen solution.

3) Preparation of wound repair dressing

Soak the above-prepared RGD recombinant spidroin-polyvinyl alcohol composite fiber membrane at a constant temperature of 37°C in the above-prepared bFGF-collagen solution for 30 minutes, and then put it into a gel mold for natural gel drying at room temperature for 2 hours to obtain dry Formed composite fiber membrane.

Put the dried and formed composite fiber membrane into EDC·HCl solution with a concentration of 0.01-0.05mol/L for cross-linking for 8 hours to obtain a wound repair dressing with a thickness of 0.05mm.

Finally, the prepared wound repair dressing was put into a sterile packaging bag and sterilized with ethylene oxide. Bond the wound repair dressing to the fibrous base layer.

Comparative example 2:

Do not carry out step (2) porous treatment, other steps at the same time Example 1

Comparative example 3:

(1) Manufacture of three-dimensional fiber-based materials

The first step: disperse polylactic acid in water or ethanol to form a homogeneous suspension; in the suspension, the mass fraction of fibers is 13%; the second step: put the suspension at 40 ° C Carry out aging treatment for 20 hours to make the suspension liquid form a solidified block; the third step: remove the solidified water or ethanol in the solidified block by supercritical drying method to form a fiber interlaced material; the fourth step: dry the fiber interlaced material 6h thermal cross-linking treatment to obtain a three-dimensional fiber-based material bonded and fixed at interlaced points of fibers;

(2) Perform porous treatment

The three-dimensional fiber-based material obtained in step (1) was soaked in water, and then the porous composition was added. The treatment temperature was 15° C. and the time was 9 minutes.

The porogenic composition is: magnesium carbonate, a foaming agent and a biocompatible adhesive, wherein the foaming agent comprises phosphate and hydrogen phosphate present in the composition The molar ratio is 1:16;

(3) Impregnated collagen

The three-dimensional fiber-based material after porous treatment is impregnated with collagen hydrosol containing cell growth factors, and then dried, the content of cell growth factors is 15wt%, and the content of collagen is 100IU/mL;

(4) Cross-linking and curing

After drying, carry out cross-linking and curing, wherein the cross-linking agent is selected from 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, after cross-linking and curing, a wound repair dressing is obtained . Wherein the content concentration of the cross-linking agent in the cross-linking agent solution is preferably 0.08mol/L, and the time for cross-linking and curing is 14 hours.

Bond the wound repair dressing to the fibrous base layer.

Test of Wound Repair Dressings on Wounds

100 white rabbits were used for testing to establish animal trauma models, and were randomly divided into 5 groups: Example 1 group, Example 2 group, Example 3 group, comparative example group and blank control group, 20 rabbits in each group. After the white rabbit was anesthetized and sterilized, an incision of 3 cm × 3 cm was made, and the full layer of skin was completely removed. The wound was covered with the film of the example group and the control group of the same size as the wound respectively. The wound of the blank control was not specially treated, and then aseptic Compression bandage. Postoperative intramuscular injection of penicillin 10u/kgbw, 2 times a day, for 3 consecutive days, to prevent infection. The dressing was changed every week, the membranes of each group were removed, and the wounds were cleaned and bandaged according to the original method. After 1 to 4 weeks, observe the changes of the wounds of the animals in each group, and calculate the wound healing rate, wound healing rate=(original wound area-existing wound area)/original wound area×100%, the results are shown in Table 1 below:

Table 1 Wound healing rate of each group at different time points after operation (%)

group the first week the second week the fourth week blank control 14.91 63.33 98.94 Comparative example 1 23.76 83.58 99.97 Comparative example 2 25 79 98.88 Comparative example 3 20 81 98.90 Example 1 27 90 99.99 Example 2 29 89 99.97

Table 1 shows that the second week healing rate of the present invention is significantly higher than that of wound repair dressings made by other methods. There was no obvious scar contracture, redness and inflammation in the wound surface of the example group, edema and inflammation in the blank control group, and obvious scar contracture in the comparative example.

Determination of porosity: under constant temperature conditions, fill a 5ml pycnometer with absolute ethanol, weigh (W1), and weigh the composite fiber membrane (Ws). And put the membrane in a pycnometer, let it stand for 15 minutes, and use a vacuum pump to degas until no bubbles escape, so that ethanol can fully diffuse into the pores of the membrane, fill up with ethanol, and weigh (W2). Take out the sample soaked in ethanol, and weigh the remaining ethanol and pycnometer (W3). Counting formula: porosity=(W2-W3-Ws)/(W1-W3)

Table 2

Porosity(%) Example 1 88% Example 2 86% Comparative example 1 82% Comparative example 2 65% Comparative example 3 83%

Claims (1)

1. a kind of no immunological rejection adhesive bandage, it is characterised in that: adhesive bandage includes that fibrous base layer, adhesive layer and wound repair are applied The bed of material；Its manufacturing method includes the following steps:

(1) three-dimensional fiber sill is manufactured

Step 1: Biodegradable fibers are dispersed in water or ethyl alcohol, homogeneous suspension is formed；In the suspension, fiber Mass fraction be 1-10%；Step 2: the suspension is carried out ripening 8-15h at 15-36 DEG C, make suspension shape At coagulated mass；Step 3: removing the water or ethyl alcohol solidified in the coagulated mass using supercritical drying drying method, forms fiber and interlock Material；Step 4: the fiber material that interlocks is carried out 1-5h thermal crosslinking treatment, the three-dimensional fiber that is adhesively fixed of fiber cross-point is obtained Sill；

Biodegradable fibers are selected from: polylactic acid, polycaprolactone, polyglycolide, polyurethane, polyvinyl alcohol or silk-fibroin, elastic force Fiber made of the one or more substances of peptide polymer, alginic acid of albumen mimicry；

(2) porous processing is carried out

The three-dimensional fiber sill dipping that step (1) is obtained in water, then adds and causes porous combination object, treatment temperature 20 ~60 DEG C, the time is 10~60min；

The cause porous combination object are as follows: magnesium carbonate, foaming agent and biocompatible adhesive, wherein the foaming agent includes phosphate And hydrophosphate, the phosphate and hydrophosphate existing molar ratio in the composition are 1:3-1:15, the composition water It reacts to generate the carbon dioxide as gas component when conjunction, wherein releasing the gas component in group from the composition At least 8% porosity is generated in conjunction object；

(3) collagen is impregnated

Porous treated three-dimensional fiber sill is impregnated into the collagen hydrosol containing Porcine HGF, is then done Dry, Porcine HGF content is 1-10wt%, and the content of collagen is 130-1500IU/mL；

(4) crosslinking curing

Crosslinking curing is carried out after drying, wherein it is sub- that crosslinking agent is selected from 1- ethyl -3- (3- DimethylAminopropyl)-carbonization two Amine, glutaraldehyde, dialdehyde starch, glycol glycidyl ethers, propanetriol-diglycidyl-ether, myrica extract, wattle extract, 1,6- Any one of own diisocyanate；After crosslinking curing, wound repair dressing is obtained；

(5) adhesive bandage is manufactured

Wound repair dressing is bonded in the fibrous base layer.