A kind of wound repair dressing
Technical field
The present invention relates to a kind of wound repair dressing, belong to medical aid field.
Background technique
The surface of a wound is normal skin (tissue) causes injury the factor such as surgical operation, external force, heat, electric current, chemical substance, low in the external world
Damage caused by under the effects of temperature and body internal factor such as local blood supply obstacle.It is often accompanied by the broken of skin integrity
The loss of bad and a certain amount of normal tissue, meanwhile, the normal function of skin is impaired.Also referred to as wound or wound.The surface of a wound is repaired
Multiple both wound reparations.Wound repair is most important, the most basic problem that wound, burns unit or even entire medical field are faced
One of, but it is really carried out system and in-depth study as an independent project, recent 20 years just cause people
The attention of height.On the one hand, many basic problems of wound repair are on the other hand, modern in the past there is no really achieving a solution
The development of medicine, especially molecular biology proposes many new problems or even some important concepts to wound repair again
Also in continuous update and development.If traditional dressing (gauze) only plays simple flap coverage, and it is present, develop dressing
Concept basic variation has had occurred, i.e. flap coverage is not only wanted in dressing, should also have the function of promoting tissue repair, i.e. institute
It calls " active dressing " or " revolutionary dressing ".Secondly, the requirement with the increasingly improvement of living standards of the people, to quality of life
It is higher and higher, thus the chronic skin ulcer less paid attention in the past for people is also increasingly paid attention to by people with scar prevention.
Therefore, further pay attention to wound repair research be both after learned needs and social development to certain phase to medicine and
The new demand that biology proposes.
Foreign countries attach great importance to wound repair, and basic research has been goed deep into cell, molecule and gene level.The seventies with
Come, due to can effectively obtain large amount of cell factor and for zoopery, so that with growth factor and wound repair relationship
It walks for the tissue repair research foreign countries of breach in forefront, and has thus driven the development of entire wound repair.By nearly 20
Year effort, the cytology of tissue repair, extracellular matrix and collagenic supersession, growth factor promote (suppression) wound repair mechanism,
Chronic refractory pathophysiological features and the promoting healing method for closing ulcer, the origin cause of formation of hyperplastic scar and control, active dressing are ground
System and gene therapy etc. achieve the progress to attract people's attention, and many Basic Research Results have started to be applied to clinic.
We are continued for constantly in the national research in relation to wound repair, and obtain in fields such as burn wound reparations
Encouraging success.But generally, holistic approach of the China in this field still lags behind western developed country, and basic research is fallen again
Afterwards in clinical treatment.Since wound repair is a system engineering, it is related to many medicine necks such as surgery, traumatology department, burn, shaping
Domain, and with biochemistry, biology, molecular biology, biomethanics and biomaterial etc. it is many basis and applied science
There is extensive connection.Therefore, if its project great as one is not carried out interdisciplinary, multi-disciplinary tackling key problem, it is clear that
It is difficult to make a breakthrough.It is large quantities of that the famous academician of the Chinese Academy of Engineering Sheng Zhi in China is bravely taught, 304 hospital of Beijing pays professor dogface etc.
Medicine celebrity began to deliver a large amount of papers or monograph successively early in 2003, and proposed and " to make full use of the modern times
The achievement of High biotechnology is explored the normally secret with tissue repair generation out of control from cell, molecule and gene level, is found
It is reliable to promote restorative procedure, accelerate the exploitation and application of new product." viewpoint.Currently, Commercialization application is in clinic
Skin wound covering has: epidermal sheet, acellular dermal matrix, collagen sponge membrane, collagen gel film etc..1. epidermis
Cell patch: diaphragm (KC) disadvantage is that the skin biopsy sample of patient must be taken, needs 2-3 weeks time, lack
Dermal components, diaphragm belittle frangible [O ' ConnerNE, Malliken JB, Bankaclilegcls, et al.Grafting of
burns with cultured epitheliunt prepared from autologous epidermal cells[J]
.Lancet, 1981,1:75-78].2. acellular dermal matrix: the disadvantage is that un-cleared antigenic substance may be contained, there is biography
It catches an illness the danger of poison, and material hole connectivity is poor.3. collagen sponge membrane: such as 94118836.1 He of Chinese patent
01134743.0, the disadvantage is that the raw sub- factor of cell is not contained in material, and poor mechanical property, it cannot be anti-infective;It is Chinese special
Sharp 200510022581.X does not introduce microsphere sustained-release technology although being directly added into growth factor in material, and growth factor is easy
Lose bioactivity.4. collagen gel: such as Chinese patent CN02117585.3 and CN03130382.X, the disadvantage is that production process
Complexity, collagen gel can shrink 80% or so, and resistance degraded by collagenase ability is poor, is subject to virus infection and immunological rejection is anti-
It answers, brittleness is big, and surgical procedure is difficult.
Summary of the invention
The present invention provide in view of the deficiencies of the prior art it is a kind of it is extremely low with no immunological rejection or immunological rejection effect, answer
With in extensive range, wound repair excellent wound repair dressing.Above-mentioned purpose that the invention is realized by the following technical scheme.
1. a kind of wound repair dressing is porous material, is characterized in that, surface is attached with the collagen of Porcine HGF
Albumen.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,
The mass fraction of fiber is 1-10%;Step 2: the suspension is carried out ripening 8-15h at 15-36 DEG C, make suspended
Liquid forms coagulated mass;Step 3: removing the water or ethyl alcohol solidified in the coagulated mass using supercritical drying drying method, fiber is formed
Staggeredly material;Step 4: the fiber material that interlocks is carried out 1-5h thermal crosslinking treatment, the three-dimensional that is adhesively fixed of fiber cross-point is obtained
Fiber-based material;
Biodegradable fibers are selected from: polylactic acid, polycaprolactone, polyglycolide, polyurethane, polyvinyl alcohol or silk-fibroin,
Fiber made of the one or more substances of peptide polymer, alginic acid of elastin mimicry.
(2) porous processing is carried out
The Dressing substrate dipping that step (1) is obtained in water, then adds and causes porous combination object, and 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 phosphorus
Hydrochlorate and hydrophosphate, the phosphate and the hydrophosphate existing molar ratio in the composition are 1:3-1:15, the combination
Reaction is when object is hydrated to generate the carbon dioxide as gas component, wherein releasing the gas component from the composition
At least 8% porosity is generated in the composition;
(3) collagen is impregnated
Porous treated three-dimensional fiber sill is impregnated into the collagen hydrosol containing Porcine HGF, then
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 the crosslinking agent is selected from 1- ethyl -3- (3- DimethylAminopropyl) -
Carbodiimides, glutaraldehyde, dialdehyde starch, glycol glycidyl ethers, propanetriol-diglycidyl-ether, myrica extract, wattle skin
Any one of own diisocyanate of tannin extract, 1,6-;After crosslinking curing, wound repair dressing is obtained.
Wherein the content concn of crosslinking agent is preferably 0.01~0.05mol/L in the cross-linking agent solution, more preferably
0.03mol/L;The time of the crosslinking curing is preferably 5~12h, more preferably 8~9h.
The cell factor is the factor gone back to the nest or chemotactic or cell differentiation work to cell, these factors can be selected from
Cell directional migration factor (SDF-1), epidermal growth factor (EGF), fibroblast growth factor (FGF), interleukin I L-3,
Angiogenin binding factor (ECM), transforminggrowthfactor-α (TGF- α), platelet-derived growth factor (PDGF) or thin
Born of the same parents' directional migration factor, insulin-like growth factor, bone morphogenetic protein, bone morphogenesis protein-2, vascular endothelial growth factor
Son, Connective Tissue Growth Factor, basic fibroblast growth factor, osteopontin, growth hormone (such as: somatotropin)
Equal cytotaxis and adhesion factor
In the biocompatible adhesive further include: nucleic acid, carbohydrate, protein, polypeptide is poly- ('alpha '-hydroxy acids),
Poly- (lactone), it is poly- (amino acid), it is poly- (acid anhydrides), it is poly- (ortho esters), it is poly- (acid anhydrides-CO- acid imide), it is poly- (orthocarbonic ester), gather
(Alpha-hydroxy alkanoic acid ester), 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), poly butyric ester (PHB), polycarboxylic acids is poly- (hydrochloric acid allylamine), poly- (chlorination diallyl dimethyl
Ammonium), poly- (ethylenimine), poly- fumaric acid propylene glycol ester, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, poly- methyl
Methyl acrylate, carbon fiber, polyethylene glycol, poly(ethylene oxide)polymers are poly- (vinyl alcohol), poly(vinyl pyrrolidone), epoxy second
Alkane-CO- propylene oxide block copolymer, poly- (ethylene glycol terephthalate), polyamide and their copolymer.
The biocompatible adhesive is selected from: alginic acid, arabic acid, guar gum, xanthan gum, gelatin, chitin, takes off second
Acyl chitin, acetic acid chitosan, lactic acid chitosan, chondroitin sulfate, N, the deacetylated shell of O- carboxymethyl are more
Sugar, glucan, Fibrin Glue, glycerol, hyaluronic acid, Sodium Hyaluronate, cellulose, aminoglucose, proteoglycans, starch, cream
Acid, ethylene oxide and propylene oxide copolymers, sodium glycero-phosphate, collagen, glycogen, keratin, silk and their mixture.
Compared with prior art, the invention has the following beneficial effects:
(1) so that dressing has higher and more evenly hole than conventional wound-surface plaster, enhancing is applied for the introducing of pore composition
The gas permeability of material in use;
(2) manufacturing method of three-dimensional fiber base is more simple relative to the electrostatic spinning technique of traditional surface of a wound film, is easy control
System, no matter raw material or process costs it is all more cheap, with preferable breathable moisture permeability;
(3) Wound dressing produced by the present invention can promote dermal fibroblasts to grow, and accelerate the healing of damage skin,
For hospital gauze, the required days minus that animal skin heals completely is a half left and right, and is not in the surface of a wound
Red and swollen and cicatricial contracture.
Specific embodiment
Embodiment 1:
(1) three-dimensional fiber sill is manufactured
Step 1: vinal is dispersed in water, homogeneous suspension is formed;In the suspension, the matter of fiber
Measuring score is 7%;Step 2: the suspension is carried out ripening 8h at 15 DEG C, suspension is made to form coagulated mass;Third
Step: removing the water or ethyl alcohol solidified in the coagulated mass using supercritical drying drying method, forms fiber and interlocks material;Step 4:
The fiber material that interlocks is subjected to 5h thermal crosslinking treatment, obtains the three-dimensional fiber sill that is adhesively fixed of fiber cross-point;
(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, processing temperature
25 DEG C of degree, time 18min.
The cause porous combination object are as follows: magnesium carbonate, foaming agent and biocompatible adhesive, wherein the foaming agent includes phosphorus
Hydrochlorate and hydrophosphate, the phosphate and the hydrophosphate existing molar ratio in the composition are 1:7, the composition hydration
Shi Fanying is combining to generate the carbon dioxide as gas component wherein releasing the gas component from the composition
At least 8% porosity is generated in object;
(3) collagen is impregnated
Porous treated three-dimensional fiber sill is impregnated into the collagen hydrosol containing Porcine HGF, then
Dry, Porcine HGF content is 5wt%, and the content of collagen is 1300IU/mL;
(4) crosslinking curing
Crosslinking curing is carried out after drying, wherein the crosslinking agent is glycol glycidyl ethers, and crosslinking curing terminates
Afterwards, wound repair dressing is obtained.
Embodiment 2:
(1) three-dimensional fiber sill is manufactured
Step 1: wire protein fiber is dispersed in water or ethyl alcohol, homogeneous suspension is formed;In the suspension, fiber
Mass fraction be 7%;Step 2: the suspension is carried out ripening 8h at 15 DEG C, suspension is made to form coagulated mass;
Step 3: remove the water or ethyl alcohol solidified in the coagulated mass using supercritical drying drying method, forms fiber and interlock material;4th
Step: the fiber material that interlocks is subjected to 2h thermal crosslinking treatment, obtains the three-dimensional fiber sill that is adhesively fixed of fiber cross-point;
(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, processing temperature
20 DEG C of degree, time 50min.
The cause porous combination object are as follows: magnesium carbonate, foaming agent and biocompatible adhesive, wherein the foaming agent includes phosphorus
Hydrochlorate and hydrophosphate, the phosphate and the hydrophosphate existing molar ratio in the composition are 1:6, the composition hydration
Shi Fanying is combining to generate the carbon dioxide as gas component wherein releasing the gas component from the composition
At least 8% porosity is generated in object;
(3) collagen is impregnated
Porous treated three-dimensional fiber sill is impregnated into the collagen containing basic fibroblast growth factor
Then the hydrosol is dried, basic fibroblast growth factor content is 8wt%, and the content of collagen is 130IU/mL;
(4) crosslinking curing
Crosslinking curing is carried out after drying, wherein the crosslinking agent is dialdehyde starch, after crosslinking curing, is obtained
Wound repair dressing.Wherein the content concn of crosslinking agent is 0.03mol/L in the cross-linking agent solution;The crosslinking curing
Time is 8~9h.
Comparative example 1:
1) RGD recombinant spider silk protein-polyvinyl alcohol composite fiber film is prepared
RGD recombinant spider silk protein (Ji'nan University's offer) and polyvinyl alcohol (average degree of polymerization is 2400~2500) are dissolved in
In the formic acid solution of 98wt%, it is configured to the spinning solution containing 5wt%RGD recombinant spider silk protein and 5wt% polyvinyl alcohol.Spinning
In the syringe of silk liquid sucking 2mL specification, using electrospinning technology, 80kV (voltage strength), 20cm (syringe needle away from
Collect screen surfaces), 5ml/h (spinning solution flow), under the conditions of 45 DEG C, spinning solution is prepared into RGD recombinant spider silk protein-polyethylene
Alcohol composite cellulosic membrane.
2) bFGF- collagen solution is prepared
Collagen (offer of Shijiazhuang Xu Er U.S. Biotechnology Co., Ltd) is dissolved in sterile water and is configured to 2wt%'s
Collagen solution adds bFGF (offer of Beijing Ke Xin Biotechnology Co., Ltd) by 500IU/ml, obtains bFGF- collagen egg
White solution.
3) wound repair dressing is prepared
RGD recombinant spider silk protein obtained above -37 DEG C of polyvinyl alcohol composite fiber film constant temperature is immersed in above-mentioned be made
BFGF- collagen solution in 30min, be then placed in room temperature nature gel drying 2h in gel mold, obtain drying and moulding
Composite cellulosic membrane.
The composite cellulosic membrane of drying and moulding is put into the EDCHCl solution that concentration is 0.01~0.05mol/L and is crosslinked 8h
It reinforces, obtains the wound repair dressing with a thickness of 0.05mm.
Wound repair dressing obtained is finally put into aseptic package bag, carries out ethylene oxide sterilizing.
Comparative example 2:
Without step (2) porous processing, other steps while embodiment 1
Comparative example 3:
(1) three-dimensional fiber sill is manufactured
Step 1: polylactic acid is dispersed in water or ethyl alcohol, homogeneous suspension is formed;In the suspension, the matter of fiber
Measuring score is 13%;Step 2: the suspension is carried out ripening 20h at 40 DEG C, suspension is made to form coagulated mass;The
Three steps: removing the water or ethyl alcohol solidified in the coagulated mass using supercritical drying drying method, forms fiber and interlocks material;4th
Step: the fiber material that interlocks is subjected to 6h thermal crosslinking treatment, obtains the three-dimensional fiber sill that is adhesively fixed of fiber cross-point;
(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, processing temperature
15 DEG C of degree, time 9min.
The cause porous combination object are as follows: magnesium carbonate, foaming agent and biocompatible adhesive, wherein the foaming agent includes phosphorus
Hydrochlorate and hydrophosphate, the phosphate and the hydrophosphate existing molar ratio in the composition are 1:16;
(3) collagen is impregnated
Porous treated three-dimensional fiber sill is impregnated into the collagen hydrosol containing Porcine HGF, then
Dry, Porcine HGF content is 15wt%, and the content of collagen is 100IU/mL;
(4) crosslinking curing
Crosslinking curing is carried out after drying, wherein the crosslinking agent is selected from 1- ethyl -3- (3- DimethylAminopropyl) -
Carbodiimides after crosslinking curing, obtains wound repair dressing.Wherein the content of crosslinking agent is dense in the cross-linking agent solution
Degree is preferably 0.08mol/L, the time 14h of the crosslinking curing.
Test of the wound repair dressing in the surface of a wound
It is tested with 100 white rabbits, establishes wounds in animals model, be randomly divided into 5 groups: example 1 group, 2 groups of embodiment, reality
Apply 3 groups of example, comparative example group and blank control group, every group 20.After white rabbit anesthesia disinfection, the notch at 3cm × 3cm is manufactured, it is complete
Whole removal skin holostrome, respectively with the embodiment group and comparative example group film patch flap coverage with surface of a wound same size, blank control
The surface of a wound does not do specially treated, and then sterile pressurized is wrapped up.Postoperative intramuscular injection penicillin 10u/kgbw is injected for three days on end 2 times a day,
Prevention infection.Dressing weekly, removal each group film are pasted, are wrapped up after wound clean by original method.Groups of animals wound is observed after 1 to 4 week
The variation in face calculates Wound healing rate, Wound healing rate=(original surface of a wound area-existing surface of a wound area)/original surface of a wound area
× 100%, as a result such as the following table 1:
The Wound healing rate (%) of the postoperative different time points each group of table 1
Group |
First week |
Second week |
4th 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 |
Embodiment 1 |
27 |
90 |
99.99 |
Embodiment 2 |
29 |
89 |
99.97 |
Table 1 shows that second week healing rate of the invention is apparently higher than the wound repair dressing of other methods manufacture.Embodiment
The group surface of a wound has no clear scar contracture, oedema and inflammation occurs without red and swollen and inflammation, blank control group, and comparative example part has obviously
Cicatricial contracture.
The measurement of porosity: under constant temperature conditions, dehydrated alcohol is filled into 5ml specific gravity bottle, weighed (W1), by compound fibre
Tie up film weighing (Ws).And film is placed in specific gravity bottle, 15min is stood, is de-gassed using vacuum pump, until bubble-free escapes,
It is diffused into ethyl alcohol sufficiently in the hole of film, fills it up with ethyl alcohol, weigh (W2).The sample for being saturated with ethyl alcohol is taken out, to remaining second
Alcohol and specific gravity bottle are weighed (W3).Counting Formula: porosity=(W2-W3-Ws)/(W1-W3)
Table 2
|
Porosity (%) |
Embodiment 1 |
88% |
Embodiment 2 |
86% |
Comparative example 1 |
82% |
Comparative example 2 |
65% |
Comparative example 3 |
83% |