CN106344951A - Hemostatic anti-adhesion bio-membrane and preparation method thereof - Google Patents
Hemostatic anti-adhesion bio-membrane and preparation method thereof Download PDFInfo
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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Abstract
The invention discloses a hemostatic anti-adhesion bio-membrane and a preparation method thereof. The hemostatic anti-adhesion bio-membrane is prepared by such a manner that carboxymethyl chitosan or a mixture of carboxymethyl chitosan and gelatin/collagen is selected as a raw material to be dissolved in water, is foamed, plasticized, freeze-dried at low temperature, and cured at high temperature, and finally is subjected to mechanical membrane lamination. The bio-membrane prepared in the invention has the advantages of good biosafety and rapid hemostasis, and can effectively prevent wound from adhesion and promote wound healing.
Description
Technical field
The present invention relates to pharmaceutical technology field, in particular to a kind of bleeding stopping and adherence preventing biomembrane and preparation method thereof,
Specifically with natural biologic material as raw material, the biomembrane that crosslinked, foaming, curing molding and mechanical pressure are made.With
In the local hemostasis of surgery and wounded patient with prevent the effect of each section of Clinical Surgery post-operation adhesion preventing.
Background technology
Clinically there is very big requirement to local hemostasis and post-operation adhesion preventing at present, clinically hemostasia products are various,
Dosage form is various, has liquid, powder, gel and membrane etc., and wherein natural biological hemostatic material can be dropped with the biology of its uniqueness
Solution sexual clorminance occupies leading position in clinical hemostasis application.The adhesion of local will lead to serious clinical complication,
Have a strong impact on surgical effect and patients ' life quality, increase economy and the mental burden of patient.In Surgery of spinal cord, due to art
Focal adhesion can cause the complication such as patient and the dyskinesia afterwards；The focal adhesion of tendon Orthopeadic Surgery can cause motion barrier
Hinder；The adhesion of department of obstetrics and gynecology can cause infertility, so post-operation adhesion preventing clinically has extensive purposes, can significantly reduce
Post-operative complication and second operation.
In clinical field, biological tissue occurs the bad adhesion unrelated with tissue repair, bad adhesion after surgery
Metaplasia, obstruction, distortion can be caused, cause serious consequence.For example, postoperative bad adhesion can cause pain or biological group
The dysfunction knitted, also needs to carry out other operation be used for peeling off bad adhesion in severe cases.And, postoperative generation
Bad adhesion also can become very difficult to the operation again of original disease.Existing in order to prevent postoperative bad adhesion
As generally using and there is the Antiadhesive film of excellent biocompatibility and bioresorbable to cover and to protect it may happen that adhesion
Tissue.
Chitosan-phospholipid complex is natural polymerses, belongs to aminopolysaccharide, is find up to now unique
Alkaline polysaccharide with cationic charge.It is widely present in unicellular lower eukaryote mushroom in nature, the cell of algae, a section animal shrimp,
In the shell of Eriocheir sinensiss, insecticide etc..Good biocompatibility, toxicity are low, biodegradable, are widely used in food, medicine, health care, life
The fields such as thing engineering.Shitosan has anastalsis in itself, and meanwhile, shitosan passes through its phase interaction between erythrocyte membrane
With mainly realizing to the agglutination of erythrocyte stopping blooding.
In the prior art, have been disclosed for the Antiadhesive film of various material, carry in Chinese patent cn104208758 a
One kind has been supplied to be polylactic acid-based Antiadhesive film, polylactic acid-based Antiadhesive film has good mechanical property, biodegradable and biofacies
The advantages of capacitive is good, but there is also inevitable shortcoming, wherein topmost problem be implant after easily become fragile hardening,
Impact preventing adhesiving effect, therefore using being very restricted.Chinese patent literature cn101052425a discloses a kind of bag
Antiadhesive film containing lactide and the copolymer of caprolactone, the lactide in this copolymer is 65: 35 with the mol ratio of caprolactone
～80: 20.Chinese patent cn 102327651 a provides a kind of Merlon and lactide copolymer preparation antiseized
Even film, compared with polylactic acid-based Antiadhesive film, the advantage of the Antiadhesive film that mixture that such contains Merlon is made is bullet
Property is good, but its shortcoming low, raw materials used poor biocompatibility that is mechanical strength, easily cause organism immune response, therefore use
Also it is limited by very large.
Content of the invention
It is an object of the invention to overcoming the shortcomings of above-mentioned technology, provide a kind of bleeding stopping and adherence preventing biomembrane and its preparation side
Method is it is characterised in that comprise the following steps:
1. a kind of bleeding stopping and adherence preventing biomembrane and preparation method thereof is it is characterised in that component includes: carboxymethyl chitosan or carboxylic
One of mixture of methyl chitosan and gelatin/collagen, wetting agent, cross-linking agent, foaming agent and water.With water as solvent, respectively
Component is in mass ratio: carboxymethyl chitosan or carboxymethyl chitosan/gelatin/collagen 0.5% ~ 5%；Wetting agent 0.5% ~ 5%；Crosslinked
Agent 0.01% ~ 1%；Foaming agent 0.1% ~ 2%.
2. biomembranous preparation method according to claim 1 it is characterised in that described wetting agent be glycerol,
Propylene glycol, Polyethylene Glycol, one or more of；Cross-linking agent is sodium alginate, potato starch, tapioca, glucose, many
Bar amine, hyaluronic acid；Foaming agent is poloxamer.
3. a kind of bleeding stopping and adherence preventing biomembrane according to claim 1 and preparation method thereof is it is characterised in that institute
State preparation method to comprise the following steps:
1) preparation of cross-linking agent: prepare the sodium alginate aqueous solution of suitable concentration, be then slowly added in sodium periodate solution
Mechanical agitation, then deionized water dialysis 24 h ~ 48h, vacuum freeze carries out lyophilization to reactant liquor, freezing
Time is 24h, and drying time is 48 h ~ 72h；
2) preparation of reactant liquor: described be selected from containing carboxymethyl chitosan solution: carboxymethyl chitosan sugar aqueous solution, carboxymethyl shell
One of polysaccharide and gelatin/collagen mixed solution；Will be soluble in water for the solution containing carboxymethyl chitosan, add wetting agent and
Above-mentioned cross-linking agent stirring reaction 10 min ~ 90min；Foaming agent is soluble in water, it is slowly dropped in above-mentioned mixed liquor, at a high speed
Stirring foaming 30 min ~ 90min；
3) frozen drying: above-mentioned reactant liquor is poured in mould, -20 DEG C ~ -80 DEG C freezing, after be vacuum dried, do
It is soft spongy body after dry；
4) hot setting plasticising: the material after lyophilizing is moved into reactor and carries out 20 DEG C ~ 100 DEG C high temperature plasticization reactions；
5) mechanical press mold: after curing molding, material is taken out from reactor, carry out the demoulding first, then mechanical pressure becomes
Film.
4. preparation method according to claim 3 is it is characterised in that the joining of described carboxymethyl chitosan sugar aqueous solution
Method processed is: weigh a certain amount of carboxymethyl chitosan according to concentration for 0.5% ~ 5%, dissolve in while stirring in water dissolving 15min ~
120min.
5. preparation method according to claim 3 is it is characterised in that described carboxymethyl chitosan/gelatin solution
Preparation method includes: prepares aqueous gelatin solution: medical gelatin is added in distilled water, 30 ~ 60 DEG C of heating obtain aqueous gelatin solution,
And standing 30 minutes at 0～10 DEG C to 2h, the mass concentration of institute's gelatin water solution is 0.01～20%；Then according to carboxylic first
The mass ratio of base enclosure polysaccharide and gelatin is 100: 2～20, mixes carboxymethyl chitosan sugar aqueous solution and aqueous gelatin solution, prepares
Carboxymethyl chitosan and the mixed solution of gelatin.
6. preparation method according to claim 3 is it is characterised in that described carboxymethyl chitosan/collagen solution
Preparation method includes: configuration concentration is 0.01%～2% collagen protein acetic acid solution, and at 0～10 DEG C standing 30 minutes to 2
Hour；Then according to the mass ratio of carboxymethyl chitosan and collagen is 100: 2～20, mix carboxymethyl chitosan sugar aqueous solution and glue
Raw water solution, prepares the mixed solution of carboxymethyl chitosan and collagen.
7. preparation method according to claim 3 is it is characterised in that sodium alginate water in cross-linking agent preparation process
Solution and sodium metaperiodate volume ratio are 1 ~ 10:1.
8. preparation method according to claim 3 it is characterised in that the expanding foam solution freezing time be 12 h ~
72h, vacuum drying time is 12 h ~ 72h.
9. preparation method according to claim 3 is it is characterised in that the reactor of hot setting plasticising selects drum
Wind drying baker, vacuum desiccator, constant incubator, high temperature plasticization reaction temperature is 20 DEG C ~ 100 DEG C, and the response time is 5h ~ 72h.
10. preparation method according to claim 3 is it is characterised in that biomembranous molding mode is by soft sea
Continuous body carries out mechanical compression film forming, and biomembranous thickness is in 0.1 ~ 3mm.
Due to the utilization of technique scheme, the present invention compared with prior art has the advantage that
1) because preparation process is all to carry out at a temperature of water environment with convenient operation, prepared process is gentle, easily-controllable, no
The reduction of this biological membrane biological compatibility can be caused；
2) in the present invention, biomembranous crosslinking is carried out using macromolecules cross-linking material, instead of small molecule toxic chemical (such as
Formaldehyde, glutaraldehyde etc.) use, there is more preferable histocompatibility；
3) present invention uses the biomaterials such as carboxymethyl chitosan, gelatin and collagen, enough film property and suitable crosslinking
Ensure liquid-absorbent and the biodegradability of finished product, shitosan has the effect of hemostasis sorptivety, machining film forming in itself
Afterwards, improve mechanical property, adhesion inhibiting properties strengthen, it is to avoid secondary insult, thus reach suppression cicatrix, the work(of healing acceleration
Effect；
4) in preparation process, can control biological by adjusting cryogenic temperature, the parameter such as solution concentration, solidification plasticising time
The microstructure of film, thus easily having reached control biomembrane hemostasis speed, meets the requirement of different application.
Specific embodiment:
Embodiment 1:
1) preparation of cross-linking agent: weigh 1.0 g sodium alginates and be dissolved in 140 ml water, Deca 10 ml sodium metaperiodate is molten thereto
Liquid (40 mg/ml), normal lucifuge electromagnetic agitation is reacted 4 hours.Deca 0.200 ml ethylene glycol thereto again, stirring reaction 1 hour
Afterwards, the bag filter leaching then using molecular cut off 3500 is dialysed 24 hours in deionized water, and every 4 hours of period changed a water,
Vacuum equipment lyophilization 48 hours, obtains the sodium alginate solid of hydroformylation.
2) preparation of reactant liquor: weigh 1.0 g carboxymethyl chitosans again and be dissolved in 30 ml water, during need ultrasonic or
Stirring and dissolving 30min, is formulated as follows solution: the sodium alginate of the above-mentioned hydroformylation of 50 mg is dissolved in 10 ml water at the same time；1.50
G glycerol is dissolved in 1 ml water, and 0.30 g Poloxamer 407 is dissolved in 9 ml water and 10 ml pbs.Next, after preparing
Glycerol adds in carboxymethyl chitosan solution, stirs 10min, the sodium alginate soln after last Deca dissolving, stirring reaction
30min.Finally Poloxamer 407 solution is added in above-mentioned reactant liquor, high-speed stirred 60min.
3) reactant liquor is injected in mould, freezes 24h at -20 DEG C, obtain carboxymethyl chitosan Frozen Body, be then placed in
In vacuum drier, through 48h freeze-drying process, obtain soft spongy body.
4) this spongy body is put in air dry oven, through 24h, 60 DEG C of hot setting plasticizing reactions, period keeps sponge
Body is not fallen off with mould.
5) after solidification plasticising, spongy body is taken out from reactor, carries out the demoulding first, recover 30min under room temperature, so
Mechanical pressure film forming afterwards, the thickness of film is 0.5mm.
Embodiment 2:
1) preparation of cross-linking agent is with embodiment 1 1) preparation of cross-linking agent.
2) preparation of reactant liquor: with water as solvent, each component is in mass ratio: carboxymethyl chitosan: gelatin: polyethylene
Alcohol: cross-linking agent: the ratio of Poloxamer 407=1:1:0.5:0.03:0.3 is weighed.Carboxymethyl chitosan and gelatin enter first
Row mixing, sequentially adds cross-linking agent stirring reaction 30min, and Poloxamer 407 reacts 30min.
3) reactant liquor is injected in mould, freezes 12h at -40 DEG C, obtain carboxymethyl chitosan/gelatin Frozen Body, so
After put in vacuum drier, through 48h freeze-drying process, obtain soft spongy body.
4) this spongy body is put in vacuum drying oven, evacuation is dried, temperature is 80 DEG C, plasticizing reaction 12h.
5), after solidification plasticising, spongy body is taken out from reactor, carries out the demoulding first, under room temperature, recover 30min,
Then mechanical pressure film forming, the thickness of film is 1 mm.
Embodiment 3:
1) preparation of cross-linking agent: weigh 3g potato starch and be dissolved in the sodium hydroxide solution (1 mol/l) of 25ml, then to
Wherein Deca 10 ml dmso and 10ml isopropanol.Then Deca 4 ml epoxychloropropane, aerofluxuss thereto, are stirred at room temperature reaction
48 h.Then adjust ph=7 with hydrochloric acid, then with excessive acetone precipitation.Carry out high speed centrifugation, after centrifugation, product is with a small quantity after precipitation
Purification water dissolution 1h, dialyses 24 hours in water, every 4 hours of period changed a water, vacuum equipment lyophilization 48 hours.
2) preparation of reactant liquor: weigh 3 g carboxymethyl chitosans again and be dissolved in 100 ml water, during need ultrasonic or stir
Mix dissolving 30min, be formulated as follows solution at the same time: 100 mg above-mentioned epoxy starch is dissolved in 20 ml water；3g glycerol is dissolved in 10
In ml water, 1 g Poloxamer 407 is dissolved in 50 ml water.Then the glycerol after preparing is added in carboxymethyl chitosan solution,
Stirring 300min, the epoxy starch solution after last Deca dissolving, stirring reaction 1h.Finally Poloxamer 407 solution is added
In above-mentioned reactant liquor, high-speed stirred 1h.
3) reactant liquor is injected in mould, freezes 12h at -40 DEG C, obtain carboxymethyl chitosan Frozen Body, be then placed in
In vacuum drier, through 48h freeze-drying process, obtain soft spongy body.
4) this spongy body is put in constant temperature and humidity drying case, through 72h, 50 DEG C of hot setting plasticizing reactions, period keeps
Spongy body is not fallen off with mould.
5), after solidification plasticising, spongy body is taken out from reactor, carries out the demoulding first, then mechanical pressure film forming,
The thickness of film is 1mm.
Embodiment 4:
In embodiment 1, the biomembrane of preparation promotes Rat Wound Healing to test:
Rat back depilatory loses hair or feathers, and area about 5cm × 5cm ties extremity with rubber band, is fixed on rat in ventral decubitus and fixes
On plate.Select the back of the body middle part each side in spinal column both sides to open lcm, below scapula, prepare wound surface at 2cm.In above-mentioned traumatic part processed position, use
The trepan of diameter 18mm is perpendicular to 1 circular vestige (2.54cm of each extrusion of skin2), bend surgical is cut and is cut off holostrome skin along impression
Skin (reaches deep fascia), makes circular full thickness dermal wounds, and hemostasis is standby.Every rat prepares 2 wound surface, i.e. back both sides
Respectively prepare 1 wound surface.
Experimental group: diffraction patterns for biomembrane samples covers；Positive control: sterile gauze covers.
Observe rat animation, healing state, infection conditions, cicatrix shape etc..Daily replacing covers sample.After wound
3rd day, 5 days, 7 days, 11 days, 14 days, use transparent membrane flap coverage respectively, draw film along edge of wound, cut film, putting scale division value is 0.1
The analytical balance of mg weighs quality and is converted to area, records each group wound surface area, calculates healing rate.Healing rate=(original area-
Non- repaired area)/original area × 100%.
Experimental result:
A) behavioristicss' result: during testing, rat diet, drinking-water situation are normal, and behavior is without exception, and no fur comes off extremely,
The zero accident phenomena of mortality.There was no significant difference for biofilm experiments group and rat body weight.
B) inflammatory reaction: biofilm experiments group is no substantially red and swollen, physiology section result shows the visible obvious inflammation of art one week after
Property invade, after 2 weeks, inflammatory is remarkably decreased.Sterile gauze group inflammation declines inconspicuous.
C) wound bleeding adhesion situation: sterile gauze group adhesion is serious, has resulted in secondary injury to wound, and aseptic
Gauze matched group is compared, and during biofilm experiments group dressing, oozing of blood situation is significantly less than matched group, and no any adhesion.
D) healing state: the wound surface of sections observation to biomembrane test group is substantially better than sterile gauze group, its granulation tissue
Well-grown, becomes fibrosiss substantially, and has angeogenesis.
Accompanying drawing 1 is wound healing situation map, and accompanying drawing 2 is wound healing rate figure.
Claims (10)
1. a kind of bleeding stopping and adherence preventing biomembrane and preparation method thereof is it is characterised in that component includes: carboxymethyl chitosan or carboxylic first
One of mixture of base enclosure polysaccharide and gelatin/collagen, wetting agent, cross-linking agent, foaming agent and water；With water as solvent, each group
Divide and be in mass ratio: carboxymethyl chitosan or carboxymethyl chitosan/gelatin/collagen 0.5% ~ 5%；Wetting agent 0.5% ~ 5%；Cross-linking agent
0.01%~1%；Foaming agent 0.1% ~ 2%.
2. biomembranous preparation method according to claim 1 it is characterised in that described wetting agent be glycerol, the third two
Alcohol, Polyethylene Glycol, one or more of；Cross-linking agent is sodium alginate, potato starch, tapioca, glucose, DOPA
Amine, hyaluronic acid；Foaming agent is poloxamer.
3. a kind of bleeding stopping and adherence preventing biomembrane according to claim 1 and preparation method thereof is it is characterised in that described preparation
Method comprises the following steps:
1) preparation of cross-linking agent: prepare the sodium alginate aqueous solution of suitable concentration, be then slowly added in sodium periodate solution
Mechanical agitation, then deionized water dialysis 24 h ~ 48h, vacuum freeze carries out lyophilization to reactant liquor, freezing
Time is 24h, and drying time is 48 h ~ 72h；
2) preparation of reactant liquor: described be selected from containing carboxymethyl chitosan solution: carboxymethyl chitosan sugar aqueous solution, carboxymethyl chitosan
One of sugar and gelatin/collagen mixed solution；Will be soluble in water for the solution containing carboxymethyl chitosan, add wetting agent and upper
State cross-linking agent stirring reaction 10 min ~ 90min；Foaming agent is soluble in water, it is slowly dropped in above-mentioned mixed liquor, high-speed stirring
Mix foaming 30 min ~ 90min；
3) frozen drying: above-mentioned reactant liquor is poured in mould, -20 DEG C ~ -80 DEG C freezing, after be vacuum dried, be dried
It is soft spongy body afterwards；
4) hot setting plasticising: the material after lyophilizing is moved into reactor and carries out 20 DEG C ~ 100 DEG C high temperature plasticization reactions；
5) mechanical press mold: after curing molding, material is taken out from reactor, carry out the demoulding first, then mechanical pressure becomes
Film.
4. preparation method according to claim 3 is it is characterised in that the compound method of described carboxymethyl chitosan sugar aqueous solution
For: weigh a certain amount of carboxymethyl chitosan according to concentration for 0.5% ~ 5%, dissolve in while stirring in water dissolving 15min ~
120min.
5. preparation method according to claim 3 is it is characterised in that the preparation of described carboxymethyl chitosan/gelatin solution
Method includes: prepares aqueous gelatin solution: medical gelatin is added in distilled water, 30 ~ 60 DEG C of heating obtain aqueous gelatin solution, and
At 0～10 DEG C, to 2h, the mass concentration of institute's gelatin water solution is 0.01～20% to standing within 30 minutes；Then according to carboxymethyl shell
The mass ratio of polysaccharide and gelatin is 100: 2～20, mixes carboxymethyl chitosan sugar aqueous solution and aqueous gelatin solution, prepares carboxylic first
Base enclosure polysaccharide and the mixed solution of gelatin.
6. preparation method according to claim 3 is it is characterised in that the preparation of described carboxymethyl chitosan/collagen solution
Method includes: configuration concentration is 0.01%～2% collagen protein acetic acid solution, and at 0～10 DEG C standing 30 minutes little to 2
When；Then according to the mass ratio of carboxymethyl chitosan and collagen is 100: 2～20, mix carboxymethyl chitosan sugar aqueous solution and collagen
Aqueous solution, prepares the mixed solution of carboxymethyl chitosan and collagen.
7. preparation method according to claim 3 it is characterised in that in cross-linking agent preparation process sodium alginate aqueous solution with
Sodium metaperiodate volume ratio is 1 ~ 10:1.
8. preparation method according to claim 3 is it is characterised in that the expanding foam solution freezing time is 12 h ~ 72h, very
Empty drying time is 12 h ~ 72h.
9. preparation method according to claim 3 is it is characterised in that the reactor of hot setting plasticising selects forced air drying
Case, vacuum desiccator, constant incubator, high temperature plasticization reaction temperature is 20 DEG C ~ 100 DEG C, and the response time is 5h ~ 72h.
10. preparation method according to claim 3 is it is characterised in that biomembranous molding mode is by soft spongy body
Carry out mechanical compression film forming, biomembranous thickness is in 0.1 ~ 3mm.
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