CN103418022B - Composite multifunctional biological hemostatic material and preparation method thereof - Google Patents
Composite multifunctional biological hemostatic material and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of medical equipment and relates to a composite multifunctional biological hemostatic material and a preparation method thereof. A porous tissue engineering cell growth stent made of silk fibroin is used as a core; pores of a porous network of the stent are filled withbiological hemostatic material mainly made of chitosan; the composite multifunctional biological hemostatic material can be obtained by connecting the silk fibroin and the chitosan via hydrogen bonds. The composite multifunctional biological hemostatic material has the function of local hemostasis for injury and the function of promoting regeneration of injured tissue cells.
Description
Technical field
The invention belongs to medical instruments field, relate to biological hemostatic material of a kind of composite multifunction and preparation method thereof.
Background technology
When tissue meets with damage, histoorgan breakage, hemorrhage, and produce inflammatory reaction.Damaged tissue discharges the bioactive substances such as tissue factor, extrinsic coagulation system and platelet etc. in activating, and damage local thrombus forms and stops blooding.The hemostatic material of current clinical use is mainly used the manufactures such as chitosan, oxidized regenerated cellulose, collagen protein, helps hemostasis by local compression, promotion thrombosis.The reparation of tissue injury is by regeneration.Regeneration is to repair by damage allogenic cell around, if recovered the 26S Proteasome Structure and Function of original tissue completely, is called holomorphosis.If but damage, damage location lacks the organization bracket of cell proliferation, growth, and injury repairing, take fibroid reparation as main, is carried out repair tissue damage or damaged by fibrous connective tissue hypertrophy, forms cicatrix, is called again scar repairing.In most cases, the method for above-mentioned two kinds of reparations exists simultaneously, different injuries of tissues and organs, and due to the regeneration capacity difference of tissue, the ratio of regeneration and fibroid reparation is different.So far be not still applied to the repair in trauma tissue engineering material of clinical deep organ, can promote tissue regeneration, reduce cicatricial reparation, the farthest morphology and function of repair tissue organ, more take tissue engineering bracket as hemostatic material basis, that can promote regeneration and restoration.
Summary of the invention
The object of the invention is the above-mentioned defect for prior art, biological hemostatic material of a kind of composite multifunction and preparation method thereof is provided.
Object of the present invention can be achieved through the following technical solutions:
The preparation method of the biological hemostatic material of a kind of composite multifunction, the porous organization's Growth of Cells support forming through lyophilization take fibroin albumen or other biological material is as core, in the porous network hole of described porous organization's Growth of Cells support and surface stacking and/or cover housing polysaccharide or other biological hemostatic compositions make the biological hemostatic material of described composite multifunction.
The preparation method of the described biological hemostatic material of composite multifunction, preferably by described porous organization's Growth of Cells support is dipped in the solution of chitosan or other biological hemostatic compositions, then through lyophilization, chitosan or other biological hemostatic compositions be filled in the porous network hole of described porous organization's Growth of Cells support and cover described porous organization's Growth of Cells rack surface.
The preparation method of the described biological hemostatic material of composite multifunction, preferably comprises following steps:
(1) preparation fibroin albumen or other biological material solution;
(2) fibroin albumen in step (1) or other biological material solution are poured in mould, obtain porous organization's Growth of Cells support through lyophilization;
(3) solution of preparation chitosan or other biological hemostatic compositions;
(4) porous organization's Growth of Cells support of step (2) gained is immersed in the solution of step (3), is jointly placed in mould, obtain the biological hemostatic material of composite multifunction through lyophilization.
Described other biological material is that other have the material that supports and be beneficial to cell adhesion function, preferred gelatin-compounded thing; The concentration of described silk fibroin protein solution is 5%～75%, and the molecular weight of fibroin albumen is 3000～18000; The solvent of preparing described silk fibroin protein solution or other timbering material solution is selected from a kind of solvent that water, ethanol or other and water dissolves each other or the mixture of multi-solvents.
Described chitosan is modification of chitosan or non-modification of chitosan, and chitosan solution concentration is 4%～60%, and molecular weight is 10,000～100,000; Described other biological hemostatic compositions is that other have and the material of chitosan identity function, or other are with the metal ion of positive charge, if calcium, magnesium or other ions are as the material of Trace Iodine.
In described chitosan or other biological hemostatic compositions solution, also contain 0.5%～20% material that can strengthen support and the hemostatic compositions compatibility; Preferably also contain PVP.
Described lyophilization is under certain freezing rate, freeze temperature, lyophilization a period of time, then through certain sublimation temperature, is finally warming up to 30-40 ℃ and completes freeze-drying process to pressure qualified (0.5Pa/ minute～2Pa/ minute); Wherein, freezing rate is that divide～0.1 ℃ ∕ of 2 ℃ ∕ divides, and freeze temperature is-50 ℃～-15 ℃, and sublimation drying is 1 hour～8 hours, and sublimation temperature is-5 ℃～-40 ℃.
In the preparation method of the described biological hemostatic material of composite multifunction, immersion-freezing dry process can once complete, and also can repeatedly carry out.
The pH value of the described biological hemostatic material of composite multifunction is 6.0～7.8; The form of described porous organization's Growth of Cells support, includes but not limited to membranaceous, block; Shape comprises and is not limited to circle, square; The form of the described biological hemostatic material of composite multifunction, fibroin albumen support and chitosan can be stepped constructions, can be also mutually to contain.
The biological hemostatic material of the composite multifunction of preparation according to the method described in the present invention.
Above-described " % " if no special instructions, all represents mass percent.
Beneficial effect:
The invention provides a kind of multifunctional medical biomaterial, this multifunctional biomaterials is the chitosan hemostatic material take silk fibroin porous tissue engineering bracket as core.Silk fibroin porous scaffold is three-dimensional network shape, between its hole, is interconnected, and aperture is 100-400 μ m, is beneficial to Growth of Cells.On prefabricated fibroin albumen support, chitosan molecule is filled in the hole of fibroin albumen support and covers rack surface by freeze-dry process.This multifunctional composite biological material can be according to clinical needs, are prepared into membranaceous (thickness >=2mm) or block (thickness is 5mm～10mm) that size is different.According to different operations, can be applied to the surgical wound surface of organ, also can clog in damaged organ, the surgical wound surface of for example hepatectomy or the wound of liver traumatic rupture, in performance hemostatic function, play the effect that promotes damaged tissue Regeneration and Repair, it promotes the function of regeneration and restoration and hemostasis to be all obviously better than using separately fibroin albumen or chitosan, and mechanism is as follows:
1) fibroin albumen: contain in fibroin albumen as cell adhesion seat and well-known tripeptide sequence: arginine-glycine-aspartic acid acid, the research of recent domestic shows, the speed of growth of cell on fibroin protein film is suitable with the speed of growth on collagen.By the control to silk fibroin molecular amount, can control its degradation time (several weeks～several months) in vivo.Therefore, fibroin albumen can be made into the reparation of tissue engineering bracket for wound tissue.Experimental result shows: the three-dimensional porous rack that fibroin albumen is made is placed into damage location, histiocyte (hepatocyte or epithelial cell, fibroblast and vascular endothelial cell) can be grown along fibroin albumen support, can effectively promote the regeneration of histoorgan, reduce cicatricial reparation, [controllability fibroin albumen biomaterial is in feasibility analysis and the Mechanism Study thereof of the application of hernia and stomach wall surgical field to be conducive to the function reparation of organ, Fudan University's doctorate paper, 2012].
2) chitosan: chitosan is a kind of alkaline polysaccharide of uniqueness is a kind of good, generally acknowledged hemostatic material.It excites endogenous, external source hemostasis by following three approach: with erythrocyte generation aggreation, to hematoblastic stimulation, by complement activation system and other blood constituent coagulant, last metabolism becomes Portugal's amine sugar.Except as hemostatic material, there is many research to show, chitosan also has the growth that promotes wound site cell, promote the function [Wang Zheng that epithelial cell is repaired, Liu Wanshun, Han Baoqin etc. the preparation of different molecular weight carboxymethyl chitosan and the impact [J] on skin flbroblast and keratinocyte growth thereof. biomedical engineering's magazine, 2007,24(2): 340～344].
3) chitosan can promote the regeneration and restoration function of fibroin albumen support: because Growth of Cells needs extracellular matrix; extracellular matrix be in body development process by emiocytosis to extracellular various macromole; these macromole form gel or the fibrous network of high degree of hydration at cell peripheral, cell colony is had to the effect of defining, support, protecting.And the chitosan of cationic form can and serum in major part show the epicene protein of tool and carry out ion-type interaction, formation pentalyte (PEC), as gel etc.This gel filling that chitosan forms is in fibroin albumen brace aperture and cover rack surface, and cell growth plays the effect of extracellular matrix, thereby effectively promotes the growth of cell on fibroin albumen support.
4) fibroin albumen support improves chitosan haemostatic effect: chitosan hemostatic material is being applied ointment or plaster or clogged behind damaged organ place, chitosan is brought into play the biological function of hemostasis within initial a few minutes, but soften because absorb moisture very soon, lose the hemostasis by compression effect to wound face blood vessel; And fibroin albumen support-Chitosan Composites, because fibroin albumen scaffold degradation is wherein slow, more than about several weeks, porous network wherein can reduce the disperse of chitosan, chitosan absorbs serum or moisture and expands, and wound is formed to hemostasis by compression, thereby effectively promotes the haemostatic effect of chitosan.
5) fibroin albumen support and chitosan have different degradation rates, and in the time that fibroin albumen support-Chitosan Composites is applied to wound site, chitosan can be degraded in 72 hours, and formed gel inside and outside the hole of fibroin albumen support.The progressively degraded more than 4 weeks of fibroin albumen support.So in early days, fibroin albumen local compression has strengthened the haemostatic effect of chitosan, and the pentalyte that chitosan forms has strengthened fibroin albumen and promoted the ability that organ tissue regeneration is repaired.
Accompanying drawing explanation
Fig. 1 5% fibroin albumen support scanning electron microscope (SEM) photograph
Fig. 2 5%-4% fibroin-chitosan compound rest scanning electron microscope (SEM) photograph
Fig. 3 20% fibroin albumen support scanning electron microscope (SEM) photograph
Fig. 4 20%-30% fibroin-chitosan compound rest scanning electron microscope (SEM) photograph
The block diagram of Fig. 5 cell OD value and incubation time
Wherein * p<0.001, every group is followed successively by matched group, chitosan group, fibroin albumen support group and compound rest group from left to right.
The specific embodiment
Embodiment 1
(1) silk fibroin water solution that the molecular weight of preparation 5wt% is 5000, be poured in mould, 0.1 ℃/point of the freezing rate of adjusting freezer dryer, freeze temperature-45 ℃, lyophilization time 2 h, 10 ℃ of sublimation temperatures, finally be warming up to 30-40 ℃ while being 0.5Pa/ minute to pressure, complete freeze-drying process, obtain fibroin albumen support (being porous organization's Growth of Cells support), scanning electron microscope (SEM) photograph is shown in Fig. 1.
(2) chitosan aqueous solution that the molecular weight of preparation 4wt% is 10,000, fibroin albumen support prepared by previous step is immersed in chitosan aqueous solution, jointly be placed in mould, 2 ℃/point of the freezing rates of adjusting freezer dryer, freeze temperature-15 ℃, 3 hours lyophilization time, 20 ℃ of sublimation temperatures, finally be warming up to 30-40 ℃ while being 0.5Pa/ minute to pressure, complete freeze-drying process, obtaining aperture is the biological hemostatic material of membranaceous fibroin-chitosan composite multifunction of 100 μ m, and scanning electron microscope (SEM) photograph is shown in Fig. 2.
Embodiment 2
(1) silk fibroin water solution that the molecular weight of preparation 20wt% is 8000, be poured in mould, 1 ℃/point of the freezing rate of adjusting freezer dryer, freeze temperature-30 ℃, 4 hours lyophilization time, 15 ℃ of sublimation temperatures, finally be warming up to 30-40 ℃ while being 2Pa/ minute to pressure, complete freeze-drying process, obtain fibroin albumen support (being porous organization's Growth of Cells support), scanning electron microscope (SEM) photograph is shown in Fig. 3.
(2) chitosan aqueous solution that the molecular weight of preparation 30wt% is 30,000, fibroin albumen support prepared by previous step is immersed in chitosan aqueous solution, jointly be placed in mould, 1.5 ℃/point of the freezing rates of adjusting freezer dryer, freeze temperature-30 ℃, 2.5 hours lyophilization time, 10 ℃ of sublimation temperatures, finally be warming up to 30-40 ℃ while being 2Pa/ minute to pressure, complete freeze-drying process, obtaining aperture is the biological hemostatic material of membranaceous fibroin-chitosan composite multifunction of 150 μ m, and scanning electron microscope (SEM) photograph is shown in Fig. 4.
Embodiment 3
1) silk fibroin water solution that the molecular weight of preparation 20wt% is 8000, be poured in mould, 1 ℃/point of the freezing rate of adjusting freezer dryer, freeze temperature-30 ℃, 4 hours lyophilization time, 15 ℃ of sublimation temperatures, are finally warming up to 30-40 ℃ while being 2Pa/ minute to pressure, complete freeze-drying process, obtain fibroin albumen support (being porous organization's Growth of Cells support).
2) chitosan aqueous solution that the molecular weight of preparation 30wt% is 30,000, wherein contain the PVP of 5wt%, fibroin albumen support prepared by previous step is immersed in chitosan aqueous solution, is jointly placed in mould, 1.5 ℃/point of the freezing rates of adjusting freezer dryer, freeze temperature-30 ℃, 2.5 hours lyophilization time, 10 ℃ of sublimation temperatures, are finally warming up to 30-40 ℃ while being 2Pa/ minute to pressure, complete freeze-drying process, obtain the biological hemostatic material of membranaceous fibroin-chitosan composite multifunction.
Embodiment 4
Liver hemostasis trial:
Healthy White Rabbit 30 is divided into 6 groups, and 5 every group, the biological hemostatic material of the composite multifunction of preparing with above-described embodiment 1, embodiment 3 respectively, gelfoam, oxidation regeneration fiber, collagen protein sponge, relatively haemostatic effect of this six set product of chitosan.Prepare liver middle period excision Hemorrhage Model according to methods such as Matsuoka.Lumbar injection 3% pentobarbital sodium (40mg/kg) anesthetized rat, under arcus costarum, be about 2cm stringer otch along ventrimeson, cut off abdominal muscle along ventrimeson, extruding abdominal part is extruded the liver middle period from incision, blot liver around after peritoneal fluid, the quick excision liver middle period in the above 2cm of liver middle period lower edge place.Adhere to immediately the hemostatic material of weighing according to grouping, and start timing, until stopped bleeding, to ooze out without BRB as stopped bleeding standard, the disperse time of total amount of bleeding, bleeding stopping period and hemostatic material in last logistic, in table 1.
Table 1
| Group | Amount of bleeding (g/kg) | Bleeding stopping period (s) | The disperse time (s) |
| 1 group of embodiment | 1.27±0.23 | 224±28 | Leave over fibroin albumen support |
| 3 groups of embodiment | 1.18±0.17 # | 210±30 # | Leave over fibroin albumen support |
| Gelatin foam group | 1.63±0.21* | 292±31* | 10～15 minutes |
| Oxidation regeneration fiber group | 1.57±0.23* | 261±23* | 45～60 minutes |
| Collagen protein sponge group | 1.61±0.08* | 285±30* | About 15 minutes |
| Chitosan group | 1.48±0.05* | 173±12* | About 30 minutes |
#:P>0.05, compared with 1 group of embodiment, there was no significant difference
*: P<0.05, compared with 1 group of embodiment, has significant difference
Above-mentioned six groups of result of the tests fully show, the biological hemostatic material of composite multifunction take Properties of Chitosan Fibroin Blend albumen as main body (3 groups of 1 group of embodiment and embodiment) demonstrates the shortest bleeding stopping period and minimum amount of bleeding, be better than commonly using gelfoam, hemostatic gauze, bio-sponge.Compared with simple chitosan hemostatic material, its haemostatic effect of composite multifunction hemostatic material (3 groups of 1 group of embodiment and embodiment) take fibroin albumen as support obviously improves.
Embodiment 5
Primary mouse liver cell proliferation test
CCK-8 cell proliferation experiment is used to investigate the survival rate of the primary mouse liver cell of cultivation on fibroin-chitosan compound rest in 7 days culture periods.
Obtain primary hepatocyte by mice original position collagenase perfusion digestion.Hepatocellular survival rate, by determination of trypan blue staining, remains on 90%～95%.
1) test grouping
Matched group: primary mouse liver cell single culture
Chitosan group: primary mouse liver cell is cultivated altogether with chitosan (concentration and embodiment 1 are used identical)
Fibroin albumen support group: primary mouse liver cell is cultivated propagation in fibroin albumen support (embodiment 1 step 1) co-cultured cell
Compound rest group: primary mouse liver cell and fibroin-chitosan compound rest (embodiment 1) are cultivated altogether
2) cell culture processes
To be total to after culture materials sterilizing, be immersed in 10ml(10%) in HepatoZYME serum-free medium culture fluid 12 hours, put into anti-adherent 48 well culture plates after treatment through Poly-HEMA.The primary mouse liver cell of the trophophase of taking the logarithm, with 10
5the cell concentration of/ml is inoculated in 48 orifice plates, in 5%CO
2, 37 ℃, shaking table low speed (30～40rpm/min) suspension culture 7 days, respectively 1,3, sampling afterwards in 7 days, the OD value of application CCK-8 kit detection cell, every group 6 multiple hole.When detection, every hole adds CCK-8 liquid 20ul, at 5%CO
2, hatch 3 hours for 37 ℃.Before measurement, respectively ask for 110ul liquid in 96 orifice plates, measure absorbance (OD) under microplate reader 450nm wavelength, test repeats six times, the results are shown in Figure 5.OD value size and cell proliferation positive correlation, quantity that can indirect reaction cell.Fig. 5 shows, fibroin-chitosan compound rest, compared with other groups, has significantly short proliferative advantage, is more suitable for the growth of primary hepatocyte, is expected to the reparation for tissue injurys such as livers in body.
Claims (5)
1. the preparation method of the biological hemostatic material of composite multifunction, it is characterized in that the porous organization's Growth of Cells support forming through lyophilization take fibroin albumen is as core, in the porous network hole of described porous organization's Growth of Cells support and Surface filling and/or cover housing polysaccharide make the biological hemostatic material of described composite multifunction; Specifically comprise following steps:
(1) preparation silk fibroin protein solution, the concentration of described silk fibroin protein solution is 5wt% ~ 75 wt %, the molecular weight of fibroin albumen is 3000 ~ 18000;
(2) silk fibroin protein solution in step (1) is poured in mould, obtains porous organization's Growth of Cells support through lyophilization;
(3) solution of preparation chitosan, chitosan solution concentration is 4 wt % ~ 60 wt %, molecular weight is 10,000 ~ 100,000; In described chitosan solution, also contain the polyvinylpyrrolidone of 0.5 wt % ~ 20 wt %;
(4) porous organization's Growth of Cells support of step (2) gained is immersed in the solution of step (3), is jointly placed in mould, obtain the biological hemostatic material of composite multifunction through lyophilization; Described lyophilization is under certain freezing rate, freeze temperature, lyophilization a period of time, then through certain sublimation temperature, be finally warming up to 30-40 ℃ to the qualified freeze-drying process that completes of pressure; Wherein, freezing rate is that divide ~ 0.1 ℃ ∕ of 2 ℃ ∕ divides, and freeze temperature is-50 ℃ ~-15 ℃, and sublimation drying is 1 hour ~ 8 hours, and sublimation temperature is-5 ℃ ~-40 ℃; Immersion-freezing dry process once completes, or repeatedly carries out.
2. the preparation method of the biological hemostatic material of composite multifunction according to claim 1, the solvent that it is characterized in that preparing described silk fibroin protein solution is selected from a kind of solvent that water, ethanol or other and water dissolves each other or the mixture of multi-solvents.
3. the preparation method of the biological hemostatic material of composite multifunction according to claim 1, is characterized in that described chitosan is modification of chitosan or non-modification of chitosan.
4. the preparation method of the biological hemostatic material of composite multifunction according to claim 1, is characterized in that the pH value of the biological hemostatic material of described composite multifunction is 6.0 ~ 7.8; The form of described porous organization's Growth of Cells support is membranaceous, block; Be shaped as circular, square.
5. the biological hemostatic material of composite multifunction of preparing according to the method described in any one in claim 1 ~ 4.
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| CN104189943B (en) * | 2014-03-30 | 2018-10-30 | 浙江圣兆药物科技股份有限公司 | A kind of medical composite biological material application and preparation method |
| CN103908692B (en) * | 2014-03-30 | 2016-05-18 | 浙江圣兆医药科技有限公司 | A kind of composite biological material is applied ointment or plaster and preparation method |
| CN105695392B (en) * | 2015-12-15 | 2018-11-13 | 大连医科大学 | A kind of cultural method that liver cell vitro differentiation phenotype and function can be improved |
| CN106390209A (en) * | 2016-08-31 | 2017-02-15 | 奥美医疗用品股份有限公司 | Silk fibroin biological material compounded with epidermal growth factor and preparation method of silk fibroin biological material |
| CN106310366B (en) * | 2016-09-29 | 2019-04-30 | 武汉生物工程学院 | A kind of Guide Periodontal Tissue Regeneration barrier film and the preparation method and application thereof |
| CN107137757A (en) * | 2017-04-26 | 2017-09-08 | 浙江大学 | A kind of RGD bacteriophages/fibroin compound hemostatic material and preparation method thereof |
| CN107982568A (en) * | 2017-09-30 | 2018-05-04 | 重庆市畜牧科学院 | Degradable biological auxiliary material and its preparation method and application |
| CN108042841A (en) * | 2017-12-11 | 2018-05-18 | 罗卫 | A kind of biological dressing and preparation method thereof and purposes |
| CN112717195B (en) * | 2021-01-14 | 2022-05-27 | 上海长欧生物科技有限公司 | Biodegradable rapid hemostatic granule and preparation method thereof |
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