CN101905038A - Growth factor-loaded collagen group composite material as well as preparation method and application thereof - Google Patents
Growth factor-loaded collagen group composite material as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a growth factor-loaded collagen group composite material and a preparation method thereof. The growth factor-loaded collagen group composite material is prepared from collagen, a growth factor, chitosan and sodium heparin, a dense layer collagen film and a loose layer collagen film form a double-layer structure, and a growth factor-loaded chitosan-heparin nano particle is compounded between the double layers. The dosage of the growth factor is 50-10,000ng/cm<2>; and the average thickness of the double-layer film is 1-4mm. The preparation method comprises the steps of preparing the dense collagen film and the loose collagen film, preparing the growth factor-loaded nano particle, compounding the collagen films and the nano particle, and the like. The collagen group composite material prepared by the invention has orient difference control slow release function on the loaded growth factor, has a slow release period longer than 20 days, maintains the activity of the growth factor and can be used for the restoration treatment of the disease defect tissue.
Description
Technical field:
The present invention relates to a kind of growth factor-loaded collagen group composite material and manufacture method thereof and application, this material has directed difference control slow releasing function to the somatomedin of its load, can be used for the repairing and treating of disease defective tissue.
Background technology:
Collagen is the Main Ingredients and Appearance of extracellular matrix (ECM), belongs to structural protein, accounts for 1/3 of mammalian proteins matter gross mass, is present in a large number in connective tissues such as skin, ligament, cartilage, flesh key or the organ.Collagen has excellent biological compatibility, implant and have no side effect and zest, be difficult for causing organism immune response, and help sticking, breed and breaking up of cell, accelerate wound healing, and degradable and for cambium provides enough spaces, during the research and development that is widely used in biomaterial utilizes.But homogenous material exists problems such as biological activity, intensity, and the especially growth factor-loaded material superior bioactive of giving of composite is present technical field of biological material main direction of studying.
In recent years, the tissue renovation material research of composite growth factor is very extensive, tissue renovation material with growth factor nano slow releasing function demonstrates remarkable advantages gradually, and mainly showing as compound somatomedin or other bioactive molecule etc. can be positioned at particle inside by dissolving, package action, or is positioned at particle surface by absorption, adhewsive action, the envelop rate height, volume is little, can directly act on target tissue/cell, reduces usage factor dosage, slow-release time is long, and it is convenient to preserve.Introducing and histiocyte hypertrophy, the relevant multiple somatomedin of differentiation, is to improve the bioactive effective way of material.In the guide tissue regeneration process, introduce somatomedin, its objective is, come the repairing damage tissue by intending ecology or imitation forming process from the embryo to preceding this section tissue in period of childbirth.A kind of effect of somatomedin just may cause multiple molecular biology, biochemistry and morphologic cascade reaction, and this series reaction finally reaches the effect of tissue repair.But the easy mostly degraded of these somatomedin, the half-life is short, and research is arranged by comparing the effect of variable concentrations bFGF, proves that the bioactive performance of bFGF has dose dependent.So must consider the protection of protein active and the control of burst size when in the guide tissue regeneration material, introducing somatomedin.The development of drug delivery system has improved somatomedin transport efficacy in vivo.But the control slow release stent material of bio-absorbable both can wrap and carry a somatomedin, simultaneously again can according to biological requirement with suitable concentration lentamente with growth factor release to destination organization to reach the reparation purpose.There are some researches show that the somatomedin bag is stated from behind the microsphere compound with the PLGA timbering material, the slow-release time of somatomedin can be kept 15 days.But used comparatively violent condition in most research process,, may cause the loss of activity of somatomedin as the use of organic solvent; The prominent phenomenon of releasing of the most existence of the release of somatomedin simultaneously, and do not control for the release direction of somatomedin, somatomedin both can be released to disease and decrease tissue, may be released to around the disease defective tissue again, thereby produce unpredictalbe consequence, and caused the waste of somatomedin itself.Therefore, be necessary to design novel growth factor release system, and then the guide tissue regeneration material of preparation composite growth factor, be used for the Regeneration and Repair that disease is decreased tissue.Someone adds histidine in collagen-based materials, and by the crosslinking time of change EDAC/NHS to collagen-based materials, thereby reach the effect that changes the material aperture, investigated further and wrapped the release rule of the material in the different apertures of having carried medicine medicine.The result shows that the structure of collagen-based materials and drug release rate have tangible dependency.According to this result of study, utilize collagen-based materials to can be used as the thesaurus effect of somatomedin simultaneously, the collagen composite materials of preparation multilamellar different structure may obtain somatomedin is had the collagen group composite material of directed difference release action.
Summary of the invention
The object of the invention is to overcome the deficiency of existing tissue renovation material, and a kind of growth factor-loaded collagen group composite material and manufacture method thereof and application are provided.It is to be used for the advanced composite material (ACM) that tissue defect is repaired.This material has the biologic activity of initiatively inducing damaged place regeneration and restoration, realizes that simultaneously the directed difference of somatomedin is released to the tissue defect place, avoids the unpredictable consequence that the unordered release of somatomedin causes and the waste of the factor itself.
Growth factor-loaded collagen group composite material provided by the invention is that to receive with collagen, somatomedin, chitosan, heparin be feedstock production, form double-decker by compacted zone collagem membrane and weaker zone collagem membrane, double-deck middle superpacket carries the chitosan-heparin nanoparticle of somatomedin.Every square centimeter of crosslinked weaker zone collagem membrane somatomedin consumption is 50-10000ng; Duplicature average thickness 1-4mm.
Concrete preparation technology: the collagem membrane after the collagen swelling solution is air-dry is crosslinked in crosslinked fluid, and is air-dry, gets the compact structure collagem membrane; The collagen swelling solution is in the lyophilization of pre-freeze final vacuum, flatten, lyophilizing, in crosslinked fluid crosslinked after vacuum lyophilization once more, short texture porous collagen film; Stir down the acetic acid solution of chitosan mixes the chitosan-heparin nanoparticle that obtains somatomedin with the heparin solution that contains somatomedin; Crosslinked weaker zone collagem membrane surface in moistening drips chitosan-heparin nanoparticle that bag carries somatomedin, and is air-dry, the more crosslinked compacted zone collagem membrane of moistening paved in crosslinked weaker zone collagem membrane surface, air-dry.
The mass ratio of chitosan and heparin is 4-8: 5-10; The molecular weight 3000-20000 of heparin; The molecular weight 8000-20000 of chitosan, deacetylation 70-90%.
The step that growth factor-loaded collagen group composite material preparation method provided by the invention comprises:
1) get the collagen swelling solution and be diluted to the 0.3-0.8% mass percent concentration, 4-8 ℃ air-dry, promptly get the compact structure collagem membrane; Fine and close collagem membrane is put in the crosslinked fluid crosslinked and air-dry once more, promptly gets crosslinked compacted zone collagem membrane;
2) the collagen swelling solution with 0.3-0.8% adds in the container, and the lyophilization of-20--40 ℃ of pre-freeze final vacuum is taken out the back and flattened, and promptly gets short texture porous collagen film.Freeze dried collagem membrane put in the crosslinked fluid crosslinked after vacuum lyophilization once more, promptly get crosslinked weaker zone collagem membrane.
Crosslinked fluid prescription: 0.05-0.4mol.L-1 ribose+2.5%-20% acetone+0.5-4% ammonia.
3) under the stirring condition with the 1-4mgml of pH 6.
-1Chitosan-acetic acid solution splashes into the 0.5-2mgml that contains somatomedin
-1Heparin solution in, drip a fast 10-60 and drip/min, obtain wrapping the chitosan-heparin nanoparticle that carries somatomedin.The mass ratio of chitosan and heparin is 4-8: 5-10; Speed of agitator is 500-700rpm.The particle diameter of nanoparticle is 100-1000nm.
4) will tile after the moistening of crosslinked weaker zone collagem membrane distilled water, slowly drip chitosan-heparin nanoparticle that bag carries somatomedin on its surface, 4-8 ℃ air-dry down to the no working fluid in surface, to pave after the moistening of crosslinked compacted zone collagem membrane again in crosslinked weaker zone collagem membrane surface, thoroughly air-dry under 4-8 ℃, promptly get growth factor-loaded collagen group composite material.
Described collagen can be I Collagen Type VI or II Collagen Type VI.Described collagen is the beef tendon source, also can be the collagen protein in other kind animal such as pig source.
Step 2) the negative available D-ribose of collagem membrane is crosslinked by Maillard reaction, also can be to adopt chemical reagent such as physical method such as photochemical method, roentgenization or glutaraldehyde, epoxide, carbodiimides 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimides (EDC), genipin crosslinked.
The nanometer particle process method of step 3) is an ionic cross-linking, also can be the nanoparticle of other method preparation, as ultrasonic method, solvent evaporation method, film dispersion method etc.
Described growth factor-loaded be basic fibroblast growth factor, bone morphogenetic protein, transforming growth factor-beta, insulin like growth factor, platelet derived growth factor, and in the bioactive peptide of above-mentioned these somatomedin of synthetic one or more mix to use.
Growth factor-loaded collagen group composite material provided by the invention is used for initiatively inducing damaged place tissue repair, and composite has directed difference control slow releasing function to the somatomedin of institute's load, and the external control slow release cycle is 7-20 days or longer.Described directed difference control slow releasing function shows as, somatomedin via weaker zone to discharging speed that liquid discharges with different to the speed that discharges liquid release via compacted zone.Described release liquid comprises PBS, normal saline, serum and other simulated body fluid.
The basis set repair materials of knitting of oriented growth factor control slow release collagen of the present invention is a double-decker, be respectively fine and close collagem membrane and loose collagem membrane, the centre is equipped with chitosan-heparin nanoparticle that bag carries somatomedin, has Stability Analysis of Structures, the characteristics that have no side effect, compound somatomedin wherein there is directed difference control slow releasing function, thereby realizes that somatomedin initiatively induces damaged place tissue repair.This material also has excellent biological compatibility, biological degradability and extremely low immunogenicity, and various raw material is easy to get, and preparation process condition is gentle, is a kind of sick preferably defective tissue repair materials.
Description of drawings
Fig. 1 carries chitosan-heparin nanoparticle transmission electron microscope picture of bFGF for bag.
Fig. 2 carries chitosan-heparin nanoparticle mean diameter figure of bFGF for bag.
Fig. 3 is the basis set repair materials field emission scanning electron microscope figure (CAF: compacted zone, CFF: weaker zone) that knits of compound bFGF collagen.
Fig. 4 knits HSA 20d cumulative release percentage curves in PBS in the repair materials for compound HSA collagen is basis set.
Fig. 5 knits HSA 10d cumulative release percentage curves in collagenase solution in the repair materials for compound HSA collagen is basis set.
The specific embodiment
Embodiment 1: the preparation of loose and fine and close two kinds of collagem membranes
1. the preparation of beef tendon I Collagen Type VI swelling solution
Commercial fresh beef tendon is fully cleaned, remove paratenon and stndon sheath and fascia, wash in the rearmounted refrigerator freezing.Take out freezing beef tendon and laterally be cut into thick about 1mm section, add ficin enzymatic solution (concentration 0.05-0.25%) and handle, stir enzymolysis 24h in the rearmounted calorstat, add excessive H again
2O
2Cessation reaction, distilled water flushing 3-4 time is strained and is added 0.3% malonic acid solution swelling 24h after doing.Tendon sheet after the swelling fully stirs 6h, regulates viscosity with 0.3% malonic acid solution, and the positive press filtration of 80-120 order stainless (steel) wire is removed impurity and swelling thing not, encapsulates promptly.
2. the preparation of air-dry collagem membrane.
Get the collagen swelling solution of above-mentioned preparation, add 0.3% malonic acid solution dilution to 0.6% mass percent concentration, press 250g collagen swelling solution and add in area 14cm * 12cm container, air-dry 72h promptly gets air-dry collagem membrane.
3. the preparation of lyophilized collagen film
Above-mentioned 0.6% collagen swelling solution is pressed 250g add in 14cm * 12cm * 1.5cm container-35 ℃ of pre-freeze 2h final vacuum lyophilization 72h.Freeze-dry process condition: first section temperature-30 ℃, 1 ℃/min of rate of temperature fall, constant temperature time 30h; Second section temperature-15 ℃, 1 ℃/min of heating rate, constant temperature time 20h; 0 ℃ of the 3rd section temperature, 1 ℃/min of heating rate, constant temperature time 12h; 10 ℃ of the 4th section temperature, 1 ℃/min of heating rate, constant temperature time 6h; 15 ℃ of the 5th section temperature, 1 ℃/min of heating rate, constant temperature time 4h.Taking-up lyophilized collagen film places between two politef flat boards and flattens, and promptly gets the lyophilized collagen film.
4. air-dry collagem membrane and lyophilized collagen film crosslinked
4.1 crosslinked fluid prescription: 0.2mol.L
-1Ribose+10% acetone+2% ammonia.
4.2 air-dry collagem membrane is crosslinked
Air-dry collagem membrane places crosslinked fluid cross-linking reaction 48h, takes out, and soaks 24h behind the deionized water rinsing 5 times, and is air-dry once more, promptly gets crosslinked air-dry collagem membrane (fine and close collagem membrane).
4.3 the lyophilized collagen film is crosslinked
The lyophilized collagen film places crosslinked fluid cross-linking reaction 48h, takes out, and soaks 24h ,-35 ℃ of pre-freeze 2h final vacuum lyophilization 24h behind the deionized water rinsing 5 times.Freeze-dry process condition: first section temperature-30 ℃, 1 ℃/min of rate of temperature fall, constant temperature time 10h; Second section temperature-15 ℃, 1 ℃/min of heating rate, constant temperature time 6h; 0 ℃ of the 3rd section temperature, 1 ℃/min of heating rate, constant temperature time 4h; 10 ℃ of the 4th section temperature, 1 ℃/min of heating rate, constant temperature time 2h; 15 ℃ of the 5th section temperature, 1 ℃/min of heating rate, constant temperature time 2h.Taking-up is placed between two politef flat boards and flattens, and promptly gets crosslinked lyophilized collagen film (loose collagem membrane).
Embodiment 2: ionic cross-linking prepares chitosan-heparin-bFGF nanoparticle
1. chitosan (molecular weight 10000, deacetylation 85%) is dissolved in 1% acetic acid solution, filters back dialysis 4d, lyophilization obtains the purification chitosan.
2. take by weighing the 0.2g chitosan and be dissolved in 5ml 1% acetic acid, 0.1molL
-1NaOH transfers pH to 6.0, is settled to 100ml, and obtaining concentration is 2mgml
-1Chitosan solution filters, and removes wherein impurity.
3. at 1mgml
-1Add the bFGF that estimates consumption in heparin (molecular weight 12000) solution, mix spend the night (8-12 hour).At 4 ℃, rotating speed 700rpm stirs down, with 2ml 2mgml
-1Chitosan solution dropwise splashes into 5ml 1mgml
-1In the compound bFGF heparin, drip 20/min of speed, promptly obtain wrapping the chitosan-heparin nanoparticle that carries bFGF.
The nanoparticle that makes is observed size than homogeneous under transmission electricity ytterbium, see Fig. 1; The nanoparticle particle size distribution is narrower, and mean diameter is 149.5nm, sees Fig. 2.
Embodiment 3: the preparation of load bFGF collagen group composite material
Tile after the crosslinked weaker zone collagem membrane distilled water moistening that the above embodiments are made, drip the Ch-He nanoparticle that bag carries bFGF on its surface slowly, be paved with whole surface.4 ℃ air-dry down to the no mobile phase liquid in CFF surface, to pave after the moistening of crosslinked compacted zone collagem membrane again in the crosslinked weaker zone collagem membrane surface that retains small amount of liquid, thoroughly air-dry under 4 ℃, promptly get the collagen group composite material of load bFGF, wherein the amount of bFGF is 100ng/cm
-2
With double layer material transverse section metal spraying, field emission scanning electron microscope is observed visible (Fig. 3): composite is compounded to form by double-layer structure, the compacted zone compact structure is smooth, and weaker zone is loose porous, and this structure can satisfy the directed release of difference to the different requirement of double layer material both sides density degree.Fine and close and loose how the qualification
Embodiment 4: collagen group composite material release in vitro dynamic experiment
Above-mentioned composite can load bFGF, bone morphogenetic protein(BMP) (BMP), vascular endothelial cell growth factor multiple bioactie agents such as (VEGF), to be applicable to the tissue repair of multi-field or different repairing phases, with human serum albumin (HSA) is factor of a model, carries out load HSA collagen composite materials release in vitro dynamics research.
1.6mg HSA is dissolved in 50mmol.L
-1Among the phosphate buffer 800 μ l, 0.5mg toluene-sodium-sulfonchloramide and 0.5mg sodium metasulfite are dissolved in respectively among the phosphate buffer 100 μ l.
Get HSA 100 μ l and add in the micro-labelling pipe, add Na again
125I 1.6 μ l (0.5mCi) add 50 μ l toluene-sodium-sulfonchloramides, and the room temperature Chun adds 50 μ l sodium metasulfite cessation reactions after swinging 5min.Reactant liquor is transferred to uses 50mmol.L
-1In phosphate buffer balance and the Sephadex-G50 post that adsorbed by blank HSA.Add 10 μ l 1%NaI liquid in the reactant liquor as separation
125The I carrier.
Sephadex-G50 post 50mmol.L
-1The phosphate buffer flushing is collected 1 pipe for per 10, and 10 of per minutes are collected 45 pipes altogether.Get 1 μ l in each pipe and measure radioactive intensity, determine the radioactive intensity of unit mass HSA.
Above phosphate buffer pH is 7.4.
By the material of every diameter 13mm, its radioactive intensity is 1 μ Ci (1 μ Ci=1.55 * 10
6Cpm) ratio is with a certain amount of
125I-HSA mixes with 2ml 1mg.ml-1 heparin, and 4 ℃ of bags that spend the night and prepare carry
125The chitosan of I-HSA-heparin nanoparticle, and make bag and carry
125The basis set repair materials of knitting of the collagen of I-HSA.
Using stream pond method detects: diameter 13mm bag is carried
125It is in the filter of 13mm that the collagen group composite material of I-HSA places internal diameter, release liquid is flowed out from double layer material, effusive direction is respectively the extremely loose collagem membrane of fine and close collagem membrane, loose collagem membrane to fine and close collagem membrane, discharge liquid and be respectively PBS (pH7.4) solution or 0.5 μ g I Collagen Type VI enzymatic solution, flow velocity is 10ml/12h.Get the release liquid 200 μ l that each group is collected, radioimmunoassay gamma counter detection of radioactive intensity, and calculate every d and always collect the liquid radioactive intensity.
Under PBS aqueous solution swelling action, HSA, has been embodied bag and has carried a proteic directed release property (Fig. 4) to the cumulative release percentage rate (56.4%) of weaker zone 20d cumulative release percentage rate (69.4%) greater than rightabout release by compacted zone; In collagenase solution, and the cumulative release percentage rate that HSA is discharged less than rightabout to weaker zone 10d cumulative release percentage rate (52.1%) by compacted zone (64.5%, Fig. 5), show the directed difference release action of composite to the HSA of load.And just in time opposite in the collagenase solution, relative with the weaker zone collagen structure loose porous, easily relevant by degraded by collagenase, also show the directed difference release action of composite to the HSA of load.
Claims (10)
1. growth factor-loaded collagen group composite material, it is characterized in that it is that to receive with collagen, somatomedin, chitosan, heparin be feedstock production, form double-decker by compacted zone collagem membrane and weaker zone collagem membrane, double-deck middle superpacket carries the chitosan-heparin nanoparticle of somatomedin; Concrete preparation technology: the collagem membrane after the collagen swelling solution is air-dry is crosslinked in crosslinked fluid, and is air-dry, gets the compact structure collagem membrane; The collagen swelling solution is in the lyophilization of pre-freeze final vacuum, flatten, lyophilizing, in crosslinked fluid crosslinked after vacuum lyophilization once more, short texture porous collagen film; Stir down the acetic acid solution of chitosan mixes the chitosan-heparin nanoparticle that obtains somatomedin with the heparin solution that contains somatomedin; Crosslinked weaker zone collagem membrane surface in moistening drips chitosan-heparin nanoparticle that bag carries somatomedin, and is air-dry, the more crosslinked compacted zone collagem membrane of moistening paved in crosslinked weaker zone collagem membrane surface, air-dry.
2. composite according to claim 1, the mass ratio that it is characterized in that described chitosan and heparin is 4-8: 5-10; The molecular weight 3000-20000 of heparin; The molecular weight 8000-20000 of chitosan, deacetylation 70-90%.
3. composite according to claim 1 is characterized in that every square centimeter of crosslinked weaker zone collagem membrane somatomedin consumption is 50-10000ng; Duplicature average thickness 1-4mm.
4. the preparation method of the described growth factor-loaded collagen group composite material of claim 1 is characterized in that the step that comprises:
1) get the collagen swelling solution and be diluted to the 0.3-0.8% mass percent concentration, 4-8 ℃ air-dry, promptly get the compact structure collagem membrane; Fine and close collagem membrane is put in the crosslinked fluid crosslinked and air-dry once more, promptly gets crosslinked compacted zone collagem membrane;
2) the collagen swelling solution with 0.3-0.8% adds in the container, the lyophilization of-20--40 ℃ of pre-freeze final vacuum is taken out the back and is flattened, and promptly gets short texture porous collagen film, freeze dried collagem membrane put in the crosslinked fluid crosslinked after vacuum lyophilization once more, promptly get crosslinked weaker zone collagem membrane;
Crosslinked fluid prescription: 0.05-0.4mol.L-1 ribose+2.5%-20% acetone+0.5-4% ammonia;
3) under the stirring condition with the 1-4mgml of pH 6.
-1Chitosan-acetic acid solution splashes into the 0.5-2mgml that contains somatomedin
-1Heparin solution in, drip a fast 10-60 and drip/min, obtain wrapping the chitosan-heparin nanoparticle that carries somatomedin; Speed of agitator is 500-700rpm.The particle diameter of nanoparticle is 100-1000nm;
4) will tile after the moistening of crosslinked weaker zone collagem membrane distilled water, slowly drip chitosan-heparin nanoparticle that bag carries somatomedin on its surface, 4-8 ℃ air-dry down to the no working fluid in surface, to pave after the moistening of crosslinked compacted zone collagem membrane again in crosslinked weaker zone collagem membrane surface, thoroughly air-dry under 4-8 ℃, promptly get growth factor-loaded collagen group composite material.
5. the preparation method of composite according to claim 4 is characterized in that described collagen can be type i collagen or II Collagen Type VI; Described collagen is the beef tendon source or the collagen protein of other kind animal origin.
6. the preparation method of composite according to claim 4 is characterized in that described collagen swelling solution is a beef tendon type i collagen swelling solution.
7. the preparation method of composite according to claim 4, it is characterized in that step 2) the negative available D-ribose of collagem membrane crosslinked by Maillard reaction, also can be to adopt physical method such as photochemical method, roentgenization or glutaraldehyde, epoxide, carbodiimides 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimides (EDC), genipin chemical reagent crosslinked.
8. the preparation method of composite according to claim 4, the nanometer particle process method that it is characterized in that step 3) is an ionic cross-linking, also can be that ultrasonic method, solvent evaporation method, film dispersion method prepare nanoparticle.
9. the preparation method of composite according to claim 4, it is characterized in that describedly growth factor-loadedly being basic fibroblast growth factor, bone morphogenetic protein, transforming growth factor-beta, insulin like growth factor, platelet derived growth factor, and in the bioactive peptide of above-mentioned these somatomedin of synthetic one or more mix and use.
10. the described growth factor-loaded collagen group composite material of claim 1 is used for initiatively inducing damaged place tissue renovation material.
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