CN106693050A - Preparation method for composite scaffold material based on collagen and collagen fibers - Google Patents

Preparation method for composite scaffold material based on collagen and collagen fibers Download PDF

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CN106693050A
CN106693050A CN201710109808.7A CN201710109808A CN106693050A CN 106693050 A CN106693050 A CN 106693050A CN 201710109808 A CN201710109808 A CN 201710109808A CN 106693050 A CN106693050 A CN 106693050A
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collagen
collagenous fibres
preparation
material based
compound
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CN106693050B (en
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但卫华
但年华
刘新华
刘婷
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Sichuan University
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Abstract

The invention discloses a preparation method for a composite scaffold material based on collagen and collagen fibers; the preparation method is characterized in that collagen and aggregative-state structural body collagen fibers are mixed organically, functional oxidized polysaccharide and graphene oxide are used for composite synergistic modification of a collagen-collagen fiber composite solution, next, the collagen-collagen fiber composite solution is co-mixed with a certain amount of chitosan and polyvinyl alcohol, and then through 3D printing, microwave drying film formation, electric spraying, sterilization and other processes, the composite scaffold material based on the collagen and the collagen fibers is finally obtained. The material adopts the collagen fibers having a natural collagen structure and having stronger biomimetic property, the microstructure and morphology of the scaffold are biologically designed by using the 3D printing technology, natural active tissues are fully mimicked in the chemical composition and the natural structure, and the obtained scaffold material has the advantages of stable structure, superior physical and chemical properties, and good cell compatibility and biodegradability, also can induce tissue regeneration and repair, and can be used as various types of tissue engineering scaffolds.

Description

A kind of preparation method of the compound support frame material based on collagen and collagenous fibres
Technical field
The present invention relates to a kind of compound support frame material based on collagen and collagenous fibres, belong to bio-medical material preparation Field.
Background technology
Tissue engineering bracket is the most basic framework of engineered tissue, for cell and tissue growth provide suitable ring Border, and gradually degrade and disappear with the structure of tissue, so as to new space is supplied into tissue and cell.The structure is thin Born of the same parents obtain the place of nutrition, gas exchanges, waste discharge and growth metabolism, are to form the new group with certain form and function Knit, the basis of organ.Recent decades, people manufacture active mass all the time by one " two-step method ".The first step is to use certain The support of Biodegradable material design organization.In order that with the support of conventional method designing for manufacturing, researcher is needed for it Model, carve out, or go out a porous shape using chemicals etch.Second step is to cultivate a branch using living cells Frame.Numerous studies prove that these technologies have many drawbacks, such as largely use highly toxic organic solvent, and the manufacturing cycle is long, Labour-intensive flow, it is impossible to remove the residue in polymeric matrix completely, repeatability is poor, and hole is presented irregular shape Cannot fully be connected between shape, hole, structure is partially thin etc..Additionally, the most uncontrollable shapes of these methods.
Compared with this method, shape and structure that 3D printing is organized needed for can accurately printing.The bone of 3D printing is planted Enter thing, corona, contact lenses and audiphone etc. and repair form without life to be already present on the internal of thousands of people all over the world. At present, 3D printing body part uses single material, such as metal, ceramics or plastics.They have commercial significance, because they Market value can be brought into close contact with a special body of shape from them.However, these materials are also only capable of turning into Abiotic alternative site, real 3D biometric prints should be creation active mass.Biometric print, the i.e. use of " ink living ", it is interior Portion left floating the printable gel of living cells.By living cells and " gap fillers "（Such as collagen, with temporary transient packing space until with Other cell fusions）The many special and accurate shape of tissue is printed, living cells secrets out of material and enters hydrogel, from And ultimately form a support parent.With the growth of cell, parent develops into active mass.
Collagen and collagenous fibres, with good biocompatibility and biodegradability, and promote cell growth with The performance of adhesion, and with pH and temperature sensitivity, beneficial to shaping, it has been applied to 3D printing active mass field.However, pure The 3D printing active mass of collagen or collagenous fibres is also not enough to support the tissue of definite shape in mechanical property, therefore adds Plus other biomaterials or micro crosslinking agent turn into necessary element during 3D printing.
Therefore a kind of method of compound support frame material based on collagen and collagenous fibres that this patent is obtained is in 3D printing Active mass field has broad application prospects.
The content of the invention
The purpose of the present invention is directed to the deficiency of existing correlation technique and provides a kind of based on collagen and collagenous fibres Compound support frame material.The timbering material cell compatibility is excellent, is very beneficial for growth, propagation and the migration of cell, cell energy It is enough preferably to grow into internal stent, but the effects such as with certain anti-inflammatory, anti-oxidant, antibacterial, bioactivity is good, can be used as tissue Engineering rack.
The purpose of the present invention can be realized that its preparation methods steps are as follows by following technology of preparing：
（1）The preparation of the collagen-collagen fiber composite swelling solution based on oxidation of polysaccharides and graphene oxide：To in mass ratio be 1 Collagen and the collagenous fibres mixing of~9: 9~1 1~2 weight portion, stir the vinegar for being swollen in that pH is 4.0 at 4~10 DEG C In acid-sodium acetate buffer system, the collagen-collagen fiber composite swelling solution that concentration is 1~2wt% is obtained；Then to above-mentioned compound The oxidation of polysaccharides of 0.05~0.4 weight portion is added in swelling solution, lucifuge reacts 10~24h at 4~10 DEG C, after the completion of question response, The graphene oxide of 0.01~0.2 weight portion is added to compound swelling solution again, continues to react 24~48h at 4~10 DEG C, obtain base In oxidation of polysaccharides and the collagen-collagen fiber composite swelling solution of graphene oxide；
（2）The preparation of the stoste of the compound support frame material based on collagen and collagenous fibres：By the shitosan of 0.5~1.5 weight portion Above-mentioned collagen-collagen fiber composite swelling solution is added to, is stirred at 4~10 DEG C to whole dissolvings, obtain mixed liquor A；40~ At 80 DEG C by the polyvinyl alcohol dissolving of 6~12 weight portions in deionized water, the polyvinyl alcohol water that concentration is 6~12wt% is obtained Solution；To be stirred at 4~10 DEG C to filling by volume for 1~10: 0.01~2 mixing A liquid mixes with polyvinyl alcohol water solution Divide molten altogether, obtain the stoste of the compound support frame material based on collagen and collagenous fibres；
（3）The preparation of the compound support frame material based on collagen and collagenous fibres：Computer is used according to required support form, structure Autocad develops the program of control platform movement, by the above-mentioned compound support frame material based on collagen and collagenous fibres Stoste injects 3D biometric print machines, and 3D printing shaping obtains collagen-collagen fibrous composite scaffold, and compound rest is transferred to micro- Film forming on ripple drying machine；In the acetum of 0.05~0.5M, it is configured to dense followed by by 1~2 weight portion collagen solution The collagen solution collagen for 1~2wt% is spent, above-mentioned collagen solution is sprayed on collagen-collagen fiber composite using electrostatic sprayer Support tow sides, final freeze-dried, dosage is 6~30KGy/h60Gamma-rays sterilization produced by Co, shaping bag Dress, obtains the final finished of the compound support frame material based on collagen and collagenous fibres.
In above-mentioned preparation method, step（1）Middle use oxidation of polysaccharides is by carboxymethylcellulose calcium, hyaluronic acid, shell Glycan, glucan etc. through sodium periodate oxidation gained, specific preparation method with reference to this seminar early stage publication [but defend China, Liu Xinhua, but time, wait to have the collagen aggregate composite type medical fiber Chinese invention patents of antibacterial/bacteriostasis efficacy 201510127304.9；But time, but China is defended, Liu Xinhua waits to aoxidize chitosan oligosaccharide and preparation method thereof patent authorization numbers：CN 104004112 A；But defend China, Liu Xinhua, but time, wait aoxidize the modified pig dermis collagen micro-nano fiber film of chitosan graft and Its preparation method patent authorization numbers：CN 104013995 A]；Step（1）Described in graphene oxide, polyvinyl alcohol, shell gather Sugar is medical grade；Step（1）The 3D printing program of the compound support frame material of middle collagen and collagenous fibres need to be according to specific support Depending on purposes, form, fine structure.
The invention has the advantages that：
（1）From the collagen class timbering material of report is different mostly, present invention employs collagen and collagenous fibres, wherein collagen Fiber is the aggregation of collagen, and its structure is increasingly complex, more can in bionical active mass's body collagen presence structural form, research Show that its physicochemical property, bioactivity, tissue regeneration induction repair ability are significantly stronger；
（2）It is the modifying agent of collagen that the present invention uses oxidation of polysaccharides and graphene oxide, and one side oxidation of polysaccharides can be sent out with collagen Remain to keep the feature of its body after raw schiff bases bond is closed and reaches effective effect being crosslinked, and polysaccharide is oxidized, have very much Beneficial to the preparation of functionalization collagen；On the other hand it is that graphene oxide be able to can show while collagenous biological activity is not influenceed The physicochemical property of enhancing collagen is write, and can assign collagen certain antibacterial/biocidal property；
（3）Bionical biological design can be carried out to the form of support, microstructure etc. using 3D printing technique, by regulating and controlling support Microstructure, pattern realizing the control for growing into, growing to cell.
Specific embodiment
Below by implementing to be specifically described the present invention, it is necessary to it is pointed out here that to be that the present embodiment is served only for right The present invention is described further, and it is not intended that limiting the scope of the invention, the person skilled in the art in the field can Nonessential modifications and adaptations are made with according to the content of foregoing invention.
Embodiment 1
（1）The preparation of the collagen-collagen fiber composite swelling solution based on oxidation of polysaccharides and graphene oxide：To in mass ratio be 1: Collagen and the collagenous fibres mixing of 91 weight portion, stir the Acetic acid-sodium acetate buffer body for being swollen in that pH is 4.0 at 4 DEG C In system, the collagen-collagen fiber composite swelling solution that concentration is 1wt% is obtained；Then to adding 0.05 weight in above-mentioned compound swelling solution The oxidation of polysaccharides of part is measured, lucifuge reaction 24h at 4 DEG C, after the completion of question response, then to adding 0.2 weight portion in compound swelling solution Graphene oxide, continues to react 48h at 4 DEG C, obtains the collagen-collagen fiber composite based on oxidation of polysaccharides and graphene oxide molten Swollen liquid；
（2）The preparation of the compound support frame material stoste based on collagen and collagenous fibres：The shitosan of 0.5 weight portion is added to State in collagen-collagen fiber composite swelling solution, stirred at 4 DEG C to whole dissolvings, obtain mixed liquor A；By 6 weight portions at 40 DEG C Polyvinyl alcohol dissolving in deionized water, obtain concentration be 6wt% polyvinyl alcohol water solution；Will by volume for 1: 2 it is mixed Close A liquid to mix with polyvinyl alcohol water solution, stirred at 4 DEG C to fully molten altogether, obtain the composite support based on collagen and collagenous fibres The stoste of frame material；
（3）The preparation of the compound support frame material based on collagen and collagenous fibres：Computer is used according to required support form, structure Autocad develops the program of control platform movement, by the above-mentioned compound support frame material based on collagen and collagenous fibres Stoste injects 3D biometric print machines, and 3D printing shaping obtains collagen-collagen fibrous composite scaffold, and compound rest is transferred to Film forming on microwave dryer；Followed by by 1 weight portion collagen solution, in the acetum of 0.05M, being configured to concentration is The collagen solution collagen of 1wt%, collagen-collagen fibrous composite scaffold is being sprayed on just using electrostatic sprayer by above-mentioned collagen solution Anti- two sides, final freeze-dried, dosage is 6KGy/h60Gamma-rays sterilization produced by Co, shaping packaging obtains base In collagen and the final finished of the compound support frame material of collagenous fibres.
Embodiment 2
（1）The preparation of the collagen-collagen fiber composite swelling solution based on oxidation of polysaccharides and graphene oxide：To in mass ratio be 3: Collagen and the collagenous fibres mixing of 7 1.5 weight portions, stir the Acetic acid-sodium acetate buffering for being swollen in that pH is 4.0 at 5 DEG C In system, the collagen-collagen fiber composite swelling solution that concentration is 1.5wt% is obtained；Then added in above-mentioned compound swelling solution The oxidation of polysaccharides of 0.2 weight portion, lucifuge reaction 15h at 5 DEG C after the completion of question response, then adds 0.1 weight portion to compound swelling solution Graphene oxide, continue to react 24~48h at 5 DEG C, obtain the collagen-collagen fiber based on oxidation of polysaccharides and graphene oxide Compound swelling solution；
（2）The preparation of the stoste of the compound support frame material based on collagen and collagenous fibres：The shitosan of 1 weight portion is added to Collagen-collagen fiber composite swelling solution is stated, is stirred at 5 DEG C to whole dissolvings, obtain mixed liquor A；By 8 weight portions at 60 DEG C Polyvinyl alcohol dissolves in deionized water, obtains the polyvinyl alcohol water solution that concentration is 8wt%；It will be by volume 5: 1 mixing A liquid mixes with polyvinyl alcohol water solution, is stirred at 5 DEG C to fully molten altogether, obtains the compound rest based on collagen and collagenous fibres The stoste of material；
（3）The preparation of the compound support frame material based on collagen and collagenous fibres：Computer is used according to required support form, structure Autocad develops the program of control platform movement, by the above-mentioned compound support frame material based on collagen and collagenous fibres Stoste injects 3D biometric print machines, and 3D printing shaping obtains collagen-collagen fibrous composite scaffold, and compound rest is transferred to Film forming on microwave dryer；Followed by by 1.5 weight portion collagen solutions, in the acetum of 0.1M, being configured to concentration is The collagen solution collagen of 1.5wt%, collagen-collagen fibrous composite scaffold is sprayed on using electrostatic sprayer by above-mentioned collagen solution Tow sides, final freeze-dried, dosage is 15KGy/h60Gamma-rays sterilization produced by Co, shaping packaging is obtained The final finished of the compound support frame material based on collagen and collagenous fibres.
Embodiment 3
（1）The preparation of the collagen-collagen fiber composite swelling solution based on oxidation of polysaccharides and graphene oxide：To in mass ratio be 9: Collagen and the collagenous fibres mixing of 12 weight portions, stir the Acetic acid-sodium acetate buffering for being swollen in that pH is 4.0 at 10 DEG C In system, the collagen-collagen fiber composite swelling solution that concentration is 2wt% is obtained；Then to adding 0.4 in above-mentioned compound swelling solution The oxidation of polysaccharides of weight portion, lucifuge reaction 10h at 10 DEG C after the completion of question response, then adds 0.01 weight portion to compound swelling solution Graphene oxide, continue to react 24h at 4~10 DEG C, obtain the collagen-collagen fiber based on oxidation of polysaccharides and graphene oxide Compound swelling solution；
（2）The preparation of the stoste of the compound support frame material based on collagen and collagenous fibres：The shitosan of 1.5 weight portions is added to Above-mentioned collagen-collagen fiber composite swelling solution, stirs to whole dissolvings at 10 DEG C, obtains mixed liquor A；By 6~12 at 80 DEG C The polyvinyl alcohol dissolving of weight portion in deionized water, obtains the polyvinyl alcohol water solution that concentration is 12wt%；To be by volume 10: 0.01 mixing A liquid mixes with polyvinyl alcohol water solution, is stirred at 10 DEG C to fully molten altogether, obtains based on collagen and collagen The stoste of the compound support frame material of fiber；
（3）The preparation of the compound support frame material based on collagen and collagenous fibres：Computer is used according to required support form, structure Autocad develops the program of control platform movement, by the above-mentioned compound support frame material based on collagen and collagenous fibres Stoste injects 3D biometric print machines, and 3D printing shaping obtains collagen-collagen fibrous composite scaffold, and compound rest is transferred to Film forming on microwave dryer；It is 2wt% followed by 2 weight portion collagen solutions in the acetum of 0.5M, to be configured to concentration Collagen solution collagen, above-mentioned collagen solution is sprayed on collagen-collagen fibrous composite scaffold positive and negative two using electrostatic sprayer Face, final freeze-dried, dosage is 30KGy/h60Gamma-rays sterilization produced by Co, shaping packaging is obtained based on glue The final finished of the compound support frame material of former and collagenous fibres.

Claims (3)

1. a kind of preparation method of the compound support frame material based on collagen and collagenous fibres, it is characterised in that the method includes following Step：
（1）The preparation of the collagen-collagen fiber composite swelling solution based on oxidation of polysaccharides and graphene oxide：To in mass ratio be 1 Collagen and the collagenous fibres mixing of~9: 9~1 1~2 weight portion, stir at a temperature of 4~10 DEG C, and being swollen in pH is In 4.0 Acetic acid-sodium acetate buffer system, the collagen-collagen fiber composite swelling solution that concentration is 1~2wt% is obtained；Then to The oxidation of polysaccharides of 0.05~0.4 weight portion is added in above-mentioned compound swelling solution, lucifuge reacts 10~24h, question response at 4~10 DEG C After the completion of, then to compound swelling solution add 0.01~0.2 weight portion graphene oxide, at 4~10 DEG C continue react 24~ 48h, obtains the collagen-collagen fiber composite swelling solution based on oxidation of polysaccharides and graphene oxide；
（2）The preparation of the stoste of the compound support frame material based on collagen and collagenous fibres：By the shitosan of 0.5~1.5 weight portion Above-mentioned collagen-collagen fiber composite swelling solution is added to, is stirred at 4~10 DEG C to whole dissolvings, obtain mixed liquor A；40~ At 80 DEG C by the polyvinyl alcohol dissolving of 6~12 weight portions in deionized water, the polyvinyl alcohol water that concentration is 6~12wt% is obtained Solution；To be stirred at 4~10 DEG C to filling by volume for 1~10: 0.01~2 mixing A liquid mixes with polyvinyl alcohol water solution Divide molten altogether, obtain the stoste of the compound support frame material based on collagen and collagenous fibres；
（3）The preparation of the compound support frame material based on collagen and collagenous fibres：Computer is used according to required support form, structure Autocad develops the program of control platform movement, by the above-mentioned compound support frame material based on collagen and collagenous fibres Stoste injects 3D biometric print machines, and 3D printing shaping obtains collagen-collagen fibrous composite scaffold, and compound rest is transferred to Film forming on microwave dryer；In the acetum of 0.05~0.5M, it is configured to followed by by 1~2 weight portion collagen solution Concentration is the collagen solution collagen of 1~2wt%, and above-mentioned collagen solution is sprayed on into collagen-collagen fiber using electrostatic sprayer answers Support tow sides are closed, final freeze-dried, dosage is 6~30KGy/h60Gamma-rays sterilization produced by Co, shaping Packaging, obtains the final finished of the compound support frame material based on collagen and collagenous fibres；It is compound based on collagen and collagenous fibres Timbering material, consists predominantly of collagen, collagenous fibres, four kinds of base-materials of shitosan and polyvinyl alcohol, and its Key Performance Indicator is as follows：
Average pore size：≥20μm；
Content of beary metal：≤10μg/g(m/m)；
Cytotoxicity：Cell-cytotoxic reaction is not more than 1 grade；
Sterility test：It is aseptic；
Sensitization test (STT)：Without delayed type hypersensitivity, DTH；
Intradermal reaction is tested：Primary SI PII<0.4.
2. the preparation method of the compound support frame material based on collagen and collagenous fibres described in claim 1, it is characterised in that institute The collagen and collagenous fibres stated are obtained from the middle extraction of any one of pigskin, pig tendon, ox-hide, beef tendon, donkey hide or rat-tail tendon .
3. the preparation method of the compound support frame material based on collagen and collagenous fibres described in claim 1, it is characterised in that institute The oxidation of polysaccharides stated is polysaccharide through that obtained by sodium periodate oxidation, can be gathered from oxidation shitosan, DHA, oxidation Portugal Sugar, any one in oxidated carboxymethyl cellulose.
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