CN105664245A - Injected supermolecule hydrogel and preparing method thereof - Google Patents
Injected supermolecule hydrogel and preparing method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of hydrogel and provides injected supermolecule hydrogel and a preparing method thereof. The injected supermolecule hydrogel comprises beta-cyclodextrin, gelatin and a coupling agent. Beta-cyclodextrin and a benzene ring in gelatin are combined in a subject and object mode by means of the hydrophobicity effect. The coupling agent is a silane coupling agent containing amino and/or epoxy bonds. Gelatin and the end, containing amino or epoxy bonds, of the coupling agent form covalent cross linking. The other end of the coupling agent is subjected to self-crosslinking to form a silicon dioxide network.
Description
Technical field
The invention belongs to technical field of hydrogel, particularly relate to a kind of injectable type supramolecular hydrogel and its preparation method.
Background technology
Cartilage defect is orthopaedics common clinical, and Arthroscopy finds that there is cartilage defect in about 60% joint. As treated not in time, the pathology of 60%-75% can develop into osteoarthritis by Progressive symmetric erythrokeratodermia, seriously affects the motor function of patient, and even terminate its career. Owing to joint cartilage does not have vessel innervation, its regenerative power is very limited. Therefore, at biomaterial and medical field, cartilage defect repair is the focus of research always. Up to now, cartilage defect repair is effectively solved not yet. Autologous Chondrocyte transplantation, as the gold standard for the treatment of articular cartilage defect, has obtained generally acknowledging of scholar, but there is the problems such as the limited and second operation in seed cell source, limits this technology in clinical widespread use.
The reparation cartilage defect that develops into of organizational engineering opens new approach. hydrogel, due to unique character such as its water-retentivity are extremely high, cellular affinity is strong, is widely used in cartilage tissue engineered field. the tissue engineering bracket of current clinical application is such as type i collagen gel, hyaluronic acid derivatives, fibrin gel etc., exist as mechanical property is not good, self-healing properties is poor, not injectable or not easily fix and from defects such as defect losses, limit further developing of hydrogel. recently, investigator is had to utilize alginate and polyacrylamide to develop the hydrogel (SunJY of a kind of snappiness and high tenacity, Nature, 2012.489:133-6), the dimension utilizing the 3D printer of band UV cure system to print out strengthens hydrogel (BakarichSE, AppliedMaterials&Interfaces, 2014.6 (18): 15998-6006), above-mentioned hydrogel all shows good performance, but do not possess syringeability due to it, cause it for needing external premolding time clinical, this applies the extra wound that surgical operation cannot be avoided to bring to patient clinically. therefore, develop a kind of novel injection aquagel and address the aforementioned drawbacks the important topic becoming medical science and biomaterial field in recent years. common Injectable in-situ shaping hydrogel comprises hyaluronic acid, alginates, chitosan, PNIPAM based aquagel etc. but, syringeability hydrogel is owing to being limit by its material, and its mechanical property often can not meet clinical demand.Therefore, finding out a kind of new hydrogel synthesis technique, make high-performance and syringeability be embodied on a kind of hydrogel is the focus that current tissue engineering hydrogel is studied simultaneously.
The appearance of Inorganic-organic Hybrid Material then provides new approaches for solving this difficult problem. Some syringeability hydrogels introduce inorganic components by molecular hybrid form, build inorganic-organic hybrid hydrogel in nano level compound, are expected to obtain the syringeability tissue engineering hydrogel support that mechanical property and degradation property all reach clinical needs. At present, both at home and abroad inorganic-organic hybrid biomaterial has been carried out the research of some, wherein, respective material has all been carried out the conventional performance index such as thermodynamic stability, withstand voltage properties, morphological structure and has characterized by studies in China, and attempts using infrared spectra FTIR to detect whether its inorganic and organic composition carries out covalent cross-linking. But the limitation due to FTIR technology, its result cannot directly prove the generation that this hydridization is reacted, and material is only prepared into two-dirnentional structure, and research is still in the preliminary stage of exploration. And foreign study just predicts the molecular structure of hybrid prepared by them mostly, and only using FTIR to detect its covalent linkage type, this can not verify the inorganic-organic hybrid mechanism of hybrid.
Summary of the invention
It is an object of the invention to provide that a kind of mechanical property is excellent, degradation property good, self-healing properties is good, easily fix, avoid the injectable hydrogel that runs off in body, it is intended to solve prior art Problems existing.
Another object of the present invention is to provide the preparation method of a kind of injectable hydrogel.
The present invention realizes like this, a kind of injectable hydrogel, comprise beta-cyclodextrin, gelatin and coupling agent, the phenyl ring of described beta-cyclodextrin in described gelatin is combined by hydrophobicity effect Subjective and Objective, described coupling agent is the silane coupling agent containing amino and/or epoxy bond, wherein, described gelatin and described coupling agent form covalent cross-linking containing amino or epoxy bond end, the other end of described coupling agent is spontaneous is cross-linked to form network of silica.
And, the preparation method of a kind of injectable hydrogel, comprises the following steps:
The acidic solution of gelatin is provided;
Adding coupling agent in the acidic solution of described gelatin and carry out the first crosslinking reaction, obtain gelatin/coupling agent solution, wherein, described coupling agent is the silane coupling agent containing amino and/or epoxy bond;
Described gelatin/coupling agent solution adds beta-cyclodextrin and forms mixing solutions, after mixing even leaving standstill, obtain silicon-dioxide/gelatin/beta-cyclodextrin supramolecule-hydridization Dual system hydrogel.
Injectable hydrogel provided by the invention, the phenyl ring of described beta-cyclodextrin in described gelatin is combined by hydrophobicity effect Subjective and Objective, described gelatin and described coupling agent form covalent cross-linking containing amino or epoxy bond one end, spontaneous after the other end acid hydrolysis of described coupling agent it is cross-linked to form network of silica, or it is cross-linked with each other formation network of silica to regulate and control separately the inorganic components content of hydrogel with the extra acid hydrolysis silane compound added after the other end acid hydrolysis of described coupling agent, the high performance supramolecule of the novel degradable obtained-hybridized hydrogel forms reticulated structure, there is excellence and regulatable mechanical property, degradation property, self-regeneration performance, superpower tissue adherence and injectable performance, treat articular cartilage defect for organization engineered cartilage and open new way, there is very strong novelty and clinical meaning. concrete, the following advantage of described supramolecular hydrogel:
1. owing to this injectable hydrogel has supramolecular system, its beta-cyclodextrin and gelatin are reversible by the physical property Subjective and Objective of hydrophobicity effect in conjunction with cross-linking set, in the process stretched or compress, while some cross-linking set are destroyed, have new cross-linking set to produce, thus significantly enhance the stretching/compressing performance of hydrogel.Meanwhile, the inorganic silicon network that the present invention is also introduced by molecular hybrid form so that hydrogel elastic is extremely outstanding, original state still can be recovered after extruding by gravity, and mechanical property and degradation property controlled, stronger than the toughness of simple silicon-dioxide/gelatin hybridized hydrogel, it is not easy to crumb, broken. Compared with tradition micro inorganic organic composite material, inorganic and the organic composition of hybrid material carries out covalently cross-linked on nanoscale, therefore two kinds of composition degradation speeds are consistent, good at body internal stability, and mechanical property and degradation property controllable (by regulating gelatin/silica ratios and/or coupling agent content to realize).
2. tangent plane due to supramolecule-hybridized hydrogel has the phenyl ring (from gelatin molecule) much not combined and beta-cyclodextrin, when tangent plane contacts, in conjunction with phenyl ring can again form Subjective and Objective with described beta-cyclodextrin and be combined, the hydrogel cut is made again to recover as complete one piece, thus give supramolecular hydrogel selfreparing character of the present invention so that even if described supramolecular hydrogel is after fragmentation, still can recombine and form complete hydrogel.
3. injectable hydrogel of the present invention under high shear can be changed into solution, and therefore, during by needle injection, the high shear force of existence makes described supramolecular hydrogel be injected into the tissue defect site of required filling with solution state, and fills this position full; Afterwards due to the disappearance of high shear force, solution returns to the state of hydrogel again, therefore can shift to an earlier date in vitro after plastic is cleaned and inject, thus avoid the chemical free radical that in-vivo tissue is directly exposed to uviolizing and produces thereupon; Meanwhile, the syringeability of supramolecular hydrogel of the present invention makes minimally-invasive treatment cartilage defect become possibility.
4. tissue surface fibrosis can cause the exposure of a large amount of collagen fabric, and therefore, the more healthy cartilage of cartilage surface of damage, pathology has the chemical group such as more highdensity amino (Methionin), phenyl ring (phenylalanine). And injectable hydrogel of the present invention exists a large amount of free beta-cyclodextrins, therefore possesses extremely strong viscosity, after implanting the cartilage defect of damage, pathology, Subjective and Objective can be carried out with the phenyl ring being exposed to tissue defect surface to be combined, be conducive to the adhesion on cartilaginous tissue surface of the body inner position after injecting and hydrogel, the defect easily run off after solving the injection of conventional hydrogel.
5. injectable hydrogel of the present invention can promote survival and the migration of seed cell, concrete, owing to the Subjective and Objective cross-linking set of supramolecular hydrogel is reversible existence, therefore, cell " can be untied " these cross-linking set and carry out infiltration migration, and after cell passes this region, the cross-linking set of these " by untiing " can recombine again, enable seed cell be evenly distributed in hydrogel and also it is fixed on defect area in company with hydrogel scaffold thus plays tissue repair effect.
The preparation method of injectable hydrogel provided by the invention, the phenyl ring of described beta-cyclodextrin in described gelatin is combined by hydrophobicity effect Subjective and Objective, described gelatin and described coupling agent form covalent cross-linking containing amino or epoxy bond one end, spontaneous after the other end acid hydrolysis of described coupling agent it is cross-linked to form network of silica, constructs a kind of silicon-dioxide/gelatin/beta-cyclodextrin supramolecule-hydridization Dual system hydrogel. The described injectable hydrogel prepared by the inventive method has excellence and regulatable mechanical property, degradation property, syringeability, self-healing property and short regenerating bone or cartilage repair ability, tissue can be adhered to fabulously and not easily run off simultaneously, there is good potential applicability in clinical practice.In addition, the inventive method is simple to operate, and flow process is easily controlled, and has good industrialization prospect.
Accompanying drawing explanation
Fig. 1 is the supramolecular hydrogel schematic arrangement that the embodiment of the present invention provides.
Embodiment
In order to make the technical problem to be solved in the present invention, technical scheme and useful effect clearly understand, below in conjunction with embodiment, the present invention is further elaborated. It is to be understood that specific embodiment described herein is only in order to explain the present invention, it is not intended to limit the present invention.
Composition graphs 1, the present invention executes example and provides a kind of injectable hydrogel, comprise beta-cyclodextrin, gelatin and coupling agent, the phenyl ring of described beta-cyclodextrin in described gelatin is combined by hydrophobicity effect Subjective and Objective, described gelatin and described coupling agent form covalent cross-linking containing amino or epoxy bond one end, the other end of described coupling agent is spontaneous is cross-linked to form network of silica.
The supramolecular hydrogel that the embodiment of the present invention provides, covalently cross-linked by chemistry between each material, supramolecule Subjective and Objective combines and forms network structure so that described injectable hydrogel integrally plays a role.
Concrete, described gelatin is as one of host component, and on the one hand, the carboxyl of described gelatin and amino can be covalently cross-linked with the described silane coupling agent containing amino and/or epoxy bond in acid condition; Simultaneously, owing to having the macrostructure fragment of phenylalanine in described gelatin structure, the phenyl ring in described gelatin molecule is combined with described beta-cyclodextrin Subjective and Objective (i.e. supramolecule reaction), therefore, produce supramolecule reaction between energy and described beta-cyclodextrin, form network structure. The optional Sigma article number of described gelatin powder is the gelatin of G1890-500G.
Described beta-cyclodextrin is as another host component, play a significant role, phenyl ring (phenylalanine structure) Subjective and Objective of describedization beta-cyclodextrin in described gelatin is combined, formed and there is reversible physical property cross-linking set, strengthen the toughness of hydrogel material, make hydrogel possess self-healing property, syringeability and tissue adherence.
In the embodiment of the present invention, the interpolation of described coupling agent, plays most important effect in the forming process of and network of silica covalently cross-linked in inorganic components and organic composition. As preferred embodiment, described coupling agent is γ-(2,3-glycidoxy) propyl trimethoxy silicane, at least one in aminopropyl triethoxysilane, in order to acquired can better injectable hydrogel, described coupling agent is more preferably γ-(2,3-glycidoxy) propyl trimethoxy silicane (2,3-Epoxypropoxypropyltrimethoxysilicane, GPTMS). Concrete, the epoxy bond of described coupling agent GPTMS one end is opened and carboxyl and amino with described gelatin is covalently cross-linked, the other end of described coupling agent GPTMS can become Si-OH silicon alcohol key by spontaneous hydrolysis in acid condition, As time goes on silicon alcohol key can be cross-linked with each other and form Si-O-Si network structure, thus gel.
In the embodiment of the present invention, described supramolecular hydrogel builds network structure with interrelated relation between each component, by regulating gelatin/silica ratios and coupling agent content can regulate and control degradation property and the mechanical property of this hydrogel, the content of adjustment beta-cyclodextrin can regulate and control the toughness of hydrogel, tissue adherence, self-healing property and syringeability. As a concrete preferred embodiment, the mol ratio of described coupling agent and described gelatin is (300-2000): 1;As another concrete preferred embodiment, the mass ratio of described beta-cyclodextrin and described gelatin is (1-6): 1. It is to be understood, of course, that above-mentioned preferred enforcement situation may reside in same embodiment.
As preferred embodiment, also containing silane compound in described injectable hydrogel as additional inorganic source to regulate and control separately the inorganic components content of hydrogel, the silicon alcohol key formed after described silane compound acid hydrolysis and the silicon alcohol key of described coupling agent are cross-linked to form network of silica structure. As preferred embodiment, described silane compound is at least one in tetraethoxy, tetramethoxy-silicane, trimethylethoxysilane, hexa methoxy disilane, t-butyldimethyl silane alcohol, polydimethylsiloxane, methyltrimethoxy silane, diethyl phosphorus acyl ethyl triethoxysilane, gamma-methyl allyl acyloxypropyl trimethoxysilane. By the additional inorganic source of introduction such as described tetraethoxy, can greatly improve the ratio of inorganic content, and inorganic content is regulated and controled, regulate hydrogel mechanical property. And described tetraethoxy can be hydrolyzed into silicon alcohol key in acid condition, these silicon alcohol keys with described coupling agent as the silicon alcohol key of GPTMS occurs crosslinked, can accelerate the process of gel, shorten the time of gel. By regulating, gelatin/silicon-dioxide (as used TEOS) ratio and coupling agent such as GPTMS content can regulate and control degradation property and the mechanical property of this hydrogel to the embodiment of the present invention, and the content of adjustment beta-cyclodextrin can regulate and control the toughness of hydrogel, tissue adherence, self-healing property and syringeability. As preferred embodiment, in the hybrid systems that described injectable hydrogel is formed, the mass ratio of described silicon-dioxide and described gelatin is (0.02-1): 1.
As preferred embodiment, described injectable hydrogel can also obtain the compound supramolecular hydrogel of cell by compound cells. Wherein, described cell does not clearly limit, it is possible to adopt chondrocyte or other various stem cells.
The injectable hydrogel that the embodiment of the present invention provides, the phenyl ring of described beta-cyclodextrin in described gelatin is combined by hydrophobicity effect Subjective and Objective, one end of described gelatin and described coupling agent forms covalent cross-linking, spontaneous after the other end acid hydrolysis of described coupling agent it is cross-linked to form network of silica, or the formation network of silica that is cross-linked with each other with the extra acid hydrolysis silane compound added after the other end acid hydrolysis of described coupling agent, the high performance supramolecule of the novel degradable obtained-hybridized hydrogel forms reticulated structure, there is excellence and regulatable mechanical property, degradation property, self-regeneration performance, superpower tissue adherence and injectable performance, treat articular cartilage defect for organization engineered cartilage and open new way, there is very strong novelty and clinical meaning. concrete, the following advantage of described supramolecular hydrogel:
1. owing to this injectable hydrogel has supramolecular system, its beta-cyclodextrin and gelatin are reversible by the physical property Subjective and Objective of hydrophobicity effect in conjunction with cross-linking set, in the process stretched or compress, while some cross-linking set are destroyed, have new cross-linking set to produce, thus significantly enhance the stretching/compressing performance of hydrogel. Simultaneously, the present invention executes the inorganic silicon network that example is also introduced by molecular hybrid form, make hydrogel elastic extremely outstanding, original state still can be recovered after extruding by gravity, and mechanical property and degradation property controlled, stronger than the toughness of simple silicon-dioxide/gelatin hybridized hydrogel, it is not easy to crumb, broken.Compared with tradition micro inorganic organic composite material, inorganic and the organic composition of hybrid material carries out covalently cross-linked on nanoscale, therefore two kinds of composition degradation speeds are consistent, good at body internal stability, and mechanical property and degradation property controllable (by regulating gelatin/silica ratios and/or coupling agent content).
2. tangent plane due to supramolecule-hybridized hydrogel has the phenyl ring (from gelatin molecule) much not combined and beta-cyclodextrin, when tangent plane contacts, in conjunction with phenyl ring can again form Subjective and Objective with described beta-cyclodextrin and be combined, the hydrogel cut is made again to recover as complete one piece, thus give supramolecular hydrogel selfreparing character of the present invention so that even if described supramolecular hydrogel is after fragmentation, still can recombine and form complete hydrogel.
3. the present invention execute example injectable hydrogel under high shear can be changed into solution, therefore, during by needle injection, the high shear force of existence makes described supramolecular hydrogel be injected into the tissue defect site of required filling with solution state, and fills this position full; Afterwards due to the disappearance of high shear force, solution returns to the state of hydrogel again, therefore can shift to an earlier date in vitro after plastic is cleaned and inject, thus avoid the chemical free radical that in-vivo tissue is directly exposed to uviolizing and produces thereupon; Meanwhile, the present invention execute example supramolecular hydrogel syringeability make minimally-invasive treatment cartilage defect become possibility.
4. tissue surface fibrosis can cause the exposure of a large amount of collagen fabric, and therefore, the more healthy cartilage of cartilage surface of damage, pathology has the chemical group such as more highdensity amino (Methionin), phenyl ring (phenylalanine). And the present invention execute example injectable hydrogel in there is a large amount of free beta-cyclodextrins, therefore possesses extremely strong viscosity, after implanting the cartilage defect of damage, pathology, Subjective and Objective can be carried out with the phenyl ring being exposed to tissue defect surface to be combined, be conducive to the adhesion on cartilaginous tissue surface of the body inner position after injecting and hydrogel, the defect easily run off after solving the injection of conventional hydrogel.
5. the present invention executes survival and the migration that example injectable hydrogel can promote seed cell, concrete, owing to the Subjective and Objective cross-linking set of supramolecular hydrogel is reversible existence, therefore, cell " can be untied " these cross-linking set and carry out infiltration migration, and after cell passes this region, the cross-linking set of these " by untiing " can recombine again, enable seed cell be evenly distributed in hydrogel and also it is fixed on defect area in company with hydrogel scaffold thus plays tissue repair effect.
Injectable hydrogel described in the embodiment of the present invention prepares by following method.
And, the embodiment of the present invention additionally provides the preparation method of a kind of injectable hydrogel, comprises the following steps:
S01., the acidic solution of gelatin is provided;
S02. adding coupling agent in the acidic solution of described gelatin and carry out the first crosslinking reaction, obtain gelatin/coupling agent solution, wherein, described coupling agent is γ-(2,3-glycidoxy) propyl trimethoxy silicane;
S03. in described gelatin/coupling agent solution, add beta-cyclodextrin form mixing solutions, after mixing even leaving standstill, obtain silicon-dioxide/gelatin/beta-cyclodextrin supramolecule-hydridization Dual system hydrogel.
Concrete, in above-mentioned steps S01, described gelatin is dissolved in acidic solution, is conducive to the carboxyl of described gelatin and amino to be opened by the epoxy bond of described coupling agent and covalent cross-linking with it.Concrete, the acidic solution of described gelatin can be prepared by following method: 38-42 DEG C, concrete as, at 40 DEG C, 0.01NHCl solution added gelatin powder, carries out stirring reaction. More specifically, the preferred content in the solution of the addition of described gelatin is 7-9wt%, it is more preferable to be 8wt%; Described stirring reaction is stirring reaction 5-6 hour under rotating speed 450rpm preferably.
In above-mentioned steps S02, by described first crosslinking reaction so that the epoxy bond of described coupling agent open and with described gelatin covalent cross-linking; On the other hand, at acidic conditions, described coupling agent can generate silicon alcohol key by spontaneous hydrolysis. As concrete preferred embodiment, the method for described first crosslinking reaction is: under 38-42 DEG C of condition, stirring reaction 12-14 hour. Concrete, at 40 DEG C, in the acidic solution of above-mentioned gelatin, drip and add GPTMS, stirring reaction 6-14 hour under rotating speed 450rpm.
In above-mentioned steps S03, adding beta-cyclodextrin in described gelatin/coupling agent solution, the phenyl ring generation Subjective and Objective reaction in described beta-cyclodextrin and described gelatin molecule forms supramolecular system. As preferred embodiment, taking the total mass of described mixing solutions as 100%, the mass percentage of described beta-cyclodextrin is 10-50%.
After the concussion evenly of described mixing solutions, sealing leaves standstill, and forms silicon-dioxide/gelatin/beta-cyclodextrin supramolecule-hydridization Dual system hydrogel. Concrete, described standing process is put into 37 DEG C and is carried out so that described silicon alcohol key is cross-linked with each other at such a temperature, and As time goes on described silicon alcohol key can be cross-linked with each other formation network of silica, forms gel.
In the hydrogel that aforesaid method is formed, due to described coupling agent as GPTMS had both served as inorganic/organic coupling agent, serving as again inorganic components, therefore inorganic/organic mass ratio and inorganic/organic crosslinking degree cannot regulate and control separately. And inorganic/organic mass ratio mainly affects mechanical property and the biological activity of hydrogel, inorganic/organic crosslinking degree mainly affects degradation property and the mechanical property of hydrogel. In order to optimize this hydrogel further, inorganic/organic mass ratio and inorganic/organic crosslinking degree are independently regulated and controled, as further preferred embodiment, before adding beta-cyclodextrin, the silane compound adding acid hydrolysis in described gelatin/coupling agent solution, if tetraethoxy is as additional inorganic source, carries out the 2nd crosslinking reaction. After adding extra tetraethoxy, inorganic/organic crosslinking degree of acting regulatory of the full-time coupling agent of described GPTMS energy, and by regulating described tetraethoxy content to regulate and control separately inorganic/organic mass ratio. Described 2nd crosslinking reaction with the addition of extra inorganic sources, thus greatly improves the ratio of inorganic content, improves hydrogel mechanical property. Concrete, described tetraethoxy is hydrolyzed into silicon alcohol key in acid condition, and the silicon alcohol key of these silicon alcohol keys and described coupling agent is cross-linked, and accelerates the process of gel, shortens the reaction times of gel.
As specific embodiment, adding the inorganic sources tetraethoxy of acid hydrolysis in described gelatin/coupling agent solution, the method carrying out the 2nd crosslinking reaction is:
At normal temperatures, in acid condition, carry out the hydrolysis of teos solution, make it to generate silicon alcohol key. More specifically, described hydrolytic process comprises and joins in the middle of hydrochloric acid soln by tetraethoxy (liquid state), stirring reaction 1 hour under rotating speed 450rpm, wherein, the mol ratio of hydrochloric acid and tetraethoxy is 4:1, and hydrochloric acid soln used is by 3 preparations of the volume ratio of water and HCl (1N);
Teos solution after said hydrolyzed is joined in the complete described gelatin/coupling agent solution of step S02 stirring reaction, stirring reaction 15-60min under rotating speed 450rpm. By adjusting the addition of teos solution, silicon-dioxide quality percentage composition in the whole hybrid systems of controllable, it is preferable that, in described hybrid systems, the mass percentage of silicon-dioxide is 5-40wt%, thus inorganic/organic mass ratio of controlled material.
As another preferred embodiment, it is possible to obtain the compound injectable hydrogel of cell by adding the mode of cell. In the embodiment of the present invention, after adding beta-cyclodextrin, also comprise interpolation enchylema, the mixed even standing silicon-dioxide/gelatin/beta-cyclodextrin supramolecule-hydridization Dual system hydrogel obtaining compound cells. Concrete, get the enchylema containing a certain amount of cell, centrifugal and after sucking supernatant liquor, add described silicon-dioxide/gelatin/beta-cyclodextrin pre-polymerization liquid, make cell and pre-polymerization liquid mix even with shifting liquid rifle piping and druming. Owing to adding purpose is different with cell category, the addition of described cell does not have clear and definite restriction, and as a specific embodiment, cell concn can contain 10-50 ten thousand cells for every 0.05mL silicon-dioxide/gelatin/beta-cyclodextrin pre-polymerization liquid.
In the embodiment of the present invention, each component configures the described injectable hydrogel obtained according to above-mentioned concentration, has good mechanical property, degradation property, syringeability, self-healing property and short regenerating bone or cartilage repair ability.
The preparation method of the injectable hydrogel that the embodiment of the present invention provides, the phenyl ring of described beta-cyclodextrin in described gelatin is combined by hydrophobicity effect Subjective and Objective, one end of described gelatin and described coupling agent forms covalent cross-linking, spontaneous after the other end acid hydrolysis of described coupling agent it is cross-linked to form network of silica, or the formation network of silica that is cross-linked with each other with the extra acid hydrolysis silane compound added after the other end acid hydrolysis of described coupling agent, construct a kind of silicon-dioxide/gelatin/beta-cyclodextrin supramolecule-hydridization Dual system hydrogel. The described injectable hydrogel prepared by the inventive method has excellence and regulatable mechanical property, degradation property, syringeability, self-healing property and short regenerating bone or cartilage repair ability, tissue can be adhered to fabulously and not easily run off simultaneously, there is good potential applicability in clinical practice. In addition, the inventive method is simple to operate, and flow process is easily controlled, and has good industrialization prospect.
The foregoing is only the better embodiment of the present invention, not in order to limit the present invention, all any amendment, equivalent replacement and improvement etc. done within the spirit and principles in the present invention, all should be included within protection scope of the present invention.
Claims (10)
1. an injectable hydrogel, it is characterized in that, comprise beta-cyclodextrin, gelatin and coupling agent, the phenyl ring of described beta-cyclodextrin in described gelatin is combined by hydrophobicity effect Subjective and Objective, described coupling agent is the silane coupling agent containing amino and/or epoxy bond, wherein, the amino of described gelatin and described coupling agent or epoxy bond end form covalent cross-linking, and the other end of described coupling agent is spontaneous is cross-linked to form network of silica.
2. injectable hydrogel as claimed in claim 1, it is characterised in that, described coupling agent is at least one in γ-(2,3-glycidoxy) propyl trimethoxy silicane, aminopropyl triethoxysilane.
3. injectable hydrogel as claimed in claim 1, it is characterised in that, the mol ratio of described coupling agent and described gelatin is (300-2000): 1;And/or
The mass ratio of described beta-cyclodextrin and described gelatin is (1-6): 1.
4. injectable hydrogel as claimed in claim 1, it is characterized in that, described injectable hydrogel also contains silane compound as additional inorganic source, the silicon alcohol key of the silicon alcohol key that described silane compound is formed and described coupling agent is cross-linked to form network of silica structure, wherein, described silane compound is tetraethoxy, tetramethoxy-silicane, trimethylethoxysilane, hexa methoxy disilane, t-butyldimethyl silane alcohol, polydimethylsiloxane, methyltrimethoxy silane, diethyl phosphorus acyl ethyl triethoxysilane, at least one in gamma-methyl allyl acyloxypropyl trimethoxysilane.
5. injectable hydrogel as claimed in claim 4, it is characterised in that, in the hybrid systems that described injectable hydrogel is formed, the mass ratio of described silicon-dioxide and described gelatin is (0.02-1): 1.
6. the injectable hydrogel as described in as arbitrary in claim 1-5, it is characterised in that, described injectable hydrogel also comprises cell.
7. a preparation method for injectable hydrogel, comprises the following steps:
The acidic solution of gelatin is provided;
Adding coupling agent in the acidic solution of described gelatin and carry out the first crosslinking reaction, obtain gelatin/coupling agent solution, wherein, described coupling agent is the silane coupling agent containing amino and/or epoxy bond;
Described gelatin/coupling agent solution adds beta-cyclodextrin and forms mixing solutions, after mixing even leaving standstill, obtain silicon-dioxide/gelatin/beta-cyclodextrin supramolecule-hydridization Dual system hydrogel.
8. the preparation method of injectable hydrogel as claimed in claim 7, it is characterised in that, also it is included in before adding beta-cyclodextrin, the silane compound adding acid hydrolysis in described gelatin/coupling agent solution, as additional inorganic source, carries out the 2nd crosslinking reaction.
9. the preparation method of injectable hydrogel as described in claim 5 or 6, it is characterised in that, the method for described first crosslinking reaction is: under 38-42 DEG C of condition, stirring reaction 6-14 hour.
10. the preparation method of injectable hydrogel as described in claim 5 or 6, it is characterised in that, taking the total mass of described mixing solutions as 100%, the mass percentage of described beta-cyclodextrin is 10-50%.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108619574A (en) * | 2018-06-05 | 2018-10-09 | 佛山皖阳生物科技有限公司 | A kind of preparation method of high-adhesiveness nano bone repair hydrogel material |
| CN109329588A (en) * | 2018-10-24 | 2019-02-15 | 浙江海洋大学 | Compound feed for marine fish for deep-water cage culture |
| CN109867801A (en) * | 2018-12-19 | 2019-06-11 | 深圳市第二人民医院 | A kind of preparation method of magnetic Nano hydrogel and its application in cartilage tissue engineered |
| CN110507847A (en) * | 2019-09-04 | 2019-11-29 | 中国科学院海洋研究所 | A kind of hybrid inorganic-organic dressing and its preparation method and application for wound repair |
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| CN111617317A (en) * | 2020-04-10 | 2020-09-04 | 四川大学 | Cross-linking and fixing method for biological tissue |
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| WO2023026585A1 (en) * | 2021-08-24 | 2023-03-02 | 国立研究開発法人物質・材料研究機構 | Adhesive, wound-covering material, anti-adhesion material, hemostatic material, sealant, and spray kit |
| WO2023026586A1 (en) * | 2021-08-24 | 2023-03-02 | 国立研究開発法人物質・材料研究機構 | Adhesive, wound dressing, and anti-adhesion material |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101254416A (en) * | 2007-12-07 | 2008-09-03 | 厦门大学 | Preparation of gelatine-epoxy radicals silicone hydride-anodised aluminium compound film |
| CN101848737A (en) * | 2007-09-07 | 2010-09-29 | 皇家创新公司 | Bioactive nanocomposite material |
| CN103613769A (en) * | 2013-11-08 | 2014-03-05 | 西安交通大学 | Preparation method of bionic injectable gelatin-silane composite medical hydrogel |
| CN103724657A (en) * | 2013-12-25 | 2014-04-16 | 同济大学 | Preparation method of crosslinked chitosan/gelatin composite porous scaffold |
| CN105176095A (en) * | 2015-09-08 | 2015-12-23 | 四川大学 | Collagen-based organic silicon rubber porous composite membrane and preparation method thereof |
| CN105199662A (en) * | 2015-10-27 | 2015-12-30 | 四川大学 | Method for preparing timber adhesive by taking hydrolyzed collagen as raw material |
-
2016
- 2016-02-18 CN CN201610090779.XA patent/CN105664245B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101848737A (en) * | 2007-09-07 | 2010-09-29 | 皇家创新公司 | Bioactive nanocomposite material |
| CN101254416A (en) * | 2007-12-07 | 2008-09-03 | 厦门大学 | Preparation of gelatine-epoxy radicals silicone hydride-anodised aluminium compound film |
| CN103613769A (en) * | 2013-11-08 | 2014-03-05 | 西安交通大学 | Preparation method of bionic injectable gelatin-silane composite medical hydrogel |
| CN103724657A (en) * | 2013-12-25 | 2014-04-16 | 同济大学 | Preparation method of crosslinked chitosan/gelatin composite porous scaffold |
| CN105176095A (en) * | 2015-09-08 | 2015-12-23 | 四川大学 | Collagen-based organic silicon rubber porous composite membrane and preparation method thereof |
| CN105199662A (en) * | 2015-10-27 | 2015-12-30 | 四川大学 | Method for preparing timber adhesive by taking hydrolyzed collagen as raw material |
Non-Patent Citations (5)
| Title |
|---|
| C.TONDA-TURO ET AL.: "《Comparative analysis of gelatin scaffolds crosslinked by genipin and silane coupling agent》", 《INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES》 * |
| WEI ZHANG ET AL.: "《Novel surface modified molecularly imprinted polymer using acryloyl-β-cyclodextrin and acrylamide as monomers for selective recognition of lysozyme in aqueous solution》", 《JOURNAL OF CHROMATOGRAPHY A》 * |
| WEI ZHANG ET AL.: "《Protein imprinted polymer using acrroloyl-β-cyclodextrin and acrylamide as monomers》", 《APPLIED SURFACE SCIENCE》 * |
| 陈建华等: "《γ -(2,3 环氧丙氧)丙基三甲氧基硅烷改性海藻酸钠和明胶渗透蒸发杂化膜的制备及乙酸脱水性能研究》", 《广东化工》 * |
| 黄金等: "《环氧基有机硅改性明胶及其稳定性的研究》", 《皮革科学与工程》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN111617317A (en) * | 2020-04-10 | 2020-09-04 | 四川大学 | Cross-linking and fixing method for biological tissue |
| WO2023026585A1 (en) * | 2021-08-24 | 2023-03-02 | 国立研究開発法人物質・材料研究機構 | Adhesive, wound-covering material, anti-adhesion material, hemostatic material, sealant, and spray kit |
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