CN111420125A - Medical hydrogel and preparation method thereof - Google Patents
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Abstract
The invention provides a preparation method of medical hydrogel, which comprises the following steps: providing an acidic aqueous solution of gelatin; adding a coupling agent into the acidic aqueous solution of the gelatin to carry out a first crosslinking reaction to obtain a gelatin/coupling agent solution, wherein the coupling agent is a silane coupling agent containing amino and/or epoxy bonds; standing the gelatin/coupling agent solution at 1-4 ℃ to obtain gelatin/silicon dioxide hybrid hydrogel; and (2) soaking the gelatin/silicon dioxide hybrid hydrogel in a specific salt solution for 1-2 days, and drying at room temperature for 2-3 days to obtain the gelatin/silicon dioxide toughened hydrogel, wherein the specific salt solution is a salt solution formed by sulfate radicals, monohydrogen phosphate radicals, dithiosulfate anions, ammonium ions and sodium ions.
Description
Technical Field
The invention belongs to the technical field of hydrogel, and particularly relates to medical hydrogel and a preparation method thereof.
Background
Cartilage defect is a common clinical disease in orthopedics department, and about 60 percent of joints have cartilage defect through arthroscopy. If the disease is not treated in time, 60% -75% of the pathological changes can be progressively developed into osteoarthritis, which seriously affects the motor function of patients and even terminates the career of the patients. Since articular cartilage is not innervated by blood vessels, its regenerative capacity is very limited. Therefore, cartilage defect repair has been a focus of research in the fields of biomaterials and medicine. To date, cartilage defect repair has not been effectively addressed. Autologous chondrocyte transplantation is recognized by scholars as a gold standard for treating articular cartilage defects, but has the problems of limited seed cell sources, secondary operation and the like, and limits the wide clinical application of the technology.
The development of tissue engineering opens up a new way for repairing cartilage defects. Medical hydrogel, especially natural polymer medical hydrogel, is successfully applied to the field of cartilage tissue engineering due to the unique properties of extremely high water retention, strong cell affinity and the like. At present, the natural polymer hydrogel clinically applied, such as gelatin hydrogel, type I collagen hydrogel, hyaluronic acid hydrogel, fibrin hydrogel and the like, is limited by the material, mainly has the defect of poor mechanical property, and seriously restricts the further development of the natural polymer medical hydrogel.
In order to improve the mechanical properties of medical natural polymer hydrogel, researchers mostly adopt a method of compounding the hydrogel with synthetic polymer materials to prepare natural polymer/synthetic polymer composite hydrogel. Recently, researchers developed a highly elastic and tough hydrogel using alginate and polyacrylamide (Sun JY, Nature,2012.489:133-6), a dimensionally reinforced hydrogel printed using a 3D printer with a UV curing system (Bakarrich SE, Applied Materials & Interfaces,2014.6(18): 15998-. However, due to the existence of the synthetic macromolecules, the biocompatibility of the composite hydrogel is inferior to that of the natural macromolecule hydrogel. Meanwhile, because the natural polymer and the synthetic polymer are only compounded on the micron level, the problem that the mechanical property is greatly reduced due to the fact that the degradation rates of the natural polymer and the synthetic polymer are not consistent easily occurs when the hydrogel is degraded. Therefore, the development of a novel mechanically tough natural polymer hydrogel to solve the above-mentioned drawbacks has become an important issue in the fields of medicine and biomaterials in recent years.
Disclosure of Invention
The invention aims to provide a medical hydrogel with high mechanical property, excellent biocompatibility and good degradability, and aims to solve the problem that the mechanical property and the biocompatibility of the existing medical hydrogel can not be considered at the same time.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of medical hydrogel on one hand, which comprises the following steps:
providing an acidic aqueous solution of gelatin;
adding a coupling agent into the acidic aqueous solution of the gelatin to carry out a first crosslinking reaction to obtain a gelatin/coupling agent solution, wherein the coupling agent is a silane coupling agent containing amino and/or epoxy bonds;
standing the gelatin/coupling agent solution at 1-4 ℃ to obtain gelatin/silicon dioxide hybrid hydrogel;
and soaking the gelatin/silicon dioxide hybrid hydrogel in a specific salt solution to enable the gelatin in the gelatin/silicon dioxide hybrid hydrogel to be spontaneously crosslinked, and drying the gelatin/silicon dioxide hybrid hydrogel for 2 to 3 days at room temperature after soaking for 1 to 2 days to obtain the gelatin/silicon dioxide toughened hydrogel, wherein the specific salt solution is a salt solution formed by sulfate radicals, monohydrogen phosphate radicals, dithiosulfate anions, ammonium ions and sodium ions.
And a medical hydrogel which is prepared by adopting gelatin, a coupling agent and a specific salt solution according to the preparation method of the medical hydrogel, wherein,
the coupling agent is a silane coupling agent containing amino and/or epoxy bonds, covalent crosslinking is formed between the gelatin and the amino end or the epoxy bond end of the coupling agent, and a silicon dioxide network is formed by spontaneous crosslinking at the other end of the coupling agent; the gelatin is cross-linked and wound; the specific salt solution is a salt solution formed by sulfate radical, monohydrogen phosphate, dithiosulfate radical anion, ammonium ion and sodium ion.
According to the preparation method of the medical hydrogel, covalent crosslinking is formed between the gelatin and the amino terminal or epoxy bond end of the coupling agent, and the other end of the coupling agent is spontaneously crosslinked to form a silicon dioxide network, so that the gelatin/silicon dioxide hydrogel is formed. Further, the gelatin/silicon dioxide hybrid hydrogel is soaked in a specific salt solution, and the salting-out effect of specific anions and cations in the specific salt solution on gelatin in the gelatin/silicon dioxide hydrogel is adopted to promote the molecular chains of the gelatin to be tangled, enhance the crosslinking effect of the gelatin in the gelatin/silicon dioxide hybrid hydrogel, greatly improve the mechanical property of the hydrogel and promote the gelatin/silicon dioxide hydrogel to be extremely tough. The high-toughness medical hydrogel prepared by the method has excellent and adjustable mechanical property, degradation property and biocompatibility, and has good clinical application prospect. In addition, the method is simple to operate, the flow is easy to control, and the method has a good industrialization prospect.
The medical hydrogel provided by the invention is prepared by the method. One end of the gelatin and the coupling agent containing amino or epoxy bonds forms covalent crosslinking, and the other end of the coupling agent forms a silica network through spontaneous crosslinking after acid hydrolysis. On the basis, particularly, the salting-out effect of specific anions and cations in the specific salt solution on gelatin in the gelatin/silicon dioxide hydrogel is adopted to promote the molecular chains of the gelatin to be intertwined, enhance the crosslinking effect of the gelatin in the gelatin/silicon dioxide hybrid hydrogel, greatly enhance the toughness of the gelatin, endow the medical hydrogel with excellent and adjustable mechanical property, degradation property and biocompatibility, open up a new way for treating articular cartilage defects by using tissue-engineered cartilage, expand the application range and practicability of protein hydrogel, and have strong innovation and clinical significance.
Drawings
Fig. 1 is a schematic structural diagram of a medical hydrogel provided in an embodiment of the present invention.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
The embodiment of the invention provides a preparation method of medical hydrogel, which comprises the following steps:
s01, providing an acidic aqueous solution of gelatin;
s02, adding a coupling agent into the acidic aqueous solution of the gelatin to perform a first crosslinking reaction to obtain a gelatin/coupling agent solution, wherein the coupling agent is a silane coupling agent containing amino and/or epoxy bonds;
s03, standing the gelatin/coupling agent solution at 1-4 ℃ to obtain gelatin/silicon dioxide hybrid hydrogel;
s04, soaking the gelatin/silicon dioxide hybrid hydrogel in a specific salt solution to enable gelatin in the gelatin/silicon dioxide hybrid hydrogel to be spontaneously crosslinked, and drying the gelatin/silicon dioxide hybrid hydrogel for 2 to 3 days at room temperature after soaking for 1 to 2 days to obtain the gelatin/silicon dioxide toughened hydrogel, wherein the specific salt solution is a salt solution formed by sulfate radicals, monohydrogen phosphate radicals, dithiosulfate anions, ammonium ions and sodium ions.
According to the preparation method of the medical hydrogel provided by the embodiment of the invention, covalent crosslinking is formed between the gelatin and the amino terminal or epoxy bond end of the coupling agent, and the other end of the coupling agent is spontaneously crosslinked to form a silicon dioxide network, so that the gelatin/silicon dioxide hydrogel is formed. Further, the gelatin/silicon dioxide hybrid hydrogel is soaked in a specific salt solution, and the salting-out effect of specific anions and cations in the specific salt solution on gelatin in the gelatin/silicon dioxide hydrogel is adopted to promote the molecular chains of the gelatin to be tangled, enhance the crosslinking effect of the gelatin in the gelatin/silicon dioxide hybrid hydrogel, greatly improve the mechanical property of the hydrogel and promote the gelatin/silicon dioxide hydrogel to be extremely tough. The high-toughness medical hydrogel prepared by the method disclosed by the embodiment of the invention has excellent and adjustable mechanical property, degradation property and biocompatibility, and has a good clinical application prospect. In addition, the method provided by the embodiment of the invention is simple to operate, the flow is easy to control, and the method has a good industrialization prospect.
Specifically, in step S01, the gelatin is dissolved in an acidic aqueous solution to form an acidic aqueous solution of gelatin, which facilitates the carboxyl group and the amino group of the gelatin to open the epoxy bond of the coupling agent and covalently crosslink the epoxy bond. Specifically, the acidic solution of gelatin can be prepared by the following method: adding gelatin powder into 0.01N HCl solution at 38-55 deg.C, specifically 50 deg.C, and stirring for reaction. More specifically, the gelatin is preferably added in an amount of 7 to 15 wt%, more preferably 10 wt% in the solution; the stirring reaction is preferably carried out at a rotation speed of 450rpm for 1 to 2 hours.
In step S02, a coupling agent is added to the acidic aqueous solution of gelatin to cause a first crosslinking reaction. Wherein the coupling agent is a silane coupling agent containing amino and/or epoxy bonds. By the first crosslinking reaction, the epoxy bonds of the coupling agent are opened and covalently crosslinked with the gelatin; on the other hand, under acidic conditions, the coupling agent is capable of spontaneously hydrolyzing to form silanol bonds. As a specific preferred embodiment, the method of the first crosslinking reaction is: stirring and reacting for 4-14 hours at the temperature of 38-55 ℃. Specifically, gamma- (2, 3-Epoxypropoxy) propyltrimethoxysilane (2,3-Epoxypropoxy propyltrimethoxysilane, GPTMS) is added dropwise into the acidic gelatin solution at 50 ℃, and the reaction is stirred at the rotating speed of 450rpm for 6-14 hours.
In the step S03, the gelatin/coupling agent solution is stood at 1-4 ℃ to obtain the gelatin/silicon dioxide hybrid hydrogel. Specifically, the gelatin/coupling agent solution is placed in a Teflon mold, sealed and kept stand. In one aspect, the structure of the gelatin gradually recovers from the irregular rolling state to an ordered triple helix structure when the temperature of the gelatin is reduced to below the freezing point (35 ℃), so that a primary gelatin network structure is formed. On the other hand, the silanol bonds crosslink with each other at this temperature, and the silanol bonds crosslink with each other with the passage of time, slowly forming a silica network. The gelatin network structure and the silica network act simultaneously to obtain a primary gelatin/silica hydrogel. In this case, the gelatin/silica hydrogel has a partial network structure, but the partial network structure has a poor degree of crosslinking, and does not satisfy the usability of the hydrogel, and thus cannot be used as a medical hydrogel.
In view of this, in the step S04, the gelatin/silica hybrid hydrogel is soaked in the specific salt solution for 1 to 2 days, and the specific salt ions are adopted to have a salting-out effect on the gelatin in the gelatin/silica hydrogel, so as to promote the molecular chains of the gelatin to be entangled, and enhance the crosslinking effect of the gelatin in the gelatin/silica hybrid hydrogel, thereby greatly improving the mechanical toughness and elasticity of the hydrogel.
However, not any salt solution has a salting-out effect on gelatin in gelatin/silica hydrogel, thereby promoting entanglement of the gelatin molecular chains. In the embodiment of the invention, the specific salt solution is a salt solution formed by sulfate radical, monohydrogen phosphate, dithiosulfate anion, ammonium ion and sodium ion. Preferably, the specific salt solution is selected from one of ammonium sulfate solution, sodium monohydrogen phosphate solution, ammonium dithiosulfate solution and sodium dithiosulfate solution. The three preferable specific salt solutions have good effect of promoting the entanglement of gelatin molecular chains, and the obtained medical hydrogel has excellent mechanical toughness and elasticity.
Specifically, the specific salt solution can be prepared by the following method: a specific salt such as ammonium sulfate powder is added to ultrapure water at room temperature, and a stirring reaction is carried out. The stirring reaction is preferably carried out at a rotation speed of 450rpm for 1 to 2 hours.
The mass percentage of the specific salt is 5-50% based on 100% of the total mass of the specific salt solution, which is beneficial to promoting the cross-linking winding of gelatin molecular chains. If the mass percentage of the specific salt is too low, crosslinking and winding among gelatin molecules are not favorably initiated; if the mass percentage of the specific salt is too high, the gelatin/silicon dioxide hybrid hydrogel can be dehydrated, so that the obtained product is seriously dehydrated, the quality of the product is influenced, and the application of the product is limited. More preferably, the mass percentage of the specific salt is 15-25% based on 100% of the total mass of the specific salt solution.
In the hydrogel formed by the method, since the coupling agent such as GPTMS serves as both an inorganic/organic coupling agent and an inorganic component, the inorganic/organic mass ratio and the inorganic/organic crosslinking degree cannot be independently controlled. The inorganic/organic mass ratio mainly influences the mechanical property and the biological activity of the hydrogel, and the inorganic/organic crosslinking degree mainly influences the degradation property and the mechanical property of the hydrogel. In order to further optimize the hydrogel so that the inorganic/organic mass ratio and the inorganic/organic crosslinking degree can be independently controlled, as a further preferred embodiment, before soaking the gelatin/silica hybrid hydrogel in the specific salt solution, a second crosslinking reaction is performed by adding an acid-hydrolyzed silane compound as an additional inorganic source to the gelatin/coupling agent solution. After the additional silane compound is added, the inorganic/organic crosslinking degree can be regulated and controlled by the action of the coupling agent, and the inorganic/organic mass ratio can be regulated and controlled by regulating the content of the silane compound, so that the inorganic content ratio can be greatly increased, and the mechanical property of the hydrogel can be improved. In addition, the additionally added silane compound is hydrolyzed into silanol bonds under acidic conditions, and the silanol bonds are crosslinked with the silanol bonds of the coupling agent to form a silica network structure, so that the gelling process is accelerated, and the reaction time of gelling is shortened. According to the embodiment of the invention, the inorganic silicon network is introduced in a molecular hybridization manner, so that the hydrogel has extremely excellent elasticity, can still recover to the original shape after being extruded by gravity, has controllable mechanical property and degradation property, has stronger toughness than the pure silicon dioxide/gelatin hybrid hydrogel, and is not easy to knead and break. Compared with the traditional micron-sized inorganic-organic composite material, the inorganic and organic components of the hybrid material are subjected to covalent bond crosslinking on a nanometer scale, so that the degradation speed of the two components is consistent, the stability in vivo is good, and the mechanical property and the degradation property can be regulated and controlled (realized by regulating the gelatin/silicon dioxide ratio and/or the content of the coupling agent).
Specifically, the silane compound is at least one selected from the group consisting of tetraethoxysilane, tetramethoxysilane, trimethylethoxysilane, hexamethoxydisilane, t-butyldimethylsilanol, polydimethylsiloxane, methyltrimethoxysilane, diethylphosphorylethyltriethoxysilane, and γ -methacryloxypropyltrimethoxysilane, and more preferably tetraethoxysilane.
As a specific example, the method of adding acid-hydrolyzed inorganic source tetraethoxysilane to the gelatin/coupling agent solution to perform the second crosslinking reaction is as follows:
at normal temperature, the hydrolysis of the tetraethoxysilane solution is carried out under an acidic condition to form a silanol bond. More specifically, the hydrolysis process comprises reacting a mixture of hydrochloric acid and tetraethoxysilane in a molar ratio of 4: 1, adding tetraethoxysilane (liquid state) into a hydrochloric acid solution, and stirring and reacting for 1 hour at the rotating speed of 450rpm, wherein the hydrochloric acid solution adopts a reaction mixture with the volume ratio of 3: 1 water was made up with HCl (1N) 1.
And (4) adding the hydrolyzed tetraethoxysilane solution into the gelatin/coupling agent solution which is stirred and reacted in the step S02, and stirring and reacting for 15-60min at the rotating speed of 450 rpm. The mass percentage of the silicon dioxide in the whole hybrid system can be regulated and controlled by regulating the addition of the tetraethoxysilane solution, preferably, the mass percentage of the silicon dioxide in the hybrid system is 5-40%, so that the inorganic/organic mass ratio of the material is regulated and controlled.
In the embodiment, the components are prepared according to the concentration to obtain the high-toughness medical hydrogel which has better mechanical property, degradation property and biocompatibility.
Accordingly, embodiments of the present invention provide a medical hydrogel, which is prepared by using gelatin, a coupling agent and a specific salt solution according to the method of the present invention, wherein,
the coupling agent is a silane coupling agent containing amino and/or epoxy bonds, as shown in figure 1, covalent crosslinking is formed between the gelatin and the amino end or the epoxy bond end of the coupling agent, and the other end of the coupling agent is spontaneously crosslinked to form a silicon dioxide network; the gelatin is cross-linked and wound; the specific salt solution is selected from one of sulfate, monobasic phosphate and dithiosulfate.
The medical hydrogel provided by the embodiment of the invention is prepared by adopting the method. One end of the gelatin and the coupling agent containing amino or epoxy bonds forms covalent crosslinking, and the other end of the coupling agent forms a silica network through spontaneous crosslinking after acid hydrolysis. On the basis, particularly, the salting-out effect of specific anions and cations in the specific salt solution on gelatin in the gelatin/silicon dioxide hydrogel is adopted to promote the molecular chains of the gelatin to be intertwined, enhance the crosslinking effect of the gelatin in the gelatin/silicon dioxide hybrid hydrogel, greatly enhance the toughness of the gelatin, endow the medical hydrogel with excellent and adjustable mechanical property, degradation property and biocompatibility, open up a new way for treating articular cartilage defects by using tissue-engineered cartilage, expand the application range and practicability of protein hydrogel, and have strong innovation and clinical significance.
Specifically, the gelatin is used as one of main components, on one hand, under an acidic condition, carboxyl and amino of the gelatin can be covalently crosslinked with the silane coupling agent containing amino and/or epoxy bonds, so that silicon dioxide enters a hydrogel network in a molecular hybridization manner, the hydrogel strength is improved, and the degradation performance of the hydrogel is optimized; meanwhile, when the temperature of the gelatin is reduced to be lower than the freezing point (35 ℃), the structure is gradually restored to an ordered triple-helix structure from a random coil state, so that a network structure (namely, gel) is formed. The gelatin powder can be selected from gelatin with Sigma commercial number G1890-500G.
The specific salt solution is a salt solution formed by sulfate radical, monohydrogen phosphate, dithiosulfate radical anion, ammonium ion and sodium ion. The special salt solution is used as another main component to play an important role, and the special salt solution is used for soaking gelatin/silicon dioxide hydrogel formed by gelatin and a coupling agent, so that gelatin molecular chains in the gelatin/silicon dioxide hydrogel are twisted, and the mechanical properties of the hydrogel are greatly improved due to the multi-factor synergistic effect of hydrophobic effect, micro-phase separation region and the like in a hydrogel network. Preferably, the specific salt solution is selected from one of ammonium sulfate solution, sodium monohydrogen phosphate solution, ammonium dithiosulfate solution and sodium dithiosulfate solution.
In the embodiment of the invention, the addition of the coupling agent plays a crucial role in the covalent crosslinking of the inorganic component and the organic component and the formation of the silica network. As a preferred embodiment, the coupling agent is at least one of γ - (2, 3-Epoxypropoxy) propyltrimethoxysilane and aminopropyltriethoxysilane, and in order to obtain an injectable hydrogel with better performance, the coupling agent is more preferably γ - (2, 3-Epoxypropoxy) propyltrimethoxysilane (GPTMS). Specifically, an epoxy bond at one end of the coupling agent GPTMS is opened and is in covalent bond crosslinking with a carboxyl group and an amino group of the gelatin, the other end of the coupling agent GPTMS is spontaneously hydrolyzed into a Si-OH silanol bond under an acidic condition, and the silanol bonds are mutually crosslinked to form a Si-O-Si network structure along with the passage of time, so that the gelatin is obtained.
In the embodiment of the invention, the components in the high-toughness medical hydrogel construct a network structure in a mutual correlation relationship, the degradation performance and the mechanical strength of the hydrogel can be regulated and controlled by regulating the gelatin/silicon dioxide ratio and the content of the coupling agent, and the mechanical toughness and the elasticity of the hydrogel can be regulated and controlled by regulating the content of the solute of a specific salt solution. As a specific preferred embodiment, the molar ratio of the coupling agent to the gelatin is (300- & ltwbr & gt2000): 1, the inorganic/organic crosslinking degree is improved, and meanwhile, the toughness of the hydrogel is not greatly reduced due to the increase of the inorganic content in the coupling agent. As another specific preferred embodiment, the medical hydrogel comprises water in an amount of 45-95% by mass based on 100% by total weight, and the medical hydrogel does not have poor mechanical properties due to too high gelatin content while ensuring good biocompatibility. In the medical hydrogel, the mass ratio of the gelatin content to the solute in the specific salt solution is (1-5.5): 1. the salt solute with proper content can enhance the toughness of the hydrogel and simultaneously prevent the hydrogel from being dehydrated too much to influence the biocompatibility of the hydrogel. It will of course be appreciated that the preferred embodiments described above may exist in the same embodiment.
In the above embodiment, since the coupling agent such as GPTMS functions as both an inorganic/organic coupling agent and an inorganic component, the inorganic/organic mass ratio and the inorganic/organic crosslinking degree cannot be individually controlled. The inorganic/organic mass ratio mainly influences the mechanical property and the biological activity of the hydrogel, and the inorganic/organic crosslinking degree mainly influences the degradation property and the mechanical property of the hydrogel. In order to further optimize the hydrogel, so that the inorganic/organic mass ratio and the inorganic/organic crosslinking degree can be independently regulated and controlled, as a preferred embodiment, the high-toughness medical hydrogel contains an additional inorganic source to separately regulate and control the inorganic component content of the hydrogel, the additional inorganic source is a silane compound, and a silanol bond formed by the silane compound is crosslinked with a silanol bond of the coupling agent to form a silica network structure. After the additional silane compound is added, the inorganic/organic crosslinking degree can be regulated and controlled by the action of the coupling agent, and the inorganic/organic mass ratio can be regulated and controlled by regulating the content of the silane compound, so that the inorganic content ratio can be greatly increased, and the mechanical property of the hydrogel can be improved. In addition, the additionally added silane compound is hydrolyzed into silanol bonds under acidic conditions, and the silanol bonds are crosslinked with the silanol bonds of the coupling agent to form a silica network structure, so that the gelling process is accelerated, and the reaction time of gelling is shortened. According to the embodiment of the invention, the inorganic silicon network is introduced in a molecular hybridization manner, so that the hydrogel has extremely excellent elasticity, can still recover to the original shape after being extruded by gravity, has controllable mechanical property and degradation property, has stronger toughness than the pure silicon dioxide/gelatin hybrid hydrogel, and is not easy to knead and break. Compared with the traditional micron-sized inorganic-organic composite material, the inorganic and organic components of the hybrid material are subjected to covalent bond crosslinking on a nanometer scale, so that the degradation speed of the two components is consistent, the stability in vivo is good, and the mechanical property and the degradation property can be regulated and controlled (realized by regulating the gelatin/silicon dioxide ratio and/or the content of the coupling agent).
Specifically, the silane compound is at least one selected from the group consisting of tetraethoxysilane, tetramethoxysilane, trimethylethoxysilane, hexamethoxydisilane, t-butyldimethylsilanol, polydimethylsiloxane, methyltrimethoxysilane, diethylphosphorylethyltriethoxysilane, and γ -methacryloxypropyltrimethoxysilane, and more preferably tetraethoxysilane.
As a preferred embodiment, in the hybrid system formed by the medical hydrogel, the mass ratio of the silicon dioxide to the gelatin is (0.02-1): 1. within this range, the silica network can be tightly crosslinked, and the strength of the hydrogel can be improved without greatly decreasing the toughness of the medical hydrogel, because the excessive silica can improve the mechanical strength, but can also make the hydrogel brittle.
The following description will be given with reference to specific examples.
Example 1
A preparation method of medical hydrogel comprises the following steps:
s11, adding gelatin powder into a 0.01N HCl solution at 38-55 ℃, and stirring for reaction to prepare an acidic aqueous solution of gelatin;
s12, dropwise adding GPTMS into the acidic solution of the gelatin at 50 ℃, stirring at the rotating speed of 450rpm for reaction for 6-14 hours, and carrying out a first crosslinking reaction to obtain a gelatin/coupling agent solution;
s13, standing the gelatin/coupling agent solution at 1-4 ℃ to obtain gelatin/silicon dioxide hybrid hydrogel;
s14, adding specific salt such as ammonium sulfate powder into ultrapure water at room temperature, and carrying out stirring reaction to prepare a sulfate ion solution; and soaking the gelatin/silicon dioxide hybrid hydrogel in a sulfate ion solution to enable the gelatin in the gelatin/silicon dioxide hybrid hydrogel to be spontaneously crosslinked, and drying for 2-3 days at room temperature after soaking for 1-2 days to obtain the gelatin/silicon dioxide toughened hydrogel.
Example 2
A preparation method of medical hydrogel comprises the following steps:
s11, adding gelatin powder into a 0.01N HCl solution at 38-55 ℃, and stirring for reaction to prepare an acidic aqueous solution of gelatin;
s12, dropwise adding GPTMS into the acidic solution of the gelatin at 50 ℃, stirring at the rotating speed of 450rpm for reaction for 6-14 hours, and carrying out a first crosslinking reaction to obtain a gelatin/coupling agent solution;
s13, standing the gelatin/coupling agent solution at 1-4 ℃ to obtain gelatin/silicon dioxide hybrid hydrogel; adding the hydrolyzed tetraethoxysilane solution into the gelatin/coupling agent solution, and stirring and reacting at the rotating speed of 450rpm for 15-60min to obtain a hydrogel hybrid system;
s14, adding specific salt such as ammonium sulfate powder into ultrapure water at room temperature, and carrying out stirring reaction to prepare a sulfate ion solution; and (3) soaking the hydrogel hybrid system in a sulfate ion solution to enable gelatin in the hydrogel hybrid system to be spontaneously crosslinked, and drying for 2-3 days at room temperature after soaking for 1-2 days to obtain the gelatin/silicon dioxide toughened hydrogel.
Comparative example 1
A preparation method of medical hydrogel comprises the following steps:
D11. adding gelatin powder into 0.01N HCl solution at 38-55 deg.C, stirring for reaction, and preparing acidic aqueous solution of gelatin;
D12. dropwise adding GPTMS into the acidic solution of the gelatin at 50 ℃, stirring at the rotation speed of 450rpm for reaction for 6-14 hours, and carrying out a first crosslinking reaction to obtain a gelatin/coupling agent solution;
D13. and standing the gelatin/coupling agent solution at 1-4 ℃ to obtain the gelatin/silicon dioxide hybrid hydrogel.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A preparation method of medical hydrogel is characterized by comprising the following steps:
providing an acidic aqueous solution of gelatin;
adding a coupling agent into the acidic aqueous solution of the gelatin to carry out a first crosslinking reaction to obtain a gelatin/coupling agent solution, wherein the coupling agent is a silane coupling agent containing amino and/or epoxy bonds;
standing the gelatin/coupling agent solution at 1-4 ℃ to obtain gelatin/silicon dioxide hybrid hydrogel;
and soaking the gelatin/silicon dioxide hybrid hydrogel in a specific salt solution to enable the gelatin in the gelatin/silicon dioxide hybrid hydrogel to be spontaneously crosslinked, and drying the gelatin/silicon dioxide hybrid hydrogel for 2 to 3 days at room temperature after soaking for 1 to 2 days to obtain the gelatin/silicon dioxide toughened hydrogel, wherein the specific salt solution is a salt solution formed by sulfate radicals, monohydrogen phosphate radicals, dithiosulfate anions, ammonium ions and sodium ions.
2. The medical hydrogel of claim 1, wherein said specific salt solution is selected from one of ammonium sulfate solution, sodium monohydrogen phosphate solution, ammonium dithiosulfate solution, and sodium dithiosulfate solution.
3. The medical hydrogel according to claim 1, further comprising adding an acid hydrolyzed silane compound as an additional inorganic source to the gelatin/coupling agent solution to perform a second crosslinking reaction before soaking the gelatin/silica hybrid hydrogel in the specific salt solution; and/or
The method of the first crosslinking reaction is as follows: stirring and reacting for 4-14 hours at the temperature of 38-55 ℃.
4. The method for producing a medical hydrogel according to any one of claims 1 to 3, wherein the mass percentage of the specific salt is 5 to 50% based on 100% of the total mass of the specific salt solution.
5. A medical hydrogel, which is prepared by adopting gelatin, a coupling agent and a specific salt solution according to the method of any one of claims 1 to 4, wherein the coupling agent is a silane coupling agent containing amino and/or epoxy bonds, the gelatin and the amino end or the epoxy bond end of the coupling agent form covalent crosslinking, and the other end of the coupling agent spontaneously crosslinks to form a silica network; the gelatin is cross-linked and wound; the specific salt solution is a salt solution formed by sulfate radical, monohydrogen phosphate, dithiosulfate radical anion, ammonium ion and sodium ion.
6. The medical hydrogel of claim 5, wherein said specific salt solution is selected from one of ammonium sulfate solution, sodium monohydrogen phosphate solution, ammonium dithiosulfate solution, and sodium dithiosulfate solution.
7. The medical hydrogel of claim 5, wherein said coupling agent is selected from at least one of γ - (2, 3-epoxypropoxy) propyltrimethoxysilane, aminopropyltriethoxysilane; and/or
The molar ratio of the coupling agent to the gelatin is (300- & 2000): 1; and/or
The total weight of the medical hydrogel is 100%, and the mass percentage of water in the medical hydrogel is 45-95%; and/or
In the medical hydrogel, the mass ratio of the gelatin content to the solute in the specific salt solution is (1-5.5): 1.
8. the medical hydrogel according to any one of claims 5 to 7, wherein an additional inorganic source is contained in the medical hydrogel, wherein the additional inorganic source is a silane compound, and the silanol bond formed by the silane compound is crosslinked with the silanol bond of the coupling agent to form a silica network structure.
9. The medical hydrogel according to claim 8, wherein said silane compound is at least one selected from the group consisting of tetraethoxysilane, tetramethoxysilane, trimethylethoxysilane, hexamethoxydisilane, tert-butyldimethylsilanol, polydimethylsiloxane, methyltrimethoxysilane, diethylphosphorylethyltriethoxysilane, and gamma-methacryloxypropyltrimethoxysilane.
10. The medical hydrogel according to any one of claims 5 to 7, wherein said medical hydrogel forms a hybrid system in which the mass ratio of said silica to said gelatin is (0.02 to 1): 1.
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