CN109876194B - A kind of POSS-PEG hybrid hydrogel with adjustable degradation rate, its preparation method and its application - Google Patents
A kind of POSS-PEG hybrid hydrogel with adjustable degradation rate, its preparation method and its application Download PDFInfo
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Abstract
本发明涉及一种可调节降解速率的POSS‑PEG杂化水凝胶及其制备方法和其应用，该制备方法为：将4‑arm‑PEG‑MAL与POSS‑SH在有机溶剂中通过Michael加成反应制得POSS‑PEG预聚物；将POSS‑PEG预聚物与交联剂溶解于缓冲液中得到预成胶溶液，将预成胶溶液在反应温度下通过Michael加成反应制得一种可调节降解速率的POSS‑PEG杂化水凝胶；其中，预成胶溶液中交联剂由PEG‑dithiol及PEG‑diester‑dithiol混合形成。本发明提供的POSS‑PEG杂化水凝胶具有孔洞结构均一、生物相容性好、成胶快、力学性能好、无毒的优点。
The invention relates to a POSS-PEG hybrid hydrogel with adjustable degradation rate and a preparation method and application thereof. The preparation method comprises: adding 4-arm-PEG-MAL and POSS-SH in an organic solvent through Michael adding The POSS-PEG prepolymer is obtained by the reaction; the POSS-PEG prepolymer and the cross-linking agent are dissolved in the buffer to obtain a pregel solution, and the pregel solution is prepared by Michael addition reaction at the reaction temperature. A POSS-PEG hybrid hydrogel with adjustable degradation rate; wherein, the cross-linking agent in the pregel solution is formed by mixing PEG-dithiol and PEG-diester-dithiol. The POSS-PEG hybrid hydrogel provided by the invention has the advantages of uniform pore structure, good biocompatibility, fast gel formation, good mechanical properties and non-toxicity.
Description
Technical Field
The invention relates to the field of hydrogel high molecular materials, in particular to POSS-PEG hybrid hydrogel capable of adjusting degradation rate, a preparation method and application thereof.
Background
3D scaffolds play a crucial role in tissue engineering and 3D cell culture applications. With the rapid development of tissue engineering, 3D scaffolds have great application potential in various biomedicines, and thus the requirements for it are also increasing. In order to induce cell adhesion, proliferation and activation to direct the growth and differentiation of specific cells, the materials used to prepare the scaffold must be biocompatible, have a suitable degradation rate, porosity, suitable mechanical stability and suitable chemical induction for molecular biological recognition of the cells.
The use as scaffold material for 3D cell culture requires a period of biocompatibility and mechanical strength and should eventually degrade in vivo at the required degradation rate while avoiding any immune response. Poly (ethylene glycol) (PEG) hydrogels are one of the most widespread scaffold materials for cell encapsulation and transplantation in tissue engineering, with excellent biocompatibility, hydrophilicity, non-immunogenicity, and resistance to protein adsorption. In addition, their biodegradability is another important feature. Biodegradability of PEG hydrogels can be achieved by enzymatic, hydrolytic, or environmental means such as incorporation of degradable components. In addition, by varying the molecular weight and concentration of PEG, the mechanical properties of PEG hydrogels can be improved.
The polyhedral oligomeric silsesquioxane (POSS) has a cubic cage-shaped nano structure, the molecular size is 1-3nm, and an organic-inorganic nano hybrid structure consisting of an inorganic framework consisting of core Si-O-Si bonds and external organic substituents has good biocompatibility, special surface performance and high mechanical performance. By introducing monofunctional typical POSS molecules onto PEG hydrogels, small amounts of POSS can cause significant changes in hydrogel properties. The POSS-PEG hybrid hydrogel prepared by the method not only can enhance the mechanical property of the hydrogel, but also can delay the degradation rate for a certain time, but the degradation rate is fixed and unadjustable, and cannot meet the requirements of various use situations.
Disclosure of Invention
Aiming at the problems of the hydrogel, the POSS-PEG hybrid hydrogel with adjustable degradation rate, the preparation method and the application thereof are provided, and the purpose is to provide a hydrogel material with good biocompatibility, fast gelling, good mechanical property, no toxicity and adjustable degradation rate.
The specific technical scheme is as follows:
the first aspect of the invention provides a preparation method of POSS-PEG hybrid hydrogel capable of adjusting degradation rate, which has the characteristics that the preparation method comprises the following steps: carrying out Michael addition reaction on 4-arm-PEG-MAL and POSS-SH in an organic solvent to prepare POSS-PEG prepolymer; dissolving POSS-PEG prepolymer and a cross-linking agent in a buffer solution to obtain a pre-gel solution, and preparing the pre-gel solution into POSS-PEG hybrid hydrogel with adjustable degradation rate through Michael addition reaction at a reaction temperature; wherein, the cross-linking agent in the second step is formed by mixing PEG-dithiol and PEG-ester-dithiol.
The above production method is further characterized in that the organic solvent is one selected from tetrahydrofuran, dichloromethane, methanol and acetone.
The above-mentioned production method is also characterized in that the molar ratio of the functional group-MAL to the functional group-SH (total-SH number in the crosslinking agent) in the 4-arm-PEG-MAL is 1: 1-1.5.
The above-mentioned production method is also characterized in that the buffer is TEA.
The above production method is also characterized in that TEA has a pH of 7.4 and a concentration of 4 mM.
The preparation method is also characterized in that the reaction temperature is 25-40 ℃, and the crosslinking time is 0-30 min.
The above-mentioned preparation method is also characterized in that the mass percent of the cross-linking agent in the hybrid hydrogel is 25-100%.
The 4-arm-PEG-MAL (tetradendritic maleimide functionalized polyethylene glycol) is a commercial product (provided by Beijing Jiankei science and technology Co., Ltd.), and preferably, the 4-arm-PEG-MAL with the average molecular weight of 5-20kDa is selected in the invention.
POSS-SH (Single-angle mercapto polyhedral oligomeric silsesquioxane) of the present invention is a commercially available product (supplied by Sigma Co., Ltd.) having CAS number 480438-85-5.
In the present invention, PEG-dithiol (polyethylene glycol dithiol) is a commercially available product (available from Beijing Jiankei science and technology Co., Ltd.), and preferably, PEG-dithiol having an average molecular weight of 2-4kDa is selected in the present invention.
The PEG-ester-dithiol (polyethylene glycol diester dithiol) is a laboratory self-synthesized product (reference: Zustik S.P., Leach J.B.Hydrolytically degradable poly (ethylene glycol) hydrogel capsules with a structural degradation and a mechanical properties [ J ] Biomacromolecules,2010,11: 1348-phase 135), and is characterized by various testing means, wherein the average molecular weight of the PEG-ester-dithiol is 2-4 kDa.
The second aspect of the invention is to provide a POSS-PEG hybrid hydrogel with adjustable degradation rate, which is prepared by the preparation method.
The third aspect of the invention is to provide an application of the POSS-PEG hybrid hydrogel capable of adjusting the degradation rate, which has the characteristics and is used as a tissue engineering 3D scaffold material.
The beneficial effect of above-mentioned scheme is:
1) the POSS-PEG hybrid hydrogel provided by the invention has the advantages of uniform pore structure, good biocompatibility, quick gelling, good mechanical property and no toxicity;
2) the degradation period of the POSS-PEG hybrid hydrogel provided by the invention can be prolonged by adjusting the degradation rate of the hybrid hydrogel.
Drawings
FIG. 1 is a scanning electron microscopy test image of a POSS-PEG hybrid hydrogel provided in an example of the present invention;
FIG. 2 is a plot of degradation rate for a POSS-PEG hybrid hydrogel provided in an example of the present invention (2A) and a bar graph (2B);
FIG. 3 is a scanning electron microscope test chart of degraded POSS-PEG hybrid hydrogel provided in the examples of the present invention;
FIG. 4 is a graph of staining of cells cultured in vitro and viable with POSS-PEG hybrid hydrogels provided in the examples of the present invention;
FIG. 5 is a 3D cultured HUVEC cell morphology map of POSS-PEG hybrid hydrogel provided in the examples of the present invention;
FIG. 6 is a fluorescent microscopic test image of the live and dead cells staining of BMSCs cultured in 3D using POSS-PEG hybrid hydrogels provided in the examples of the present invention;
FIG. 7 is a staining test chart of alizarin red for osteogenic differentiation of BMSCs cultured in POSS-PEG hybrid hydrogel 3D provided in the example of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
The invention is further described with reference to the following drawings and specific examples, which are not intended to be limiting.
A POSS-PEG hybrid hydrogel capable of adjusting degradation rate is prepared by the following steps: dissolving commercially available 4-arm-PEG-MAL and POSS-SH in tetrahydrofuran, stirring at room temperature for a period of time, and removing the tetrahydrofuran by rotary evaporation to obtain a POSS-PEG prepolymer; then, dissolving the POSS-PEG prepolymer and a cross-linking agent (formed by mixing PEG-dithiol and PEG-diester-dithiol, wherein the molar ratio of the functional group-MAL to the functional group-SH is 1:1-1.5) in 4mM triethanolamine buffer solution with the pH value of 7.4, and fully and uniformly mixing the two to obtain pre-formed colloid solution; and finally transferring the pre-formed gel solution to a 500-mu L mold, and reacting in a biochemical incubator at 37 ℃ for 15min to obtain the POSS-PEG hybrid hydrogel (the mass percentage of the cross-linking agent in the hybrid hydrogel is 25-100%) with adjustable degradation rate.
The parameters of examples 1 to 3 of the present invention and comparative examples are shown in the following table:
as shown in figure 1, a scanning electron microscope shows that the POSS-PEG hybrid hydrogel provided by the invention is in a porous sponge structure, the pore diameters of the POSS-PEG hybrid hydrogel are uniform, the average pore size is 20-40 nm, and the POSS-PEG hybrid hydrogel has high porosity.
Degradation Rate test
The POSS-PEG hybridized hydrogel is freeze-dried, the weight of the POSS-PEG hybridized hydrogel is accurately weighed, then the dried hydrogel is added with 0.01M phosphate buffer solution (PBS, PH 7.4 and 10mL), the mixture is placed in a constant-temperature biochemical incubator at 37 ℃, distilled water is rinsed after 4 weeks, the freeze-drying and the weighing are carried out, the cumulative degradation percentage (%) of each group of hydrogel in the solution is calculated to be (the weight of the hydrogel before degradation-the mass of the hydrogel after degradation)/the weight of the hydrogel before degradation multiplied by 100%, in order to ensure the experimental accuracy, 3 test samples are taken from each group of hydrogel, and the average value of the three test samples is taken.
As shown in FIG. 2, the POSS-PEG hybrid hydrogel provided by the invention has gradually increased mass loss along with the gradual increase of the PEG-ester-dithiol content in the cross-linking agent, and when the hydrogel is degraded to the 4 th week, the hydrogel provided in example 3 can not maintain the gel shape, and the mass loss weighing calculation can not be carried out.
As shown in FIG. 3, with the gradual increase of PEG-ester-dithiol content in the cross-linking agent and the prolongation of degradation time, the originally clear and uniform pore structure in the POSS-PEG hybrid hydrogel provided by the present invention gradually collapses, and after the fourth week, the three-dimensional structure of the hydrogel provided in example 3 is substantially completely destroyed. In vitro cell culture experiments
1.2mL of each POSS-PEG hybrid hydrogel pre-prepared glue solutionMixing with Human Umbilical Vein Endothelial Cells (HUVEC) at a cell density of 1 × 106Each 100. mu.L of each was placed in a ninety-six well cell culture plate with 5% CO2Incubating at 37 ℃ for 30min in a constant-temperature incubator, adding 200 mu L of low-sugar DMEM medium containing 10% fetal calf serum, continuing to incubate, taking out samples within 1, 4 and 7 days respectively, staining live and dead cells to test the activity of the cells, and analyzing images by using a fluorescence microscope to observe the activity and the form of the cells.
As shown in FIG. 4, cells can be encapsulated in the hybrid hydrogel provided by the invention, and the cell viability is gradually increased along with the increase of the culture time, which indicates that the cells can survive in the hydrogel material, and indicates that the hydrogel has good biocompatibility and is nontoxic; and the cell number has higher cell proliferation speed along with the increase of the content of PEG-ester-dithiol in the cross-linking agent.
As shown in FIG. 5, cells can grow well in the hybrid hydrogel provided by the present invention, and the encapsulated cells have different cell morphologies during the growth process; meanwhile, the cell morphology is gradually changed from a slender spindle to a round shape along with the increase of the content of PEG-diesel-dithiol in the cross-linking agent, and when the content of the PEG-diesel-dithiol reaches 100%, the encapsulated cell is full and round (related to the size of a cell growth space in the hydrogel degradation process, the higher the content of the PEG-diesel-dithiol, the larger the cell growth space, the round cell is, and on the contrary, the cell is in a slender spindle shape). Live and dead cell staining test
1.2mL of each pre-colloid solution prepared by POSS-PEG hybrid hydrogel is uniformly mixed with bone marrow mesenchymal stem cells (BMSCs) with the cell density of 1 multiplied by 106Each 100. mu.L of each was placed in a ninety-six well cell culture plate with 5% CO2Incubating at 37 deg.C for 30min, adding 200 μ L low sugar DMEM medium containing 10% fetal calf serum, incubating, culturing until cell growth reaches 80%, using osteogenic differentiation medium for culturing, taking out sample at 14 days, staining for living and dead cells to test cell activity, and encapsulating in hybrid hydrogel with PEG-di ester-dithiol content of 100%BMSCs were simultaneously cultured in growth medium for comparison, and after 14 days of growth in osteogenic differentiation medium, the medium was aspirated and washed twice with PBS, then frozen sections were fixed with 4% paraformaldehyde for 20 minutes, washed three times with PBS, and then calcium deposition was determined by staining with alizarin red dye.
As shown in FIG. 6, the number of cells gradually increased with increasing PEG-diester-dithiol content in the cross-linker, and reached a maximum value when the PEG-diester-dithiol content in the cross-linker reached 100%, further confirming that BMSCs also grew well in these hybrid hydrogels.
As shown in FIG. 7, with the increase of PEG-ester-dithiol content in the cross-linking agent, osteogenic differentiation gradually increased, calcium nodules increased, and cell calcium nodules in the growth medium were less, which indicates that BMSCs can propagate and differentiate in the hydrogel material provided by the present invention, which further proves that the hydrogel material can be used as a tissue engineering 3D scaffold.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.
Claims (9)
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