Shape memory hydrogel biomaterials, methods of making and using the same

Abstract

This invention provides a shape memory hydrogel, its preparation method, and its applications. The hydrogel biomaterial comprises shape memory hydrogel layers and adhesive hydrogel layers arranged alternately in a vertical direction. The number of shape memory hydrogel layers is greater than the number of adhesive hydrogel layers, and the elastic modulus of each shape memory hydrogel layer is different. The shape memory hydrogel includes a temporary shape and an initial shape, the size of the temporary shape being smaller than the size of the initial shape. Under external stimuli, the shape memory hydrogel can transform from the temporary shape to the initial shape. The shape memory hydrogel of this invention can well meet the biomechanical needs of human tissues and organs, and can integrate well with surrounding tissue structures to promote rapid recovery of the affected area.

Description

Technical Field

[0001] This invention relates to the field of hydrogel technology, and in particular to a shape memory hydrogel biomaterial, its preparation method, and its application. Background Technology

[0002] Lumbar disc herniation (LDH) is a condition caused by factors such as degeneration of the lumbar intervertebral disc and external injury, which leads to a partial rupture of the annulus fibrosus. The nucleus pulposus bulges outward from the defect in the annulus fibrosus, compressing the spinal nerve root or cauda equina, resulting in a condition characterized by low back pain and a series of nerve root symptoms.

[0003] Currently, the main treatments for lumbar disc herniation are discectomy and artificial nucleus pulposus replacement. However, discectomy and fusion are essentially palliative and may not restore the baseline motion and mechanical load characteristics of the adult intervertebral disc. Furthermore, artificial nucleus pulposus replacement has a very high complication rate due to poor integration of the implant with surrounding structures, leading to extrusion or displacement. Simultaneously, current implant materials do not adequately meet the biomechanical requirements of human tissues and organs, thus failing to ensure that the nucleus pulposus replacement material can effectively inhibit abnormal inward bulging of the annulus fibrosus after nucleus pulposus removal and conform to the biomechanical properties of the original tissue.

[0004] Therefore, based on the above problems, there is an urgent need to provide a shape memory hydrogel biomaterial, its preparation method, and its application. Summary of the Invention

[0005] This invention provides a shape memory hydrogel biomaterial, its preparation method, and its application. The shape memory hydrogel can well meet the biomechanical needs of human tissues and organs and can be well integrated with the surrounding tissue structure to promote rapid recovery of the affected area.

[0006] In a first aspect, the present invention provides a shape memory hydrogel, the hydrogel biomaterial comprising a shape memory hydrogel layer and an adhesive hydrogel layer arranged alternately from top to bottom; wherein the number of shape memory hydrogel layers is greater than the number of adhesive hydrogel layers, and the elastic modulus of each shape memory hydrogel layer is different.

[0007] The shape memory hydrogel includes a temporary shape and an initial shape. The size of the temporary shape is smaller than that of the initial shape. Under external stimuli, the shape memory hydrogel can transform from the temporary shape into the initial shape.

[0008] Preferably, the shape memory hydrogel layer has at least three layers; the elastic modulus of each shape memory hydrogel layer changes gradually along the vertical direction.

[0009] Preferably, the change in elastic modulus between two adjacent shape memory gel layers is 50-100 kPa.

[0010] Preferably, each shape memory gel layer is prepared by cross-linking reaction using grafted monomers, shape memory materials, photoinitiators, antibacterial agents and water as reactants.

[0011] More preferably, the shape memory material is gelatin, the photoinitiator is 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone or phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, and the antibacterial agent is tannic acid or silver nanoparticles.

[0012] Preferably, the contents of each reaction raw material in the preparation of the shape memory gel layer are as follows, by weight: 10-50 parts of graft monomer, 10-20 parts of shape memory material, 0.1-0.5 parts of photoinitiator, 5-10 parts of antibacterial agent, and 50-100 parts of water.

[0013] Preferably, the adhesive gel layer is prepared by cross-linking reaction using natural polymer materials, grafted monomers, thermal initiators and water as reactants.

[0014] More preferably, the natural polymer material is hyaluronic acid, and the thermal initiator is ammonium persulfate or sodium persulfate.

[0015] More preferably, the grafting monomer is prepared by reacting glycine hydrochloride, potassium carbonate, organic solvent and acryloyl chloride.

[0016] Preferably, the contents of the reaction raw materials in the preparation of the adhesive gel layer are as follows, by weight: 5-10 parts of natural polymer material, 1-5 parts of grafted monomer, 0.1-1 parts of thermal initiator, and 100-150 parts of water.

[0017] In a second aspect, the present invention provides a method for preparing the shape memory hydrogel biomaterial according to any one of the first aspects above, the preparation method comprising the following steps:

[0018] (1) Grafted monomers, shape memory materials, photoinitiators and antibacterial agents were added to water and stirred in different proportions to obtain shape memory gel layers with different elastic moduli; wherein the content of grafted monomers in each shape memory gel layer was different.

[0019] (2) Add natural polymer materials, grafted monomers and thermal initiators to water and stir to react to obtain an adhesive gel layer;

[0020] (3) The shape memory gel layer and the adhesive gel layer are alternately placed in a mold for composite to obtain the shape memory hydrogel biomaterial.

[0021] Preferably, in step (1), the reaction is carried out under ultraviolet light irradiation for 30-60 minutes.

[0022] Preferably, in step (2), the reaction temperature is 50-60℃ and the time is 30-60min.

[0023] Thirdly, the present invention also provides the application of the shape memory hydrogel biomaterial prepared by any one of the first aspects or the preparation method described in any one of the second aspects as a nucleus pulposus replacement material.

[0024] Compared with the prior art, the present invention has at least the following beneficial effects:

[0025] In this invention, a multilayer shape memory hydrogel structure is prepared, and adjacent shape memory hydrogel layers are bonded together by an adhesive hydrogel layer. Each shape memory hydrogel layer has a different elastic modulus along the vertical direction. This allows the shape memory hydrogel biomaterial to respond differently to different cells at the annulus fibrosus, thereby regulating cell growth to meet the biomechanical needs of the human body and promoting good integration with surrounding tissues to facilitate healing of the affected area. Furthermore, the hydrogel biomaterial prepared in this invention possesses shape memory properties. During use, the prepared shape memory hydrogel is adjusted from its initial shape to a temporary shape suitable for implantation. After implantation, external stimulation causes it to return to its initial shape, thus achieving a minimally invasive effect and reducing patient discomfort. Attached Figure Description

[0026] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 This is a schematic diagram of the structure of a shape memory hydrogel biomaterial provided in an embodiment of the present invention;

[0028] Figure 2 This is a schematic diagram of the initial shape of a shape memory hydrogel biomaterial provided in an embodiment of the present invention;

[0029] Figure 3 This is a schematic diagram of a mold structure used in the preparation process of shape memory hydrogel biomaterials according to an embodiment of the present invention;

[0030] Figure 4This is a schematic diagram of the structure of a shape memory hydrogel biomaterial that transforms from an initial shape to a temporary shape, according to an embodiment of the present invention.

[0031] Figure 5 This is a schematic diagram of the structure of a shape memory hydrogel biomaterial used as a nucleus pulposus replacement material after being implanted into the lumbar disc according to an embodiment of the present invention; in the figure, 100-shape memory hydrogel layer, 200-adhesion gel layer. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0033] like Figure 1 and Figure 4 As shown, the present invention provides a shape memory hydrogel biomaterial, the hydrogel biomaterial comprising a shape memory hydrogel layer 100 and an adhesive hydrogel layer 200 alternately arranged in a vertical direction; wherein, the number of shape memory hydrogel layers is greater than the number of adhesive hydrogel layers, and the elastic modulus of each shape memory hydrogel layer is different; the shape memory hydrogel includes a temporary shape and an initial shape, the size of the temporary shape is smaller than the size of the initial shape, and the shape memory hydrogel can change from the temporary shape to the initial shape under external stimulation.

[0034] In this embodiment of the invention, a multilayer shape memory hydrogel structure is prepared, and adjacent shape memory hydrogel layers are bonded together by an adhesive hydrogel layer. Each shape memory hydrogel layer has a different elastic modulus along the vertical direction. This allows the shape memory hydrogel biomaterial to respond differently to different cells at the annulus fibrosus, thereby regulating cell growth to meet the biomechanical needs of the human body and promoting good integration with surrounding tissues to facilitate healing of the affected area. Furthermore, the hydrogel biomaterial prepared in this invention possesses shape memory properties. During use, the prepared shape memory hydrogel is adjusted from its initial shape to a temporary shape suitable for implantation. After implantation, external stimulation causes it to return to its initial shape, thus achieving a minimally invasive effect and reducing patient discomfort.

[0035] According to some preferred embodiments, the shape memory hydrogel layer has at least three layers; the elastic modulus of each shape memory hydrogel layer changes gradually along the vertical direction.

[0036] Considering the significant differences between artificial nucleus pulposus materials in related technologies and human tissues and organs, they may fail to meet the biomechanical needs of human tissues and organs after implantation, resulting in poor integration with the surrounding tissue structure of the annulus fibrosus and hindering the recovery of the affected area. The inventors have discovered that the main reason for this problem is that the annulus fibrosus and nucleus pulposus in the intervertebral disc have different biomechanical properties. Furthermore, the annulus fibrosus is highly heterogeneous in terms of cell phenotype, biomechanics, biochemistry, and microstructure, exhibiting a typical gradient characteristic along the radial direction. Therefore, in this invention, the shape memory hydrogel biomaterial, which can serve as a nucleus pulposus substitute, is designed as a multilayer structure, taking into account the above reasons. The elastic modulus of each shape memory gel layer changes sequentially along the vertical direction. This allows cells in different gradient layers of the annulus fibrosus to respond to the physical signal gradient in the shape memory hydrogel biomaterial and migrate along the direction of signal change. This allows it to regulate cell growth in accordance with the biomechanical needs of the human body, better achieving good integration with the surrounding tissues to promote the recovery of the affected area.

[0037] It should be noted that the number of shape memory gel layers in the embodiments of the present invention can be 3-25 layers. At the same time, the overall thickness of the shape memory hydrogel biomaterial can be determined according to the thickness of the fiber ring in actual application, and the thickness of each shape memory gel layer is the same.

[0038] According to some preferred embodiments, the change in elastic modulus between two adjacent shape memory gel layers is 50-100 kPa (e.g., 50 kPa, 60 kPa, 70 kPa, 80 kPa, 90 kPa or 100 kPa).

[0039] In this embodiment of the invention, by further controlling the change in elastic modulus of two adjacent shape memory gel layers, it is beneficial to achieve better controllable cell growth, which in turn facilitates better integration with surrounding tissues to achieve better therapeutic effects.

[0040] According to some preferred embodiments, each shape memory gel layer is prepared by cross-linking reaction using grafted monomers, shape memory materials, photoinitiators, antibacterial agents and water as reactants; the shape memory material is gelatin, the photoinitiator is 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone or phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, and the antibacterial agent is tannic acid or silver nanoparticles.

[0041] In this embodiment of the invention, during the preparation of the shape memory gel layer, a graft monomer is first obtained by self-preparation. This graft monomer has good mechanical properties and biocompatibility. Then, it is grafted and crosslinked with a shape memory material that has both good biocompatibility and shape memory properties under the action of a photoinitiator, thereby obtaining a shape memory gel layer with excellent mechanical properties and shape memory properties. At the same time, a certain amount of antibacterial agent is added during the preparation of the shape memory gel layer, which can endow the shape memory gel layer with good antibacterial properties, thereby effectively avoiding the problem of bacterial growth during the postoperative recovery process.

[0042] According to some preferred embodiments, the grafting monomer is prepared by reacting glycine hydrochloride, potassium carbonate, an organic solvent, and acryloyl chloride. The preparation method of the grafting monomer is as follows: glycine hydrochloride, potassium carbonate, and an organic solvent are added to water and mixed to obtain a mixed solution; acryloyl chloride dissolved in the organic solvent is added dropwise to the mixed solution and mixed to obtain a reaction product; the reaction product is subjected to pH adjustment, extraction, freeze-drying, dissolution, and rotary evaporation in sequence to obtain the grafting monomer; wherein, the organic solvent is diethyl ether.

[0043] According to some preferred embodiments, in the mixed solution, the mass ratio of glycine hydrochloride to potassium carbonate is (6-7):(9-10), the volume ratio of organic solvent to water is 3:1, and the mass-volume ratio of acryloyl chloride to organic solvent is (5-6) g:(20-30) mL.

[0044] In this embodiment of the invention, by using the above-mentioned raw materials and controlling their content to allow them to react, a graft monomer with excellent mechanical properties is prepared. After grafting and crosslinking it with shape memory materials, it is beneficial to obtain shape memory hydrogel biomaterials that can regulate cell growth.

[0045] It should be noted that in the embodiments of the present invention, the above mixing process is carried out under ice-water bath conditions, and the reaction temperature of glycine hydrochloride and acryloyl chloride is 20-30℃, and the reaction time is 4-5h. Further, after obtaining the reaction product, the pH of the reaction product solution can be adjusted to 2.0 using a 6mol / L HCl solution, and the organic phase in the reaction solution can be removed by extraction using diethyl ether as the extractant. Then, the inorganic salts in the reaction product are further removed by washing with a mixed solvent (methanol and ethanol in a volume ratio of 4:1). Finally, the solution is rotary evaporated at 40℃, and the precipitate is dried in a vacuum drying oven to obtain powdered grafted monomer.

[0046] According to some preferred embodiments, the contents of each reactant in the preparation of the shape memory gel layer are as follows, by weight: 10-50 parts of graft monomer (e.g., 10, 20, 30, 40 or 50 parts), 10-20 parts of shape memory material (e.g., 10, 12, 14, 16, 18 or 20 parts), 0.1-0.5 parts of photoinitiator (e.g., 0.1, 0.2, 0.3, 0.4 or 0.5 parts), 5-10 parts of antibacterial agent (e.g., 5, 6, 7, 8, 9 or 10 parts), and 50-100 parts of water (e.g., 50, 60, 70, 80, 90 or 100 parts).

[0047] In this embodiment of the invention, by controlling the content of the above-mentioned reactants, it is beneficial to prepare a shape memory gel layer with both excellent mechanical properties and shape memory characteristics. Experiments of this invention have confirmed that by adjusting the content of grafted monomers and shape memory materials in each shape memory gel layer, the elastic modulus of each shape memory gel layer can be controlled. Under the same shape memory material content, the elastic modulus of the shape memory gel layer increases with the increase of the grafted monomer content. However, if the grafted monomer content is too high, it will not only be detrimental to improving the elastic modulus of the shape memory gel layer, but will also reduce the shape memory performance of the shape memory gel layer. Simultaneously, experiments of this invention have confirmed that the content of antibacterial agent is positively correlated with the antibacterial performance of the shape memory gel layer. However, if the antibacterial agent content is too high, it will not only fail to significantly enhance the antibacterial performance of the shape memory gel layer, but will also result in a waste of antibacterial agent.

[0048] According to some preferred embodiments, the adhesive gel layer is prepared by cross-linking reaction using natural polymer materials, grafted monomers, thermal initiators and water as reaction raw materials; the natural polymer material is hyaluronic acid and the thermal initiator is ammonium persulfate or sodium persulfate.

[0049] In this embodiment of the invention, an adhesive gel layer is prepared using natural polymer materials and grafted monomers as reactants. The aforementioned natural polymer materials are naturally biodegradable and have good biocompatibility with the human body, and can effectively regulate the adhesive properties of the adhesive gel layer. The grafted monomers can not only form hydrogen bonds with the natural polymer materials and water, thereby further enhancing the adhesive properties of the adhesive gel layer, but also impart good mechanical properties to the adhesive gel layer. At the same time, the use of the same grafted monomers in the adhesive gel layer as in the shape memory gel layer is beneficial to maximizing the adhesion performance between adjacent shape memory gel layers.

[0050] According to some preferred embodiments, the contents of the reactants in the preparation of the adhesive gel layer are as follows, by weight: 5-10 parts of natural polymer material (e.g., 5, 6, 7, 8, 9 or 10 parts), 1-5 parts of grafted monomer (e.g., 1, 2, 3, 4 or 5 parts), 0.1-1 part of thermal initiator (e.g., 0.1, 0.2, 0.4, 0.5, 0.8 or 1 part), and 100-150 parts of water (e.g., 100, 110, 120, 130, 140 or 150 parts).

[0051] In this embodiment of the invention, by using a suitable ratio of natural polymer materials and graft monomers to initiate graft crosslinking with a thermal initiator, it is beneficial to prepare an adhesive gel layer with excellent adhesion and mechanical properties, thereby ensuring the integrity of the shape memory hydrogel biomaterial. If the content of natural polymer materials or graft monomers is too high or too low, it is not conducive to ensuring good adhesion and mechanical properties of the adhesive gel layer.

[0052] This invention also provides a method for preparing the shape memory hydrogel biomaterial described in any one of the above claims, the method comprising the following steps:

[0053] (1) Grafted monomers, shape memory materials, photoinitiators and antibacterial agents were added to water and stirred in different proportions to obtain shape memory gel layers with different elastic moduli; wherein the content of grafted monomers in each shape memory gel layer was different.

[0054] (2) Add natural polymer materials, grafted monomers and thermal initiators to water and stir to react to obtain an adhesive gel layer;

[0055] (3) The shape memory gel layer and the adhesive gel layer are alternately placed in a mold for composite to obtain the shape memory hydrogel biomaterial.

[0056] In this embodiment of the invention, the shape memory hydrogel biomaterial includes an initial shape and a temporary shape. The initial shape and the temporary shape have the same structure but different dimensions. This embodiment of the invention does not impose any particular limitation on the initial shape and temporary shape of the shape memory hydrogel biomaterial. Specifically, different molds can be used to prepare the shape memory hydrogel biomaterial into different shapes (e.g., ...) according to the needs of the actual application process. Figure 2 or Figure 4 (As shown).

[0057] It is particularly important to note that, in order to ensure good antibacterial properties of the shape memory gel layer, the preparation method of the shape memory gel layer varies depending on the type of antibacterial agent used in this embodiment of the invention. Specifically, when the antibacterial agent is tannic acid, the gel obtained by reacting the grafted monomer, shape memory material, and photoinitiator in water is immersed in an aqueous solution of the antibacterial agent to obtain a shape memory gel layer with antibacterial properties. When the antibacterial agent is silver nanoparticles, the grafted monomer, shape memory material, antibacterial agent, and photoinitiator are added to water to react, thereby obtaining a shape memory gel layer with antibacterial properties.

[0058] Meanwhile, in order to ensure a good connection between adjacent shape memory gel layers, in this embodiment of the invention, when preparing shape memory hydrogel biomaterials, the grafted monomers, shape memory materials, photoinitiators, and antibacterial agents can first be added to water in different proportions and stirred to obtain gel precursor liquids with different elastic moduli. Natural polymer materials, grafted monomers, and thermal initiators are then added to water and stirred to obtain adhesion gel precursor liquids. Afterward, the gel precursor liquids are poured into the mold in sequence and cured by light to obtain shape memory gel layers. Then, adhesion gel precursor liquids are poured onto the surface of the shape memory gel layers and cured by heating to obtain adhesion hydrogel layers. This process is repeated until shape memory gel layers are obtained.

[0059] According to some preferred embodiments, in step (1), the reaction is carried out under ultraviolet light irradiation for 30-60 min (e.g., 30 min, 40 min, 50 min or 60 min); in step (2), the temperature of the reaction is 50-60℃ (e.g., 50℃, 55℃ or 60℃) and the time is 30-60 min (e.g., 30 min, 40 min, 50 min or 60 min).

[0060] For example, using such Figure 3 In preparing a rectangular shape memory hydrogel biomaterial using a mold, a hydrogel precursor solution consisting of grafted monomers, shape memory materials, photoinitiators, antibacterial agents, and water is first added to the mold. Then, it is irradiated with 365nm ultraviolet light to react and solidify, resulting in a shape memory gel layer. Subsequently, an adhesive hydrogel precursor solution consisting of natural polymer materials, grafted monomers, thermal initiators, and water is added to its surface and heated to react and solidify, resulting in an adhesive gel layer. Then, hydrogel precursor solutions consisting of grafted monomers, shape memory materials, photoinitiators, antibacterial agents, and water in different proportions are placed on the surface of the adhesive hydrogel layer. This process is repeated to prepare an integrated rectangular shape memory hydrogel biomaterial.

[0061] This invention also provides an application of the shape memory hydrogel biomaterial described in any of the above claims as a nucleus pulposus replacement material.

[0062] In this embodiment of the invention, the shape memory hydrogel biomaterial is used as a nucleus pulposus replacement material to treat lumbar disc herniation. The specific method is as follows: The prepared shape memory hydrogel biomaterial is heated above its glass transition temperature. Considering human comfort and tolerance, the glass transition temperature of the hydrogel biomaterial in this embodiment is 40 degrees Celsius. An external force is then applied to transform it into a smaller temporary shape (which can be, for example,...). Figure 4 As shown in the figure, it is then placed at room temperature to fix it, resulting in a shape memory hydrogel biomaterial with a temporary shape. After that, it is placed at the defect of the intervertebral disc and external stimulation is applied again (for example, a certain amount of hot water can be added) to restore it to the initial shape with a larger size. Thereafter, the shape memory hydrogel biomaterial can regulate the growth and proliferation of surrounding tissue cells, thereby tightly binding with the surrounding tissue structure and promoting healing more quickly.

[0063] In this embodiment of the invention, the shape memory hydrogel biomaterial exhibits directionality. The inventors further considered that the composition of adventitia fibroblasts differs, with the internal region primarily composed of type II collagen and proteoglycans (PGs), and the external region mainly containing type I collagen. Furthermore, different types of collagen in bone marrow mesenchymal stem cells express at different rates on materials with varying mechanical properties. Therefore, when using the shape memory hydrogel biomaterial prepared above as a nucleus pulposus replacement material to treat lumbar disc herniation, such as… Figure 5 As shown, in this embodiment of the invention, the end of the shape memory hydrogel biomaterial with a lower elastic modulus can be controlled to contact the outer cells of the annulus fibrosus, while the end with a higher elastic modulus can contact the inner cells of the annulus fibrosus. This facilitates the growth of cells in different regions of the annulus fibrosus and allows them to bind tightly to the shape memory hydrogel biomaterial, thereby effectively sealing the defects in the annulus fibrosus and promoting disease recovery.

[0064] To more clearly illustrate the technical solution and advantages of the present invention, the following detailed description of a shape memory hydrogel and its preparation method is provided through several embodiments.

[0065] In the following examples, the mass of grafted monomers, shape memory materials, photoinitiators, antibacterial agents, natural polymers, thermal initiators, and water are expressed in parts by weight.

[0066] In the following examples, the graft monomers were all prepared using the following method:

[0067] Under ice-water bath conditions, 6.3 g glycine hydrochloride, 9.27 g potassium carbonate, and 18 mL organic solvent (diethyl ether) were added to 6 mL of deionized water and mixed to obtain a mixed solution. 5.7 g acryloyl chloride was dissolved in 24 mL organic solvent (diethyl ether) and then added dropwise to the mixed solution and mixed. After reacting at room temperature (25 °C) for 5 h, the pH of the reaction product solution was adjusted to 2.0 using hydrochloric acid solution. The pH-adjusted solution was then extracted three times with 150 mL of diethyl ether to remove the organic phase. The pH of the remaining solution was then adjusted to neutral using sodium hydroxide and washed with 150 mL of a mixed solvent (ethanol and methanol in a volume ratio of 4:1). Finally, the solution was recrystallized by rotary evaporation at 40 °C. The precipitate was dried to obtain the grafted monomer powder.

[0068] Example 1:

[0069] (1) Add 10 parts of graft monomer, 10 parts of shape memory material (gelatin), and 0.1 parts of photoinitiator (2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone) to 50 parts of deionized water and stir to obtain the first hydrogel precursor solution; add 30 parts of graft monomer, 10 parts of shape memory material (gelatin), and 0.3 parts of photoinitiator (2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone) to 80 parts of deionized water and stir to obtain the second hydrogel precursor solution; add 50 parts of graft monomer, 10 parts of shape memory material (gelatin), and 0.5 parts of photoinitiator (2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone) to 100 parts of deionized water and stir to obtain the third hydrogel precursor solution;

[0070] (2) Add 8 parts of natural polymer material (hyaluronic acid), 3 parts of grafted monomer and 0.5 parts of thermal initiator (ammonium sulfate) to 120 parts of deionized water, stir and mix well to obtain the adhesion hydrogel precursor solution.

[0071] (3) The first hydrogel precursor solution was placed in a cylindrical mold and irradiated with 365nm ultraviolet light for 30 minutes to react and then solidify to obtain a first shape memory gel layer; then the above-mentioned adhesive hydrogel precursor solution was poured on its surface and reacted and solidified at 50°C to obtain an adhesive hydrogel layer; then, the second hydrogel precursor solution was poured on the surface of the adhesive hydrogel layer and irradiated with 365nm ultraviolet light for 30 minutes to react and then solidify to obtain a second shape memory gel layer; then the above-mentioned adhesive hydrogel precursor solution was poured on the surface of the second shape memory gel layer and reacted and solidified at 50°C to obtain an adhesive hydrogel layer; finally, the third hydrogel precursor solution was poured on the surface of the adhesive hydrogel layer and irradiated with 365nm ultraviolet light for 30 minutes to react and then solidify to obtain a third shape memory gel layer; the gel formed after solidification was immersed in an antibacterial agent aqueous solution for 72 hours, and then the shape memory hydrogel biomaterial was obtained; wherein, the antibacterial agent was 30 parts and the water was 300 parts.

[0072] Example 2:

[0073] (1) 15 parts of grafted monomer, 20 parts of shape memory material (gelatin), 0.1 parts of photoinitiator (2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone), and 10 parts of silver nanoparticles were added to 60 parts of deionized water and stirred to obtain the first hydrogel precursor solution; 35 parts of grafted monomer, 20 parts of shape memory material (gelatin), 0.3 parts of photoinitiator (2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone), and 10 parts of silver nanoparticles were added to 80 parts of deionized water and stirred to obtain the second hydrogel precursor solution; 50 parts of grafted monomer, 20 parts of shape memory material (gelatin), 0.5 parts of photoinitiator (2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone), and 10 parts of silver nanoparticles were added to 100 parts of deionized water and stirred to obtain the third hydrogel precursor solution;

[0074] (2) Add 10 parts of natural polymer material (hyaluronic acid), 5 parts of grafted monomer and 1 part of thermal initiator (ammonium sulfate) to 150 parts of deionized water, stir and mix well to obtain the adhesion hydrogel precursor solution.

[0075] (3) The first hydrogel precursor solution was placed in a cylindrical mold and irradiated with 365nm ultraviolet light for 30 minutes to react and then solidify to obtain the first shape memory gel layer; then the above-mentioned adhesive hydrogel precursor solution was poured on its surface and reacted and solidified at 50°C to obtain the adhesive hydrogel layer; then the second hydrogel precursor solution was poured on the surface of the adhesive hydrogel layer and irradiated with 365nm ultraviolet light for 30 minutes to react and then solidify to obtain the second shape memory gel layer; then the above-mentioned adhesive hydrogel precursor solution was poured on the surface of the second shape memory gel layer and reacted and solidified at 50°C to obtain the adhesive hydrogel layer; finally, the third hydrogel precursor solution was poured on the surface of the adhesive hydrogel layer and irradiated with 365nm ultraviolet light for 30 minutes to react and then solidify to obtain the shape memory hydrogel biomaterial.

[0076] Comparative Example 1:

[0077] (1) 10 parts of grafted monomer, 10 parts of shape memory material (gelatin), and 0.1 parts of photoinitiator (2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone) were added to 50 parts of deionized water and stirred to obtain a hydrogel precursor solution. Three sets of hydrogel precursor solutions were prepared using the same ratio. The above hydrogel precursor solutions were placed in cylindrical molds and cured by ultraviolet light. The cured gels were then immersed in an antibacterial agent aqueous solution for 72 hours. After removal, three identical shape memory gel layers were obtained. The antibacterial agent was 10 parts and the water was 100 parts.

[0078] (2) Add 8 parts of natural polymer material (hyaluronic acid), 3 parts of grafted monomer and 0.5 parts of thermal initiator (ammonium sulfate) to 120 parts of deionized water, stir and mix well to obtain the adhesion hydrogel precursor solution.

[0079] (3) Place one of the shape memory gel layers in a cylindrical mold, then pour the above-mentioned adhesive hydrogel precursor liquid on its surface, and react and solidify at 50°C to obtain an adhesive hydrogel layer; then, place a shape memory gel layer on the surface of the adhesive hydrogel layer, then pour the above-mentioned adhesive hydrogel precursor liquid on it, and react and solidify at 50°C to obtain an adhesive hydrogel layer; finally, place a shape memory gel layer on the surface of the adhesive hydrogel layer again to obtain a shape memory hydrogel biomaterial.

[0080] Comparative Example 2:

[0081] Comparative Example 2 is basically the same as Example 1, except that step (2) is removed, and in step (3), the first shape memory gel layer is placed directly in a cylindrical mold, and then the second shape memory gel layer and the third shape memory gel layer are placed on its surface in sequence to obtain shape memory hydrogel biomaterial.

[0082] In the preparation process of Examples 1 to 2 and Comparative Examples 1 to 2, the first shape memory gel layer, the second shape memory gel layer, and the third shape memory gel layer were prepared according to the same proportions of raw materials in the examples and comparative examples, respectively. The hydrogel samples were made into dumbbell shapes of 2.5mm x 4mm x 2mm and tensile tests were performed at room temperature using an electronic universal tensile tester - UTM4101; the tensile speed was 50mm / min and the sensor was 100N; the test results for each layer are shown in Table 1.

[0083] Table 1

[0084]

[0085] Note: The elastic moduli of the first, second, and third layers correspond to the elastic moduli of the first, second, and third shape memory gel layers in the hydrogel biomaterial, respectively.

[0086] As can be seen from Table 1, compared with the comparative example, the shape memory hydrogel biomaterial prepared in the embodiment of the present invention is integral and has excellent mechanical properties. At the same time, its elastic modulus changes in a gradient direction in the thickness direction. When used as a nucleus pulposus replacement material, it can effectively regulate the differentiation and proliferation of tissue cells around the intervertebral disc, thereby combining well with surrounding tissue cells and promoting rapid wound healing.

[0087] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A shape memory hydrogel biomaterial, characterized in that, The hydrogel biomaterial includes shape memory hydrogel layers and adhesive hydrogel layers arranged alternately in a vertical direction; wherein, the number of shape memory hydrogel layers is greater than the number of adhesive hydrogel layers, and the elastic modulus of each shape memory hydrogel layer is different; Each shape memory hydrogel layer is prepared by cross-linking reaction using grafted monomers, shape memory materials, photoinitiators, antibacterial agents, and water as reactants. The shape memory material is gelatin, the photoinitiator is 2-hydroxy-2-methyl-1-[4-(2-hydroxyethoxy)phenyl]-1-propanone or phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, and the antibacterial agent is tannic acid or silver nanoparticles. The contents of each reactant in the preparation of the shape memory hydrogel layer are as follows by weight: 10-50 parts grafted monomer, 10-20 parts shape memory material, 0.1-0.5 parts photoinitiator, 5-10 parts antibacterial agent, and 50-100 parts water. The adhesive hydrogel layer is prepared by cross-linking reaction using natural polymer materials, grafted monomers, thermal initiators, and water as reactants; the natural polymer material is hyaluronic acid, and the thermal initiator is ammonium persulfate or sodium persulfate; the content of reactants in the preparation of the adhesive hydrogel layer is as follows by weight: 5-10 parts of natural polymer material, 1-5 parts of grafted monomers, 0.1-1 parts of thermal initiator, and 100-150 parts of water; The grafting monomer was prepared by reacting glycine hydrochloride, potassium carbonate, organic solvent and acryloyl chloride; The shape memory hydrogel includes a temporary shape and an initial shape, the size of which is smaller than that of the initial shape. Under external stimulation, the shape memory hydrogel can transform from the temporary shape to the initial shape. The shape memory hydrogel biomaterial is used as a nucleus pulposus replacement material.

2. The biomaterial according to claim 1, characterized in that, The shape memory hydrogel layer has at least three layers; the elastic modulus of each shape memory hydrogel layer changes gradually along the vertical direction.

3. The biomaterial according to claim 2, characterized in that, The change in elastic modulus between two adjacent shape memory hydrogel layers is 50-100 kPa.

4. A method for preparing a shape memory hydrogel biomaterial according to any one of claims 1 to 3, characterized in that, The preparation method includes the following steps: (1) Grafted monomers, shape memory materials, photoinitiators and antibacterial agents were added to water and stirred in different proportions to obtain shape memory hydrogel layers with different elastic moduli; wherein the content of grafted monomers in each shape memory hydrogel layer was different. (2) Add natural polymer materials, grafted monomers and thermal initiators to water and stir to react, and obtain an adhesive hydrogel layer; (3) The shape memory hydrogel layer and the adhesive hydrogel layer are alternately placed in a mold for composite to obtain the shape memory hydrogel biomaterial.

5. The preparation method according to claim 4, characterized in that, In step (1), the reaction is carried out under ultraviolet light irradiation for 30-60 min; and / or In step (2), the reaction temperature is 50-60℃ and the time is 30-60min.

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