Preparation method of hydrogel based on ice skeleton

Abstract

The invention relates to hydrogel based on an ice skeleton and a preparation method thereof, in the method, the ice skeleton is used as a template guide, a 30wt% PVA solution is poured and filled into the ice skeleton at the temperature of-4 DEG C to-6 DEG C, the ice skeleton is frozen at the temperature of-18 DEG C to-22 DEG C, then the ice skeleton is dissolved and removed at the temperature of 20 DEG C to 30 DEG C, and the hydrogel with a preset three-dimensional directional microstructure is obtained. According to the preparation method, an ice skeleton is used as a process route of template guiding, PVA solution filling, freezing shaping and ice melting demolding, the obtained hydrogel has a regular three-dimensional directional microstructure, the mechanical strength and the structural stability of the hydrogel are superior to those of random porous hydrogel, the technical problem that in a traditional method, biotoxicity residues exist or demolding is difficult is solved, and the preparation method is suitable for large-scale industrial production. The high biocompatibility, the high integrity and the accurate regulation and control of the orientation and the size of the hydrogel are realized.

Description

Technical Field

[0001] This invention relates to the field of hydrogel technology, and more specifically to a method for preparing a hydrogel based on an ice skeleton. Background Technology

[0002] Microstructured hydrogels have broad application prospects in fields such as implantable tissue scaffolds, skin-attached flexible bioelectronics, and flexible biosensors due to their soft mechanical properties and controllable porous structure. Their performance is closely related to the morphology, orientation, and cleanliness of the pores.

[0003] Currently, the construction of microstructured hydrogels relies on one approach: sacrificial template technology. The main process of sacrificial template technology is to first prepare a template, then prepare a microstructured hydrogel based on the template, and finally remove the template. However, traditional template materials mainly include paraffin wax, polymer materials, etc. These materials are difficult to completely remove, and small molecule impurities or particle fragments are easily left in the hydrogel system after treatment. In application scenarios with strict requirements for biocompatibility, these residual substances are very likely to cause adverse interfacial reactions, which seriously limits the safe application of hydrogels in biomedical fields.

[0004] The second method for constructing microstructured hydrogels is to dope pore-forming agents (including salt particles, sugar particles, etc.) to obtain a porous structure by forming voids inside the hydrogel. However, the method of doping pore-forming agents cannot achieve precise control of the pores. The internal pores formed are mostly randomly distributed, and their morphology, orientation and size are difficult to match the functional requirements of specific applications. As a result, the structure and performance of microstructured hydrogels cannot effectively adapt to the usage requirements of the target scenario.

[0005] Therefore, how to achieve precise control over the morphology, orientation, and size of pores while avoiding chemical residues, improving biocompatibility, and structural damage, and constructing microstructured hydrogels that combine high biocompatibility and functional adaptability, has become a key technical challenge that urgently needs to be overcome in this field. Summary of the Invention

[0006] To address the aforementioned technical problems, this application provides a method for preparing a hydrogel based on an ice skeleton.

[0007] To achieve the above objectives, this application employs the following technical solution:

[0008] This application provides a method for preparing a hydrogel based on an ice skeleton, comprising the following steps: S1. First, prepare an ice skeleton that matches the preset three-dimensional oriented microstructure; S2. A 30wt% PVA solution is poured into the ice skeleton of step S1 at a temperature of -4℃ to -6℃, frozen at a temperature of -18℃ to -22℃, and then placed at a temperature of 20℃ to 30℃ to dissolve and remove the ice skeleton, thereby obtaining a hydrogel with a preset three-dimensional oriented microstructure.

[0009] As a further improvement to this application, the ice skeleton is prepared by the following steps: First, a three-dimensional solid template with a preset three-dimensional oriented microstructure is prepared using polybutylene succinate. Then, it is immersed in deionized water and pre-frozen at a temperature of -4℃ to -6℃ to form an ice skeleton inside the three-dimensional solid template. Then, it is transferred to a dichloromethane solution for immersion and dissolved and removed at a temperature of -18℃ to -22℃ to obtain the ice skeleton.

[0010] As a further improvement to this application, the three-dimensional solid template is obtained by 3D printing.

[0011] As a further improvement of this application, the preset three-dimensional oriented microstructure includes microchannels with a diameter > 100 μm.

[0012] As a further improvement of this application, the level of the deionized water is 1cm to 2cm higher than the upper surface of the three-dimensional solid template, and the soaking time of the three-dimensional solid template in the deionized water is 2h to 4h.

[0013] As a further improvement of this application, the pre-freezing time is 4h to 6h.

[0014] As a further improvement of this application, the soaking time is 6h to 12h, and the volume of the dichloromethane solution is 3 to 5 times that of the three-dimensional solid template.

[0015] As a further improvement of this application, after dissolving and removing polybutylene succinate to obtain the ice skeleton, the method further includes a step of sterilizing the ice skeleton: immersing the ice skeleton in a 75wt% alcohol solution at -18℃ to -22℃ for 1h to 2h, and then draining off the residual alcohol on the surface.

[0016] As a further improvement to this application, the freezing time is 8h to 24h.

[0017] To achieve the above objectives, this application also provides a hydrogel with a predetermined three-dimensional oriented microstructure obtained by the preparation method described above.

[0018] The beneficial effects of this application are as follows: This application adopts a process route of ice skeleton as template guide, PVA solution filling, freezing and shaping, and ice melting and demolding to obtain hydrogel with a preset three-dimensional oriented microstructure.

[0019] 1) This application uses an ice template that matches the preset three-dimensional oriented microstructure as a physical template to guide the shaping of the microstructure of PVA hydrogel. The pre-constructed preset three-dimensional oriented microstructure has the advantages of good orientation and controllable size. It can accurately control the orientation, size and three-dimensional arrangement of the internal pores of the hydrogel, overcoming the problems of random pore structure, poor orientation and insufficient repeatability in traditional freeze-drying or phase separation methods. This makes the hydrogel have good consistency and repeatability in different batches.

[0020] 2) The entire preparation process of this application does not introduce organic solvents, chemical crosslinking agents or pore-forming agents. The ice skeleton can be completely removed by natural melting during the post-processing, without producing any chemical residues. The resulting hydrogel is pure in composition, highly biocompatible, and significantly safer than hydrogel materials prepared by chemical pore-forming or crosslinking methods, making it suitable for high-end biomedical applications.

[0021] 3) The preparation process of this application is completed under low temperature freezing and room temperature thawing conditions. The process conditions are mild and avoid the damage to the polymer chain structure caused by high temperature, high pressure or strong acid and alkali environment. This is conducive to maintaining the integrity of PVA molecular chain. The resulting hydrogel is superior to hydrogels prepared using other material templates in terms of structural stability and mechanical properties. Attached Figure Description

[0022] Figure 1 This is a schematic flowchart of the preparation method of the ice-based hydrogel of this application. Detailed Implementation

[0023] This application provides a method for preparing an ice-based hydrogel, achieving precise control over pore morphology, orientation, and size while avoiding chemical residues and structural damage, to construct a microstructured hydrogel with both high biocompatibility and functional adaptability. Figure 1 As shown, it includes the following steps: S1. First, prepare an ice skeleton that matches the preset three-dimensional oriented microstructure; S2. A 30wt% PVA solution is poured into the ice skeleton of step S1 at a temperature of -4℃ to -6℃, frozen at a temperature of -18℃ to -22℃, and then placed at a temperature of 20℃ to 30℃ to dissolve and remove the ice skeleton, thereby obtaining a hydrogel with a preset three-dimensional oriented microstructure.

[0024] Based on the above technical solution, an ice skeleton matching the preset three-dimensional oriented microstructure is first prepared to establish the physical template boundary. The preset three-dimensional oriented microstructure defines the microstructure morphology of the PVA hydrogel. Simultaneously, the mass transfer and solidification process is controlled by temperature gradient. The pouring and filling temperature of -4℃ to -6℃ ensures that the PVA solution maintains good fluidity and can fully fill the gap structure of the ice skeleton. Subsequently, the deep freezing environment of -18℃ to -22℃ promotes the orderly arrangement of PVA molecular chains and the formation of preliminary hydrogen bond physical cross-linking. Finally, the thawing step of 20℃ to 30℃ melts the ice skeleton, forming a hydrogel with the preset three-dimensional oriented microstructure. In this process, the collapse problem of PVA network caused by rapid ice melting is avoided. Moreover, the entire process does not require the addition of additional chemical cross-linking agents, and mainly relies on the hydrogen bonds formed between PVA molecules during freezing to build a stable hydrogel network.

[0025] This application proposes for the first time to use an ice skeleton matching a pre-defined three-dimensional oriented microstructure as a template. The ice skeleton serves as a physical template guide, and the ice template can be completely removed after molding by natural melting upon heating, eliminating the need for organic solvent extraction, chemical degradation, or lengthy cleaning processes. This fundamentally avoids the residue, pore contamination, and structural damage problems that easily occur during the removal of templates made of other materials, thus improving the purity and biocompatibility of the resulting hydrogel. Furthermore, the application employs a process route of PVA solution filling, freeze-setting, and ice-melting demolding, effectively solving the industry's technical pain points of poor microstructure orientation and uncontrollable size in traditional hydrogel preparation processes. The resulting hydrogel exhibits precisely controllable pore morphology, orientation, and size; the entire process does not introduce harmful chemical cross-linking components, demonstrating excellent biocompatibility and making it directly applicable to high-end applications such as biomedicine.

[0026] In an optional implementation, the preset three-dimensional oriented microstructure is a regular three-dimensional oriented microstructure. A regular three-dimensional oriented microstructure can effectively disperse stress concentration during stress application, improving the mechanical strength and deformation resistance of the hydrogel, enabling it to maintain stable structure and performance under long-term use or repeated loading conditions.

[0027] In an optional embodiment, the ice skeleton is prepared by the following steps: first, a three-dimensional solid template with a preset three-dimensional oriented microstructure is prepared using polybutylene succinate, then it is immersed in deionized water, and then pre-frozen at a temperature of -4℃ to -6℃ to form an ice skeleton inside the three-dimensional solid template. Then it is transferred to a dichloromethane solution for immersion, and the polybutylene succinate is dissolved and removed at a temperature of -18℃ to -22℃ to obtain the ice skeleton.

[0028] The three-dimensional solid template prepared by polybutylene succinate (PBS) in the above technical solution can provide a precise micron-level channel structure. After immersing it in deionized water, the pre-freezing temperature of -4℃ to -6℃ can guide water molecules to crystallize in an oriented manner along the template channels, thereby forming an ice skeleton that is complementary to the template structure. The ice skeleton formed in this way has a continuous and integral three-dimensional spatial structure, which can replicate the oriented pore network as a whole and match the preset three-dimensional oriented microstructure. This effectively overcomes the problems of pore dispersion, poor connectivity, and difficulty in controlling structural anisotropy caused by particle accumulation or interface discontinuity in other material templates.

[0029] Subsequently, under a low-temperature environment of -18℃ to -22℃, the selective dissolution properties of dichloromethane solution were utilized to dissolve and remove only the PBS three-dimensional solid template without damaging the crystal structure of the ice skeleton, achieving non-destructive separation of the template and the ice skeleton. Simultaneously, the low-temperature environment effectively inhibited ice crystal coarsening, ensuring the precision of the ice skeleton microstructure. Through the design and selective dissolution of the PBS template, the precise replication of the pre-defined three-dimensional oriented microstructure of the ice skeleton was achieved, providing a novel technical pathway for the preparation of oriented microstructure hydrogels.

[0030] In an optional implementation, the three-dimensional solid template is obtained by 3D printing. Utilizing the digital molding advantages of additive manufacturing technology, PBS three-dimensional solid templates can be precisely prepared according to a preset model. This allows for precise digital control of parameters such as template channel size, orientation, and porosity, thus adapting to the personalized needs of different application scenarios for hydrogel microstructures. Simultaneously, PBS material possesses excellent melt extrusion or photopolymerization molding characteristics. The mechanical strength of the 3D-printed template meets the requirements of subsequent processes such as water filling, pre-freezing, and solvent immersion, and will not deform due to external forces or environmental changes during the process. This significantly improves the customization capability of template preparation, enabling the rapid molding of complex preset three-dimensional oriented microstructures (such as branched channels and gradient pore sizes). This effectively solves the technical problems of poor flexibility and difficulty in preparing complex structure templates in traditional template molding processes. The micron-level molding precision of 3D printing technology ensures the consistency of template channel size and shape, thereby improving the structural repeatability and batch stability of the ice skeleton and the final hydrogel product.

[0031] In an optional implementation, the pre-defined three-dimensional oriented microstructure includes microchannels with a diameter > 100 μm. Based on the synergistic effect of microstructure size effect and mass transfer optimization, microchannels with a diameter > 100 μm can effectively reduce mass transfer resistance during the PVA solution filling process, ensuring that the PVA solution fills the gaps in the ice skeleton quickly and uniformly, while providing sufficient space for the uniform growth of ice crystals during freezing. In addition, microchannels in this size range can achieve a good balance between compressive strength and flexibility, effectively avoiding problems such as collapse of hydrogels during freezing / thawing due to excessively small channel size or insufficient structural stability due to excessively large size.

[0032] In an optional implementation, the three-dimensional solid template is soaked in deionized water for 2 to 4 hours. Utilizing capillary action and swelling balance mechanisms, this 2-4 hour soaking time ensures that deionized water fully penetrates the micron-level channels of the PBS template, completely expelling air from the channels and preventing structural defects such as pores and breaks during subsequent ice skeleton formation due to residual air bubbles. Simultaneously, this soaking time allows the PBS template to swell moderately in water, improving the smoothness of the template channel walls and reducing the adhesion between the subsequently formed ice skeleton and the template. This effectively ensures the structural integrity of the ice skeleton, avoiding defects caused by insufficient water filling, and ultimately improving the microstructure uniformity and batch stability of the final hydrogel product.

[0033] In an optional implementation, the pre-freezing time is 4 to 6 hours. Based on the regulation mechanism of ice crystal growth kinetics, the pre-freezing time of 4 to 6 hours provides sufficient time for water molecules to crystallize in a directional manner, allowing water molecules to grow slowly and orderly along the PBS template channels, forming ice crystals of uniform size and regular structure. This effectively avoids the microstructure disorder caused by ice crystal aggregation or branching growth during rapid freezing. At the same time, sufficient pre-freezing time ensures complete phase separation between the PBS template and the ice phase, avoiding incomplete separation when the solvent dissolves the template later due to insufficient phase separation. This significantly improves the precision of the ice skeleton microstructure and ensures the structural consistency of the product.

[0034] In an optional implementation, the soaking time is 6 to 12 hours, and the volume of the dichloromethane solution is 3 to 5 times that of the three-dimensional solid template. Complete dissolution of the PBS template is achieved through the synergistic control of solvent volume and soaking time: 3 to 5 times the volume of dichloromethane solution provides sufficient solvent kinetics for template dissolution, ensuring full contact between the solvent and the template; while the 6 to 12-hour soaking time ensures complete dissolution of the PBS template, preventing template residue from affecting the purity of the ice skeleton. Simultaneously, in a low-temperature environment of -18°C to -22°C, the viscosity and dissolution rate of the dichloromethane solution are in equilibrium, ensuring sufficient dissolution efficiency while effectively preventing the ice skeleton from melting due to temperature increases, thus achieving synergistic effects of template dissolution and ice skeleton protection.

[0035] In an optional implementation, after dissolving and removing polybutylene succinate to obtain the ice skeleton, the process further includes a step of disinfecting the ice skeleton: immersing the ice skeleton in a 75wt% alcohol solution at -18℃ to -22℃ for 1 to 2 hours, followed by draining off any residual alcohol. Utilizing the synergistic mechanism of low-temperature disinfection and structural protection, the alcohol can fully penetrate into the gaps within the ice skeleton at the -18℃ to -22℃ low-temperature environment, effectively killing bacteria, fungi, and other microorganisms, achieving a disinfection effect. Simultaneously, this low-temperature environment prevents the ice skeleton from melting or structurally damaging. Furthermore, the draining operation after alcohol immersion reduces residual moisture on the surface of the ice skeleton, preventing air bubbles from forming due to residual moisture during subsequent PVA solution filling, and ensuring a good interfacial bond between the PVA solution and the ice skeleton.

[0036] In an optional implementation, the freezing time is 8h to 24h. Sufficient freezing time enables the regularization of PVA molecular chains and the stable construction of hydrogen bond networks. The deep freezing environment of 8h to 24h allows the PVA molecular chains to fully expand, forming a more regular and stable hydrogen bond cross-linking network, thereby improving the mechanical strength and swelling stability of the hydrogel. Simultaneously, sufficient freezing time ensures that the PVA solution is uniformly distributed within the ice skeleton gaps, avoiding structural defects caused by excessively high local concentrations and guaranteeing the uniformity of the hydrogel's microstructure.

[0037] In an optional implementation, the level of the deionized water is 1 cm to 2 cm higher than the upper surface of the three-dimensional solid template. This design utilizes the hydrostatic pressure of the liquid to propel the deionized water rapidly into the micron-level channels inside the template, while simultaneously expelling air from the channels. This prevents the formation of vacuum areas due to residual air, which could lead to insufficient water filling. The liquid pressure created by this level is within a reasonable range, ensuring that excessive pressure will not deform the template structure, while insufficient pressure will not affect the filling efficiency of the deep channels. This, combined with the immersion time of 2 to 4 hours, ensures that all areas of the template are uniformly wetted by deionized water.

[0038] The technical solution of this application will be clearly and completely described below with reference to the embodiments of this application. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0039] To make the above-mentioned objectives, features and advantages of this application more apparent and understandable, the application will be further described in detail below with reference to specific embodiments.

[0040] Example 1 First, using 3D printing technology, a three-dimensional solid template with a pre-defined three-dimensional oriented microstructure (including microchannels with a diameter of 120 μm) was prepared using polybutylene succinate as the raw material. This three-dimensional solid template was then immersed in deionized water, ensuring the water level was 1 cm above the top surface of the template. After immersion for 2 hours, it was removed and pre-frozen at -6°C for 4 hours to form an ice skeleton inside the template that matched the pre-defined three-dimensional oriented microstructure. Subsequently, the template with the ice skeleton was transferred to a dichloromethane solution, with the volume of the dichloromethane solution being three times the volume of the three-dimensional solid template. The immersion temperature was controlled at -22°C. After immersion in the dichloromethane solution for 6 hours, the polybutylene succinate was completely dissolved and removed. Butylene diisocyanate was used to obtain an ice skeleton that matched the preset three-dimensional oriented microstructure. The ice skeleton was then sterilized by immersing it in a 75wt% alcohol solution at -22℃ for 1 hour. After removal, the surface residual alcohol was allowed to drain naturally. Then, a 30wt% PVA solution was prepared and slowly poured into the sterilized ice skeleton at -6℃. After filling, the sample was frozen at -22℃ for 8 hours. Finally, the frozen sample was transferred to a 20℃ room temperature environment. After the ice skeleton was completely dissolved and removed, a hydrogel with the preset three-dimensional oriented microstructure was obtained. The microchannel structure of the hydrogel was consistent with the preset ice skeleton, with uniform size and stable mechanical properties.

[0041] Example 2 A three-dimensional solid template of polybutylene succinate was prepared by 3D printing. The template had a pre-designed three-dimensional oriented microstructure containing microchannels with a diameter of 200 μm. The template was immersed in deionized water with the liquid level 2 cm above the top surface of the template for 4 hours. After immersion, it was pre-frozen in a -4°C environment for 6 hours to form an ice skeleton inside the template that matched the pre-designed three-dimensional oriented microstructure. The template was then transferred to a dichloromethane solution with a volume of 5 times its own volume and immersed in a -18°C environment for 12 hours to completely remove the polybutylene succinate template, resulting in an ice skeleton that matched the pre-designed three-dimensional oriented microstructure. The ice skeleton was disinfected by immersing it in a 75wt% alcohol solution at -18℃ for 2 hours, and then drained of the alcohol before use. A 30wt% PVA solution was prepared and poured into the gaps in the ice skeleton at -4℃. After filling, the sample was frozen at -18℃ for 24 hours. The sample was then thawed in a constant temperature environment at 30℃. After the ice skeleton was completely melted and discharged, a hydrogel with a pre-defined three-dimensional oriented microstructure was obtained. This hydrogel has a clear oriented microchannel structure, high porosity, and excellent biocompatibility, which can meet the application requirements of tissue engineering scaffolds.

[0042] Example 3 A three-dimensional solid template of polybutylene succinate was prepared using 3D printing. The template had a pre-designed three-dimensional oriented microstructure containing microchannels with a diameter of 150 μm. The template was immersed in deionized water with the water level 1.5 cm above the top surface of the template for 3 hours, followed by pre-freezing at -5°C for 5 hours to form an ice skeleton inside the template that matched the pre-designed three-dimensional oriented microstructure. The template was then transferred to a dichloromethane solution with a volume four times that of the template and immersed in the dichloromethane solution at -20°C for 9 hours to completely dissolve and remove the polybutylene succinate, resulting in a product that matched the pre-designed microstructure. A three-dimensional oriented microstructure-matched ice skeleton was prepared by immersing the ice skeleton in a 75wt% alcohol solution at -20℃ for 1.5 hours for sterilization and draining off any residual alcohol. A 30wt% PVA solution was prepared and uniformly poured into the ice skeleton at -5℃. After filling, the sample was frozen at -20℃ for 16 hours. The sample was then thawed in a 25℃ constant temperature oven. After the ice skeleton was completely dissolved, a hydrogel with a pre-defined three-dimensional oriented microstructure was obtained. This hydrogel has a clear oriented microchannel structure, high porosity, and excellent biocompatibility, which can meet the application requirements of tissue engineering scaffolds.

[0043] Although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

[0044] The detailed descriptions listed above are merely specific descriptions of feasible implementation methods of this application and are not intended to limit the scope of protection of this application. All equivalent implementation methods or modifications made without departing from the spirit of the art of this application should be included within the scope of protection of this application.

Claims

1. A method for preparing a hydrogel based on an ice skeleton, characterized in that, Includes the following steps: S1. First, prepare an ice skeleton that matches the preset three-dimensional oriented microstructure; S2. A 30wt% PVA solution is poured into the ice skeleton of step S1 at a temperature of -4℃ to -6℃, frozen at a temperature of -18℃ to -22℃, and then placed at a temperature of 20℃ to 30℃ to dissolve and remove the ice skeleton, thereby obtaining a hydrogel with a preset three-dimensional oriented microstructure.

2. The preparation method according to claim 1, characterized in that, The ice skeleton is prepared by the following steps: First, a three-dimensional solid template with a preset three-dimensional oriented microstructure is prepared using polybutylene succinate. Then, it is immersed in deionized water and pre-frozen at a temperature of -4℃ to -6℃ to form an ice skeleton inside the three-dimensional solid template. Then, it is transferred to a dichloromethane solution for immersion and dissolved and removed at a temperature of -18℃ to -22℃ to obtain the ice skeleton.

3. The preparation method according to claim 2, characterized in that, The three-dimensional solid template was obtained by 3D printing.

4. The preparation method according to claim 2, characterized in that, The preset three-dimensional oriented microstructure includes microchannels with a diameter > 100 μm.

5. The preparation method according to claim 2, characterized in that, The level of the deionized water is 1cm to 2cm higher than the upper surface of the three-dimensional solid template, and the soaking time of the three-dimensional solid template in the deionized water is 2h to 4h.

6. The preparation method according to claim 2, characterized in that, The pre-freezing time is 4 to 6 hours.

7. The preparation method according to claim 2, characterized in that, The soaking time is 6h to 12h, and the volume of the dichloromethane solution is 3 to 5 times that of the three-dimensional solid template.

8. The preparation method according to claim 2, characterized in that, After dissolving and removing polybutylene succinate to obtain the ice skeleton, the process further includes a step of sterilizing the ice skeleton: immersing the ice skeleton in a 75wt% alcohol solution at -18℃ to -22℃ for 1 to 2 hours, and then draining off any residual alcohol on the surface.

9. The preparation method according to claim 1, characterized in that, The freezing time is 8 hours to 24 hours.

10. A hydrogel with a predetermined three-dimensional oriented microstructure obtained by the preparation method according to any one of claims 1-9.

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