Restorable hydrogel capable of being pulverized and preparation method thereof

Abstract

The invention discloses a reconstitution hydrogel capable of being pulverized and a preparation method thereof, and relates to the field of biomedical materials, the hydrogel is composed of konjac glucomannan and borosilicate bioglass; the preparation method comprises the following steps: grinding and mixing konjac glucomannan and borosilicate bioglass in proportion, and stirring with deionized water to form a semi-gelatinized suspension; freezing at-80 DEG C and melting at room temperature for 1-3 times to form stable gel; freeze-drying, and grinding into powder, so as to obtain reversible hydrogel powder; after water is added into the powder, the powder can be quickly recovered into gel with injectability and self-healing performance at room temperature. The whole process is carried out under mild conditions, a traditional high-temperature and strong-alkali process is avoided, heat-sensitive active ingredients can be loaded, and the material is stably stored in a powder form, is convenient to transport, can be instantly rehydrated and used clinically and is simple and convenient to operate.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biomedical materials, in particular to a powderable reconstitutable hydrogel and a preparation method thereof. BACKGROUND

[0002] Hydrogel is a kind of three-dimensional network structure material rich in water, with strong hydrophilicity and good biocompatibility, which shows broad application prospects in biomedical fields such as tissue engineering, drug controlled release, wound dressing and biosensing. In recent years, hydrogels prepared from edible polymer konjac glucomannan have attracted more and more attention in the medical field due to their wide source, low cost and good biocompatibility. However, traditional konjac glucomannan hydrogels usually need to be formed under strong alkaline conditions by heating, and the preparation process not only involves complex chemical crosslinking or physical aggregation reactions, but also strong alkali and high temperature environment can easily lead to the inactivation of heat-sensitive bioactive substances such as polypeptides, proteins and some natural products. Thus, the application range is limited.

[0003] In addition, once such hydrogels prepared by heat and alkali method are formed, their network structure tends to be stable and is difficult to reverse or secondary process, which limits the re-molding and reuse of the material. Although the existing technology can also prepare konjac glucomannan hydrogels with self-healing function, that is, after the hydrogel is cut, the separated parts can re-adhere and restore to a complete piece, but this self-healing ability is usually effective only within a limited time after the gel is prepared, and is limited to the adhesion between blocks, and it is difficult to realize more flexible overall reprocessing.

[0004] In the food industry, the "reconstituted milk" technology dries liquid milk into milk powder for long-term storage and transportation, and the milk powder can be quickly restored to liquid milk by adding water, which greatly improves the storage stability and convenience of use. However, in the field of medical gel materials, similar reversible processing and shape conversion ability is still lacking.

[0005] At present, the hydrogel products in clinical use are mostly provided in the form of blocks, pastes or liquids, which generally contain water and are prone to physical damage during storage and transportation, and have high packaging requirements and short shelf life in a wet environment. In the existing technology, the gel is also provided in the form of a freeze-dried block, but the freeze-drying process can easily destroy the original three-dimensional network structure of the gel, making it lose its original injectability and self-healing performance, and affecting the clinical use convenience and efficacy. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a powderable reconstitutable hydrogel and a preparation method thereof, which can be formed under mild conditions, and the material has powderable reversible processing characteristics, thereby improving the long-term storage stability, transportation safety and convenience of immediate rehydration use in clinical.

[0007] To achieve the above object, the technical scheme adopted by the present application is: In a first aspect, the present application provides a powderable hydrogel and a preparation method thereof, which is composed of konjac glucomannan and borosilicate bioglass, and the hydrogel exhibits a reversible form that can be ground into powder by freeze-drying, and the powder can be restored to a gel by adding water again.

[0008] As a preferred scheme, the mass ratio of the konjac glucomannan to the borosilicate bioglass is (8-12):1.

[0009] As a preferred scheme, the borosilicate bioglass is a silicon-calcium-phosphorus-boron bioglass.

[0010] In a second aspect, the present application provides a method for preparing the hydrogel according to any one of claims 1, 2 or 3, comprising the following steps: S1, weighing konjac glucomannan, borosilicate bioglass and deionized water, and pre-adding deionized water into a mold for standby; S2, grinding the konjac glucomannan and the borosilicate bioglass together to obtain a mixed powder; S3, pouring the mixed powder obtained in step S2 into the mold containing deionized water in step S1, and stirring until the material is uniform and transparent, showing semi-gelation; S4, freezing the suspension obtained in step S3 at -80℃ for 12 hours, and then melting at room temperature for 2 hours after taking out, and repeating the freezing and thawing for 1-3 times; S5, freeze-drying the gel obtained in step S4, and grinding into powder; S6, adding deionized water to the powder obtained in step S5, and standing at room temperature until the material restores to a uniform and stable hydrogel.

[0011] As a preferred scheme, in step S1, the mass-volume ratio of the konjac glucomannan, the borosilicate bioglass and the deionized water is (8-12):1:(120-140).

[0012] As a preferred scheme, in step S2, the grinding time is 5-15 minutes.

[0013] As a preferred scheme, in step S3, the stirring time is 3-5 minutes.

[0014] As a preferred scheme, in step S6, the mass-volume ratio of the powder to the deionized water is (9-13):(120-140).

[0015] As a preferred scheme, the borosilicate bioglass is a silicon-calcium-phosphorus-boron bioglass.

[0016] According to the above technical solution, the application has the following advantages: 1. The application can make konjac glucomannan sol form stable hydrogel through repeated freezing and thawing by adding a small amount of inorganic bio-glass nano-powder without introducing a second polymer gelling component. The bio-glass has excellent biocompatibility and has potential for soft tissue and hard tissue repair, thereby widening the application range of konjac glucomannan gel in the biomedical field.

[0017] 2. The entire preparation process of the hydrogel is carried out at room temperature or low temperature, completely avoiding the high-temperature and strong-alkali environment required by traditional methods. The mild process is conducive to the introduction and maintenance of the activity of heat-sensitive drugs, proteins and other bioactive substances, thereby expanding the application prospect of the hydrogel in drug delivery and functional dressings.

[0018] 3. The hydrogel has reversible "powder-gel" conversion characteristics: it can be converted into powder state through freeze-drying and grinding; the powder can quickly and automatically recover into a structurally complete gel by adding water before use. This reversible characteristic similar to "reconstituted milk" enables the product to realize long-term stable storage and safe transportation in solid powder form, and supports on-demand use in clinics, which can be used for deep tissue filling through injection, or directly applied to body surface wounds, greatly improving the convenience and flexibility of use. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 It is a physical diagram of the rehydration of hydrogel powder of examples 1, 2 and 3. Figure 2 It is a comparison diagram of gelation time of materials of examples 1, 2 and 3. Figure 3 It is a schematic diagram of injectable performance of hydrogels of examples 1, 2 and 3. Figure 4 It is a schematic diagram of self-healing performance of hydrogels of examples 1, 2 and 3. Figure 5 It is a characterization diagram of thermal stability of hydrogels of examples 1, 2 and 3. Figure 6 It is a microscope photo of L929 cells in the cytotoxicity experiment of examples 1, 2 and 3. DETAILED DESCRIPTION

[0020] The application will be further described in detail below in combination with the drawings and specific examples.

[0021] Based on this, the application provides a powderable reconstituted hydrogel and a preparation method thereof, which comprises the following steps: S1, (8-12) : 1 : (120-140) by mass konjac glucomannan, borosilicate bioglass and deionized water, deionized water is preloaded into the mold for use; S2, the konjac glucomannan and borosilicate bioglass are placed in a agate mortar together, and are ground for 5-15 minutes to obtain a mixed powder, which is used for standby; S3, the mixed powder obtained in step S2 is poured into the mold with deionized water in step S1, and is stirred for 3-5 minutes until the material is uniform and transparent, and is semi-gelatinized; S4, the suspension obtained in step S3 is transferred to a -80℃ refrigerator and frozen for 12 hours, and is taken out and melted at room temperature for 2 hours, and the freezing and thawing cycle is repeated for 1-3 times; S5, the gel obtained in step S4 is freeze-dried, and then ground into powder using an agate mortar; S6, the powder obtained in step S5 is added to deionized water, and the mass ratio of the powder and deionized water is (9-13) : (120-140), and the powder is uniformly absorbed with water, and a uniform and stable injectable hydrogel material with self-healing performance is obtained at room temperature.

[0022] The method utilizes the composite system of konjac glucomannan and silicon calcium phosphorus boron bioglass to form a gel through a freeze-thaw method. Specifically, the water movement of the konjac glucomannan sol is limited during the freezing process and ice crystals are formed; the addition of bioglass powder forms more crystal nucleus active sites, which promotes the local aggregation and mutual contact of the konjac glucomannan molecular chains at the ice crystal interface to form a physically cross-linked micro zone. After thawing, the molecular chains are rearranged, and through repeated freeze-thaw cycles, these micro zones form a three-dimensional network gel block with stable structure, and the freeze-thaw process can effectively maintain the water-containing structure of the gel to avoid severe dehydration. After the obtained gel block is freeze-dried and ground into powder, and then an appropriate amount of water is added again, the powder can quickly absorb water and rebuild the network structure to restore the complete gel, and the recovered gel still has good injectability and self-healing performance, and can be injected before solidification, which is simple to operate. The gel is stable after formation and is not easily reversed to sol by heating. The entire preparation process is completed at room temperature or low temperature, completely avoiding the high temperature and strong alkali environment required by traditional methods, and thus it is compatible with temperature-sensitive drugs, proteins and other active ingredients. Other active substances that need to be loaded can be added together for freeze-thawing according to needs, which is beneficial to drug loading.

[0023] Example 1 The present embodiment provides a powderable reconstitutable hydrogel and a preparation method thereof, comprising the following steps: S1, 0.16g of konjac glucomannan, 0.02g of silicon calcium phosphorus boron bioglass and 2.4mL of deionized water are weighed respectively, and the mass ratio is 8:1:120, and 2.4mL of deionized water is preloaded into a forming mold for standby; S2, Place the weighed konjac glucomannan and silicon-calcium-phosphorus-boron bioglass in an agate mortar and grind them thoroughly for 5 minutes to obtain a uniformly mixed composite powder; S3. Pour the composite powder obtained in step S2 into a mold containing deionized water and stir continuously for 3 minutes until the material is uniform and transparent and semi-gelled. S4. Transfer the suspension obtained in step S3 to a -80°C freezer and freeze for 12 hours. Then take it out and thaw it at room temperature for 2 hours. This process is recorded as one freeze-thaw cycle. In this embodiment, one cycle is performed. S5, freeze-dry the gel formed after freeze-thaw in step S4, and then grind it into fine powder using an agate mortar and pestle to obtain the hydrogel powder. S6. Take the hydrogel powder obtained in step S5, add 2.4 mL of deionized water, and let it stand at room temperature to allow the powder to fully absorb water, thereby reforming a uniform and stable hydrogel with injectable and self-healing properties.

[0024] Example 2 This embodiment provides a powderable restorable hydrogel and its preparation method, including the following steps: S1, weigh out 0.2g of konjac glucomannan, 0.02g of silicon-calcium-phosphorus-boron bioglass and 2.6mL of deionized water in a mass ratio of 10:1:130, and add 2.6mL of deionized water to the molding mold in advance for later use. S2, Place the weighed konjac glucomannan and silicon-calcium-phosphorus-boron bioglass in an agate mortar and grind them thoroughly for 10 minutes to obtain a uniformly mixed composite powder; S3. Pour the composite powder obtained in step S2 into a mold containing deionized water and stir continuously for 4 minutes until the material is uniform and transparent and semi-gelled. S4, the suspension obtained in step S3 is transferred to a -80°C freezer and frozen for 12 hours, then taken out and placed at room temperature to thaw for 2 hours. This process is recorded as one freeze-thaw cycle. In this embodiment, two cycles are performed. S5, freeze-dry the gel formed after freeze-thaw in step S4, and then grind it into fine powder using an agate mortar and pestle to obtain the hydrogel powder. S6. Take the hydrogel powder obtained in step S5, add 2.6 mL of deionized water, and let it stand at room temperature to allow the powder to fully absorb water, so that a uniform and stable hydrogel with injectable and self-healing properties can be reformed.

[0025] Example 3 This embodiment provides a powderable restorable hydrogel and its preparation method, including the following steps: S1, weigh 0.24g of konjac glucomannan, 0.02g of silicon-calcium-phosphorus-boron bioglass and 2.8mL of deionized water respectively, with a mass ratio of 12:1:140, and add 2.6mL of deionized water to the molding mold for later use. S2, Place the weighed konjac glucomannan and silicon-calcium-phosphorus-boron bioglass in an agate mortar and grind them thoroughly for 15 minutes to obtain a uniformly mixed composite powder; S3. Pour the composite powder obtained in step S2 into a mold containing deionized water and stir continuously for 5 minutes until the material is uniform and transparent and semi-gelled. S4. Transfer the suspension obtained in step S3 to a -80°C freezer and freeze for 12 hours. Then take it out and thaw it at room temperature for 2 hours. This process is recorded as one freeze-thaw cycle. In this embodiment, 3 cycles are performed. S5, freeze-dry the gel formed after freeze-thaw in step S4, and then grind it into fine powder using an agate mortar and pestle to obtain the hydrogel powder. S6. Take the hydrogel powder obtained in step S5, add 2.8 mL of deionized water, and let it stand at room temperature to allow the powder to fully absorb water, so that a uniform and stable hydrogel with injectable and self-healing properties can be reformed.

[0026] The hydrogels prepared in Examples 1, 2, and 3 above were subjected to the following performance tests and characterizations: (1) Gelation time test After mixing the hydrogel powder obtained in step S6 of each embodiment with deionized water in a certain proportion, and allowing it to stand at room temperature, the material will spontaneously gel to obtain a hydrogel. Figure 1 and Figure 2 As shown, the gelation times of Examples 1, 2 and 3 are approximately 74 seconds, 47 seconds and 80 seconds, respectively, indicating that the material has the characteristic of rapid rehydration and gelation.

[0027] (2) Injectability test The hydrogel powder obtained in step S6 of each implementation case was mixed with deionized water in a certain proportion, transferred to a syringe, allowed to stand for no more than 1.5 minutes, and then injected by squeezing. The results are as follows. Figure 3 As shown, the gel can be extruded continuously and completely without breakage, exhibiting good injectability and suitability for micromanipulation.

[0028] (3) Self-healing performance test Using a sharp blade, cut the hydrogel obtained in each embodiment in half, align the two cut surfaces, and let stand for 30 minutes. Figure 4 As shown, the two cut parts reassembled into a complete gel block, indicating that the hydrogel has a significant self-healing ability.

[0029] (4) Thermal stability test The prepared gelled hydrogel was placed in an environment of 50°C, and the morphology of the material was observed every 10 minutes for 30 minutes. Figure 5 As shown, the gel remained solid throughout the heating process, without liquefaction or rheological phenomena, proving that it has a thermally irreversible stable network structure.

[0030] (5) Cytotoxicity test Following the requirements of GB / T 16886.12-2023, the sterilized materials and culture medium were prepared at a ratio of 1 g / 5 mL. The materials were completely immersed in the complete culture medium and soaked at 37°C for 24 hours. After filtration using a sterile syringe filter, the extract was aliquoted into centrifuge tubes. Cytotoxicity was assessed using L929 cells in a CCK-8 assay according to the requirements of GB / T 16886.5-2017. The experimental results are as follows: Figure 6 As shown, the relative cell proliferation rates of Examples 1, 2 and 3 were 100.5%, 102.3% and 102.5%, respectively, indicating that none of the materials had obvious cytotoxicity and good biocompatibility.

[0031] It should be noted that the above embodiments are only used to illustrate the present invention, but the present invention is not limited to the above embodiments. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A powderable reconstituted hydrogel, and a method of making the same, characterized by: The hydrogel is composed of konjac glucomannan and borosilicate bioglass, and the hydrogel exhibits reversible morphology that can be ground into powder by freeze-drying, and the powder can be restored to gel by adding water again.

2. The hydrogel of claim 1, wherein: The mass ratio of the konjac glucomannan to the borosilicate bioglass is (8-12):

1.

3. The hydrogel of claim 1, wherein: The borosilicate bioglass is a silicon-calcium-phosphorus-boron bioglass.

4. A method of preparing a hydrogel according to any one of claims 1 to 3, characterised in that: The method comprises the following steps: S1, weighing konjac glucomannan, borosilicate bioglass and deionized water, and pre-adding deionized water into a mold for standby; S2, grinding the konjac glucomannan and the borosilicate bioglass together to obtain a mixed powder; S3, pouring the mixed powder obtained in step S2 into the mold containing deionized water in step S1, and stirring until the material is uniform and transparent, and semi-gelation is achieved; S4, freezing the suspension obtained in step S3 at-80℃ for 12 hours, and then taking out and melting at room temperature for 2 hours, and repeating the freezing and melting for 1-3 times; S5, freeze-drying the gel obtained in step S4, and grinding into a powder; S6, adding deionized water to the powder obtained in step S5, and standing at room temperature until the material is restored to a uniform and stable hydrogel.

5. The method of claim 4, wherein: In step S1, the mass-volume ratio of the konjac glucomannan, the borosilicate bioglass and the deionized water is (8-12):1:(120-140).

6. The method of claim 4, wherein: In step S2, the grinding time is 5-15 minutes.

7. The method of claim 4, wherein: In step S3, the stirring time is 3-5 minutes.

8. The method of claim 4, wherein: In step S6, the mass-volume ratio of the powder to the deionized water is (9-13):(120-140).

9. The method of claim 4, wherein: The borosilicate bioglass is a silicon-calcium-phosphorus-boron bioglass. The borosilicate bioglass is a silicon-calcium-phosphorus-boron bioglass.

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