An injectable temperature-sensitive in-situ solidifying hydrogel and a preparation method thereof

Abstract

The application provides an injectable temperature-sensitive in-situ solidified hydrogel and a preparation method thereof, and the preparation method is specifically as follows: adding triple distilled water and nano-silicate bioactive glass powder in a beaker, mixing to form a suspension, then adding konjac gum, uniformly mixing to form a suspension mixed colloid A, adding xanthan gum into the suspension mixed colloid A, uniformly mixing to form a suspension mixed colloid B, transferring the suspension mixed colloid B into a syringe for packaging, and placing the packaged material in a water bath at 55-60 DEG C for heating for 25-35 min to make it gel, and then cooling at room temperature to obtain the injectable temperature-sensitive in-situ solidified hydrogel. The hydrogel prepared by the application does not need to be prepared and used immediately, and only needs to be heated simply to realize injection without special skills, and the operation is simple and easy to master.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, specifically to a novel injectable thermosensitive in-situ curing hydrogel and its preparation method. Background Technology

[0002] Repairing tissue defects is a common clinical medical issue. When tissue defects reach a critical size, they cannot be fully repaired by their own function and require external intervention. Surgical implantation of biomaterial scaffolds at the site of the defect is currently a commonly used method in clinical practice for repairing tissue defects exceeding the critical size. Due to significant market demand, a wide variety of biomaterial scaffolds have been developed for filling and repairing tissue defects.

[0003] With the development of medical science, traditional large-incision surgical procedures are increasingly being replaced by minimally invasive surgery due to their drawbacks, such as large incision areas, significant damage to the body, long recovery times, extended hospital stays, and increased patient anxiety and physical and psychological suffering. Minimally invasive surgery, with its smaller incisions, less damage to the body, less patient suffering, and faster recovery, is becoming increasingly popular and represents the future direction of clinical surgery. Similarly, the development of injectable scaffold materials for minimally invasive procedures aligns with this trend, aiming to minimize surgical trauma, reduce patient anxiety, accelerate recovery time, shorten hospital stays, and save on medical costs.

[0004] Hydrogels are an excellent class of biomaterials. These materials contain a large number of water molecules within a solid three-dimensional network, similar to the water-saturated structure of the extracellular matrix of organisms. Therefore, they exhibit good biocompatibility and strong repair capabilities, leading to their widespread clinical use. Developing hydrogel materials into injectable biomaterials for minimally invasive procedures has attracted considerable attention. However, developing injectable and in-situ curing hydrogel materials intended for use as repair scaffolds is challenging. This is because humans are homeothermic, with an internal temperature around 37°C. This necessitates that the gel material be temperature-sensitive, capable of transitioning from a flowable state to a non-flowable solid state at the injection site within a narrow temperature range, thus achieving in-situ curing and fulfilling its filling function. Simultaneously, the implantation environment is also a liquid environment, containing blood and other fluids. The gel is initially in a solution state upon injection and needs to maintain good erosion resistance to prevent it from being dispersed and migrating due to the demanding curing conditions required for injectable and in-situ curing hydrogels used as scaffolds. Therefore, the variety of injectable hydrogel scaffold materials currently available is limited. A commonly used system is the sodium β-glycerophosphate-chitosan system. This system is a liquid at room temperature, injectable, and solidifies in situ at body temperature after injection. This system uses a large amount of sodium β-glycerophosphate, which is relatively expensive. Furthermore, the gel in this system needs to be prepared fresh before use; that is, the sodium β-glycerophosphate and chitosan solution must be mixed before application, making the process rather cumbersome. Summary of the Invention

[0005] To overcome the above shortcomings, this invention provides a novel injectable, temperature-sensitive, in-situ curable hydrogel and its preparation method. The technical solution adopted by this invention is as follows: A novel method for preparing injectable, temperature-sensitive, in-situ curing hydrogel, the specific preparation method being as follows: (1) Add triple-distilled water and nano-silicate bioactive glass powder to a beaker, mix and form a suspension; (2) Add konjac gum to the suspension in step (1) and mix evenly to form a suspension mixture colloid A; (3) Add xanthan gum to the suspended mixed colloid A and mix well to form the suspended mixed colloid B; (4) Transfer the suspended mixed colloid B into a syringe and seal it. Heat the sealed material in a water bath at 55-60℃ for 25-35 minutes to gel it. Cool it at room temperature to obtain the hydrogel.

[0006] Further optimization is achieved by using nano-silicate bioactive glass powder with a particle size of 30-80 nm in step (1).

[0007] Further optimization involves mixing by magnetic stirring in steps (1), (2), and (3) for a time of 20-40 minutes.

[0008] A novel injectable thermosensitive in-situ curing hydrogel was prepared using the above method.

[0009] The beneficial effects of this invention are as follows: 1. The konjac gum and xanthan gum used in this invention are inexpensive and readily available, with low cost and stable process, making them easy to promote. Furthermore, the addition of slightly alkaline bioglass, a biomaterial that can repair both soft and hard tissues, expands the application range of the composite gel material. The slightly alkaline nature of the bioglass can promote the cross-linking of konjac gum, while konjac gum and xanthan gum have a synergistic gelling effect. This dual cross-linking mechanism gives the material a good gelling effect. 2. When using this gel, for areas requiring deep filling, it can be injected with a syringe to achieve minimally invasive filling. For irregular skin defects that are difficult to apply, it can be injected to fill them, using the tiny amount dispensed from the needle tip to achieve comprehensive filling and application. 3. The hydrogel of the present invention is in a solid state at room temperature. When this gel is encapsulated in an ordinary syringe and slightly heated to above 40°C in a microwave oven or hot water before use, the material softens and has strong rheological properties. It can be easily and completely injected and solidified in situ at body temperature. The temperature of 40°C is a temperature that the human body can withstand. 4. The material of this invention has a moisture content of more than 90%, the system is open, highly inclusive, easy to modify, and can be further developed. In summary, the hydrogel prepared by this invention does not need to be prepared and used immediately. It can be injected simply by heating, requiring no special skills and is easy to operate and master. Attached Figure Description

[0010] Figure 1 This is a schematic diagram showing the state of the hydrogel before and after heating. Figure 2 A schematic diagram showing the state of a hydrogel injected into physiological saline at 37°C. Figure 3 A schematic diagram of cell proliferation rate after irradiation sterilization of hydrogel. Detailed Implementation

[0011] The technical solutions in the embodiments of the present invention will now be clearly and completely described with reference to the accompanying drawings.

[0012] A novel method for preparing injectable, temperature-sensitive, in-situ curable hydrogel is as follows: Triple-distilled water and nano-silicate bioactive glass powder are added to a beaker and mixed to form a suspension. Konjac gum is then added and mixed evenly to form a suspension mixture A. Xanthan gum is added to suspension mixture A and mixed evenly to form suspension mixture B. Suspension mixture B is transferred into a syringe for encapsulation. The encapsulated material is heated in a water bath at 55-60℃ for 25-35 minutes to gel, and then cooled to room temperature to obtain the hydrogel.

[0013] When using the above-mentioned hydrogel, it is only necessary to heat it in a household microwave oven on low for 2 seconds or heat it in a water bath to above 40°C. The material will then become a flowable body and can be injected directly. After injection, the material will solidify immediately, changing from a flowable state to a non-flowable solid state, which is called in-situ solidification, thus fulfilling the filling function.

[0014] Example 1:

[0015] (1) Measure 25 mL of triple-distilled water and add it to a beaker. Add 0.5 g of nano-silicate bioactive glass powder with a diameter of 30-80 nm and stir magnetically for 30 minutes to form a uniform suspension. (2) Under the condition of continuous magnetic stirring, add 0.4 g of konjac gum to the suspension obtained in step (1) and mix for 30 minutes to form a uniform suspension mixture. (3) Under the condition of continuous magnetic stirring, add 0.6g xanthan gum to the suspension mixture obtained in step (2) and continue stirring for 30 minutes to form a uniform and stable suspension mixture. (4) Transfer the colloidal material obtained in step (3) into a syringe for sealing. The sealed material is heated in a water bath at 55°C for 30 minutes to gel it. After cooling to room temperature, the gel is obtained.

[0016] Example 2:

[0017] (1) Measure 25 mL of triple-distilled water and add it to a beaker. Add 0.5 g of nano-silicate bioactive glass powder with a diameter of 30-80 nm and stir magnetically for 30 minutes to form a uniform suspension. (2) Under the condition of continuous magnetic stirring, add 0.5g of konjac gum to the suspension obtained in step (1) and mix for 30 minutes to form a uniform suspension mixture. (3) Under the condition of continuous magnetic stirring, add 0.5g xanthan gum to the suspension mixture obtained in step (2) and continue stirring for 30 minutes to form a uniform and stable suspension mixture. (4) Transfer the colloidal material obtained in step (3) into a syringe and seal it. Place the sealed material in a water bath at 60°C for 30 minutes to gel it. After cooling to room temperature, the gel is obtained.

[0018] Example 3:

[0019] (1) Measure 25 mL of triple-distilled water and add it to a beaker. Add 0.5 g of nano-silicate bioactive glass powder with a diameter of 30-80 nm and stir magnetically for 30 minutes to form a uniform suspension. (2) Under the condition of continuous magnetic stirring, add 0.6g of konjac gum to the suspension obtained in step (1) and mix for 30 minutes to form a uniform suspension mixture. (3) Under the condition of continuous magnetic stirring, add 0.4g xanthan gum to the suspension mixture obtained in step (2) and continue stirring for 30 minutes to form a uniform and stable suspension mixture. (4) Transfer the colloidal material obtained in step (3) into a syringe for encapsulation. The encapsulated material is heated in a water bath at 65°C for 30 minutes to gel it. After cooling to room temperature, the hydrogel is obtained.

[0020] The hydrogels prepared in Examples 1-3 were subjected to tests for gelation properties, injectability, anti-collapse properties, and cytotoxicity, as detailed below: 1. Gelation properties The mixed colloid prepared in step (3) of Implementation 1-3 was poured into a glass vial to 1 / 3 of its volume. The vial was tilted, and a photograph was taken to record the flowable state of the colloid. Then, the heating process in step (4) was carried out on the colloid. After the process was completed, the vial was removed, tilted, and a photograph was taken to record the flow state of the colloid. The results are shown in […]. Figure 1 It can be seen that the material was fluid before heat treatment, but lost its fluidity and gelled after heat treatment.

[0021] 2. Injectable and anti-collapse properties The syringes containing gel, prepared in step (4) of each implementation case, were heated to 40°C, and the material was injected into 37°C physiological saline. The results were photographed and recorded after 10 minutes. (See attached image for details.) Figure 2 It is evident that all materials exhibit good injection performance and are resistant to collapse and dilution.

[0022] 3. Cytotoxicity The materials were sterilized by irradiation, and cytotoxicity was assessed using K7M2 cells as experimental cells, following the material extraction method described in ISO 10993. Results are shown below. Figure 3 The embedded portion of the figure represents the results of the MTT plate experiment, and the bar chart represents the absorbance results. It can be seen that the cell proliferation rate of each group of materials is close to 90%, and they do not exhibit cytotoxicity.

[0023] The foregoing has shown and described the main features, usage methods, basic principles, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention based on actual circumstances without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing an injectable, temperature-sensitive, in-situ curable hydrogel, characterized in that, The specific preparation method is as follows: (1) Add triple-distilled water and nano-silicate bioactive glass powder to a beaker, mix and form a suspension; the particle size of the nano-silicate bioactive glass powder is 30-80 nm; (2) Add konjac gum to the suspension in step (1) and mix evenly to form a suspension mixture colloid A; (3) Add xanthan gum to the suspended mixed colloid A and mix well to form the suspended mixed colloid B; (4) Transfer the suspended mixed colloid B into a syringe and seal it. Heat the sealed material in a water bath at 55-60℃ for 25-35 minutes to gel it. Cool it at room temperature to obtain the hydrogel.

2. The method for preparing an injectable, temperature-sensitive, in-situ curing hydrogel as described in claim 1, characterized in that, In steps (1), (2), and (3), the mixture is stirred by magnetic force for 20-40 minutes.

3. An injectable thermosensitive in-situ curing hydrogel prepared by the method according to any one of claims 1-2.

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