Oral bone repair hydrogel periosteum material and preparation method thereof

Abstract

The invention discloses a preparation method of an oral bone repair hydrogel periosteum material, which comprises the following steps: reacting a natural polysaccharide solution with a metal salt to obtain a gelatinous substance, then drying to obtain a membranous substance, and mineralizing and drying the membranous substance in a metal salt solution to obtain the oral bone repair hydrogel periosteum material. The periosteum material with one hydrophilic side and the other hydrophobic side is obtained through metal ion mineralization and drying reforming. The obtained periosteum material is high in tensile strength and plastic in shape, the requirement for high mechanical performance needed in oral bone repair is met, the periosteum can be well attached to the periphery of bone defect tissue, and the degradation period is matched with the treatment period of oral bone repair. The preparation method is simple, low in cost and suitable for being used as a periosteum material for oral bone repair.

Description

Technical Field

[0001] The present invention relates to an oral bone repair hydrogel periosteum material based on polysaccharide raw materials and a preparation method thereof. Background Art

[0002] Bone defects caused by various reasons such as accidents, congenital deformities, bone tumors, dental implants, periodontal diseases, craniotomy, etc. are very common in clinical practice. At present, most orthopedic clinics still choose the method of "robbing Peter to pay Paul" by taking autologous bone from patients (common sites include ilium, rib, fibula, etc.) for bone grafting treatment. Although autologous bone is recognized as the "gold standard" for bone grafting in clinical practice, this is only an evaluation of the bone defect repair effect of autologous bone. Taking autologous bone has a series of problems such as causing secondary injury to patients, donor area complications, prolonging the operation time, increasing blood loss, and limited bone mass, and it is not a perfect clinical solution.

[0003] In the dental field, dental implant bone grafting is often used for bone defect treatment. During the bone grafting process, first, bone powder from artificial synthesis or allogeneic bone is used to fill the alveolar bone defect to increase bone mass, and then a periosteum is covered on the surface of the bone powder. The main function of the periosteum is to prevent soft tissue invasion into the defect area through physical isolation, create a sterile environment during dental implant, prevent bone powder loss, maintain the spatial stability of bone powder, and promote the combination of bone powder and surrounding bone tissue. According to the degradation characteristics, periosteum can be divided into two categories: 1. Non-absorbable periosteum Represented by polytetrafluoroethylene (PTFE) membrane and titanium mesh, it has high strength and high space maintenance ability, and can meet the needs of fixing bone powder. However, its non-degradability requires a second operation to remove it after recovery, and there are limitations such as membrane exposure and high infection risk, which limit its wide application.

[0004] 2. Absorbable periosteum Mainly composed of natural / synthetic polymer materials such as collagen and polylactic acid (PLA), it has similar components to natural periosteum, and at the same time has the advantages of good biocompatibility and no need for a second operation, reducing the pain of patients. However, there are problems such as uncontrollable degradation rate and insufficient mechanical strength (for example, the membrane strength of the periosteum prepared from collagen is only 0.42 kPa), which limit its large-scale application in the clinical repair of bone defects. The degradation products of some materials may also cause a decrease in local PH and cause oral inflammation.

[0005] Due to its biocompatibility and biodegradability, hydrogel has become a candidate material for the new generation of periosteum and has great potential. For example: Current hydrogel research focuses on: ① enhancing mechanical properties through crosslinker optimization (such as introducing bisphosphonates) or composite inorganic fillers (such as nano-hydroxyapatite) to meet the mechanical property requirements in the field of oral dentistry; ② being able to be retained in the body for a long time, with degradation products being harmless to the human body.

[0006] Patent application number CN202311447542.9 discloses the preparation of a periosteum-like material, which uses a natural polymer material and an inorganic material for compounding to improve the mechanical strength of the periosteum-like material and meet the clinical application requirements in terms of mechanical properties. This preparation method involves compounding a natural polymer material, natural polysaccharide, with dopamine hydrochloride, type I collagen (ColI) as the organic component of bone, and nano-hydroxyapatite (nHAP) as the inorganic component of bone, and preparing a composite membrane material with good adhesion and ductility by optimizing the reaction conditions (solution concentration, reaction time, reaction temperature). Although the periosteum-like material prepared by this patent improves the mechanical properties to a certain extent and can meet the treatment in some bone defects, it is difficult to effectively anchor or combine with a bone scaffold in oral bone repair, and the degradation period is uncontrollable, thus limiting its application in the field of oral repair. Summary of the Invention

[0007] In order to overcome the deficiencies in the application of hydrogel materials in bone repair materials, the purpose of the present invention is to provide a hydrogel for the field of dental bone repair, which can generate a mineralized hard material with controllable morphology, relatively high mechanical strength, and good fit to the tooth defect site through in-situ mineralization, and can be used as a periosteum.

[0008] To achieve this purpose, the technical solution of the present invention is as follows: A preparation method of an oral bone repair hydrogel periosteum material, the method being: React a natural polysaccharide solution with a metal salt to obtain a gel-like substance, then dry it to obtain a film-like substance, and mineralize and dry the film-like substance in a metal salt solution to obtain the oral bone repair hydrogel periosteum material.

[0009] Further, the mass concentration of the natural polysaccharide solution is 1 - 3%.

[0010] The natural polysaccharide is one or more of hydroxypropyl carboxymethyl cellulose, xanthan gum, hyaluronic acid, and sodium alginate, preferably hydroxypropyl carboxymethyl cellulose.

[0011] The metal salt is one or more of calcium salts, magnesium salts, zinc salts, copper salts, strontium salts, iron salts, ferrous salts, and barium salts.

[0012] Further, the calcium salts include hydroxyapatite, calcium gluconate, calcium chloride, calcium sulfate, calcium carbonate, or calcium phosphate.

[0013] The zinc salt is preferably zinc sulfate.

[0014] Furthermore, it is preferred that the metal salt is zinc sulfate, calcium chloride or calcium sulfate.

[0015] The metal salt is formulated into an aqueous solution, and the mass fraction of the metal salt solution is 0.1-15%, preferably 0.2-13%.

[0016] The mass ratio of the natural polysaccharide to the metal salt is 1:0.01-5, preferably 1:0.02-3.

[0017] More preferably, the method is carried out according to the following steps: (1) A metal salt solution is added to a natural polysaccharide solution with a mass concentration of 1-3%, stirred and mixed evenly, the bubbles are removed, and then dried to obtain a film-like substance; (2) The film-like substance is mineralized in a metal salt solution and dried to obtain the oral bone repair hydrogel periosteal material.

[0018] In the step (1), the drying can be carried out at 40-50 °C for 5-6 h.

[0019] In the step (1), the concentration of the metal salt solution is 0.1-15%, preferably 0.1-13%.

[0020] In the step (1), when the metal salt solution is a zinc sulfate solution, the concentration is preferably 0.35-10%; when the metal salt solution is a calcium chloride solution, the concentration is preferably 5-15%; when the metal salt solution is a calcium sulfate solution, the concentration is preferably 0.1-0.2%.

[0021] In the step (2), the metal salt solution is preferably a calcium chloride or zinc sulfate solution, more preferably a zinc sulfate solution; the mass concentration is preferably 1%-7.5%, more preferably 3-5%.

[0022] In the step (2), when the metal salt solution is calcium sulfate, the mass concentration is preferably 0.2%.

[0023] In the step (2), the mineralization is single-sided mineralization, that is, one side of the film-like substance is immersed in the metal salt solution, and the other side does not contact the metal salt solution; In the step (2), the film-like substance can be first wetted with a small amount of water and then mineralized in the metal salt solution.

[0024] The time of the mineralization is preferably 1 h-4 h, and the temperature is room temperature.

[0025] In the step (2), the drying is generally carried out at room temperature and generally dried to a water content of less than 3%.

[0026] The present invention also provides an oral bone repair hydrogel periosteal material prepared by the above method.

[0027] The thickness of the oral bone repair hydrogel periosteal material is 100 to 300 micrometers (0.1 to 0.3 millimeters). The tensile strength is 60 to 90 Mpa, and the degradation time is 3 to 6 months.

[0028] The oral bone repair hydrogel periosteal material described in the present invention can be used as a periosteum in dental bone repair.

[0029] The present invention mainly uses natural polysaccharides (such as cellulose, hyaluronic acid, etc.) with different structural types and metal ions with different valence states as the main matrix, and is supplemented with metal salts with different solubilities (such as zinc sulfate, hydroxyapatite, calcium gluconate, calcium chloride, calcium carbonate, calcium phosphate, etc.) to prepare bio-mineralized gels with different mechanical properties and mineralization behaviors. This hydrogel with controllable mechanical properties can meet the mechanical property requirements for bone defect repair in the field of orthopedics, especially in oral medicine.

[0030] Compared with the existing bone repair materials, the present invention has the following advantages: 1. The raw materials selected are natural polysaccharides, with good biocompatibility, good adaptability in the human body when used as a bone repair material, and the biological toxicity to the human body can be reduced to the lowest level after degradation.

[0031] 2. The preparation method adopted in the present invention is simple and does not require a complex process. A gel network structure is formed by the way of drying and restructuring, without a cumbersome preparation process. By adjusting the different ratios of raw materials and the concentration of metal ions to control the gel network, and adding metal salt ions for mineralization to enhance the gel network, the material has soft and tough properties, and different mechanical strengths and degradation periods can be controlled to meet different clinical use requirements.

[0032] 3. The periosteal material prepared from the mineralized hydrogel can be well attached around the bone defect tissue. When mineralized on one side, the mineralized side is relatively rough, the surface form increases, the contact angle decreases, and it is more hydrophilic, while the unmineralized side is not treated and is relatively hydrophobic. Thus, a periosteal material with one hydrophilic side and one hydrophobic side is prepared. When used clinically, the hydrophilic side is wetted, and the membrane will spontaneously adhere to the hydrophilic end, so as to achieve better adhesion to the irregular bone defect site in the oral cavity.

[0033] 4. From the experimental data, the mechanical properties of the film after being mineralized by metal ions have been greatly improved compared with those before mineralization, and can meet the mechanical strength requirements of the clinical periosteum.

[0034] 5. The hydrogel of the present invention can regulate the degradation period by adjusting the chain segment structure and mineralization pathway. The repair period of oral bone defects is usually 3 - 6 months (depending on the size and location of the defect). The hydrogel bone membrane material prepared by the present invention can be gradually degraded within this stage. Natural periosteum is gradually replaced by new tissues during bone healing. The ideal degradation rate of periosteum should be synchronized with the bone formation rate (for example, slow degradation in the early stage to maintain support and accelerated degradation in the later stage to give way). Therefore, the degradation time of periosteum should also be between 3 and 6 months, so that the degradation period matches the treatment period, stably degrades in the early stage of bone injury healing and rapidly degrades in the later stage, is absorbed by the human body, and there is no need to remove it after surgery, thus reducing the pain of patients.

[0035] The present invention provides a high-strength, shape-plastic, and controllable mineralization biomass hydrogel film material through metal ion mineralization and dry reforming to meet the requirements of higher mechanical properties needed in oral bone repair. The prepared periosteum can adhere well to the surrounding bone defect tissues. At the same time, according to the histological structure of the periosteum, a multi-layer structure is designed to achieve stable degradation in the early stage of healing and rapid degradation in the later stage of healing. While promoting bone repair to the greatest extent, it rapidly degrades and has no other effects on the human body. The preparation method of the present invention is simple and has low cost, and is suitable as a periosteum material for oral bone repair. Description of the Drawings

[0036] Figure 1 SEM images of the network morphology of the gel before and after mineralization after freeze-drying.

[0037] Figure 2 Infrared spectra of the hydrogel before and after mineralization.

[0038] Figure 3 Physical photo of the mineralized hydrogel.

[0039] Figure 4 SEM image of the microscopic morphology of the mineralized hydrogel (before drying) in Example 1. The left figure is the outer layer of the surface of the hydrogel mineralized by metal ions, and the right figure is the three-dimensional network structure inside the gel.

[0040] Figure 5 XRD spectra of the film-like sample before mineralization and the final product after mineralization, where the left figure is before mineralization and the right figure is after mineralization.

[0041] Figure 6 SEM images of the microscopic morphology of the surface of the freeze-dried hydrogel mineralized by soaking in solutions with different metal ion concentrations.

[0042] Figure 7 Physical picture of the transparent high-strength hydrogel film.

[0043] Figure 8It is a stress-strain curve of the hydrogel. Among them, the left figure shows the data of the mechanical strength of gels with different water contents, and the right figure shows the influence of mineralization with different concentrations of metal ions on the mechanical properties of the gel.

[0044] Figure 9 It is the compression strength diagram of the mineralized gel with different metal ion concentrations added.

[0045] Figure 10 It is the degradation curve of the gel over time. Specific Embodiments

[0046] The technical solutions of the present invention will be further specifically described below through embodiments. The protection scope of the present invention includes but is not limited to this.

[0047] Example 1: Weigh 0.5 g of hydroxypropyl carboxymethyl cellulose and slowly pour it into a round-bottom flask containing 50 g of distilled water. Stir at a speed of 700 rpm for 2 h until the solution is clear and transparent to obtain a uniformly mixed hydroxypropyl carboxymethyl cellulose solution A; Weigh 0.035 g of zinc sulfate, add 10 g of distilled water to prepare a zinc sulfate solution, shake it well, and slowly add it to the above-prepared hydroxypropyl carboxymethyl cellulose solution A for stirring. The initial speed is maintained at 800 rpm / min, and then the speed is gradually reduced to 500 rpm / min to reduce the generation of bubbles and obtain solution B; Pour the solution B obtained in the above steps into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the sample performance. The thickness of the obtained gel-like substance is 4.5 - 5 mm.

[0048] Then put the petri dish into an oven, set the temperature to 40 °C, and dry it for 6 h to obtain a film-like sample. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, and add 20 mL of 5% zinc sulfate solution for single-sided mineralization. The film-like substance floats on the surface of the zinc sulfate solution, one side is immersed in the zinc sulfate solution, and the other side does not contact the zinc sulfate solution; after treatment for 2 h, wash it with deionized water 2 - 3 times, and dry it at room temperature until the water content is below 3% to obtain the final product with a thickness of 100 - 200 μm.

[0049] Example 2: Weigh 1.0 g of hydroxypropyl carboxymethyl cellulose and slowly pour it into a round-bottom flask containing 50 g of distilled water. Stir at a speed of 700 rpm for 2 h until the solution is clear and transparent to obtain a uniformly mixed hydroxypropyl carboxymethyl cellulose solution A; Weigh 0.035 g of zinc sulfate, add it to 10 g of distilled water to prepare a zinc sulfate solution, shake it well, and slowly add it to the above-prepared hydroxypropyl carboxymethyl cellulose solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B; Pour the solution B obtained in the above step into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the performance of the sample.

[0050] After that, put the petri dish into an oven, set the temperature to 40 °C, and dry it for 6 h to obtain a film-like sample. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, add 20 mL of 5% zinc sulfate solution for single-sided mineralization. One side of the film-like substance is immersed in the zinc sulfate solution, and the other side does not contact the zinc sulfate solution. After treatment for 1 h, wash it with deionized water 2 - 3 times and dry it at room temperature to obtain the final product.

[0051] Example 3: Weigh 0.5 g of xanthan gum, slowly pour it into a round-bottom flask containing 50 g of distilled water, and stir at a rotation speed of 700 rpm / min for 2 h until the solution is clear and transparent, obtaining a uniformly mixed xanthan gum solution A; Weigh 0.035 g of zinc sulfate, add it to 10 g of distilled water to prepare a zinc sulfate solution, shake it well, and slowly add it to the above-prepared xanthan gum solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B; Pour the solution B obtained in the above step into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the performance of the sample.

[0052] After that, put the petri dish into an oven, set the temperature to 40 °C, and dry it for 6 h to obtain a film-like sample. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, add 20 mL of 5% zinc sulfate solution for single-sided mineralization. One side of the film-like substance is immersed in the zinc sulfate solution, and the other side does not contact the zinc sulfate solution. After treatment for 2 h, wash it with deionized water 2 - 3 times and dry it at room temperature to obtain the final product.

[0053] Example 4: Weigh 1.5 g of hydroxypropyl carboxymethyl cellulose, slowly pour it into a round-bottom flask containing 50 g of distilled water, and stir at a rotation speed of 700 rpm / min for 2 h until the solution is clear and transparent, obtaining a uniformly mixed hydroxypropyl carboxymethyl cellulose solution A; Weigh 0.035 g of zinc sulfate, add it to 10 g of distilled water to prepare a zinc sulfate solution, shake well, and slowly add it to the above-prepared hydroxypropyl carboxymethyl cellulose solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B; Pour the solution B obtained in the above step into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the sample performance.

[0054] After that, put the petri dish into an oven, set the temperature to 40 °C, and dry for 6 h to obtain a film-like sample. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, and then add 20 mL of 5% zinc sulfate solution for single-sided mineralization. One side of the film-like substance is immersed in the zinc sulfate solution, and the other side does not contact the zinc sulfate solution. After treatment for 4 h, wash it with deionized water 2 - 3 times and dry it at room temperature to obtain the final product.

[0055] Example 5: Weigh 0.5 g of hydroxypropyl carboxymethyl cellulose, slowly pour it into a round-bottom flask containing 50 g of distilled water, and stir at a rotation speed of 700 rpm / min for 2 h until the solution is clear and transparent, obtaining a uniformly mixed hydroxypropyl carboxymethyl cellulose solution A; Weigh 0.5 g of calcium chloride, add it to 10 g of distilled water to prepare a calcium chloride solution, shake well, and slowly add it to the above-prepared hydroxypropyl carboxymethyl cellulose solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B; Pour the solution B obtained in the above step into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the sample performance.

[0056] After that, put the petri dish into an oven, set the temperature to 40 °C, and dry for 6 h to obtain a film-like sample. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, and then add 20 mL of 5% calcium chloride solution for single-sided mineralization. One side of the film-like substance is immersed in the calcium chloride solution, and the other side does not contact the calcium chloride solution. After treatment for 2 h, wash it with deionized water 2 - 3 times and dry it at room temperature to obtain the final product.

[0057] Example 6: Weigh 0.5 g of sodium alginate, slowly pour it into a round-bottom flask containing 50 g of distilled water, and stir at a rotation speed of 700 rpm / min for 2 h until the solution is clear and transparent, obtaining a uniformly mixed sodium alginate solution A; Weigh 1.0 g of zinc sulfate, add 10 g of distilled water to prepare a zinc sulfate solution, shake well, and slowly add it to the above-prepared sodium alginate solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B. Pour the solution B obtained in the above step into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the sample performance.

[0058] After that, put the petri dish into an oven, set the temperature to 40 °C, and dry for 6 h to obtain a film-like sample. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, and then add 20 mL of 5% zinc sulfate solution for single-sided mineralization. One side of the film-like substance is immersed in the zinc sulfate solution, and the other side does not contact the zinc sulfate solution. After treatment for 2 h, wash it with deionized water 2 - 3 times and dry it at room temperature to obtain the final product.

[0059] Example 7: Weigh 0.5 g of sodium alginate, slowly pour it into a round-bottom flask containing 50 g of distilled water, and stir at a rotation speed of 700 rpm / min for 2 h until the solution is clear and transparent, obtaining a uniformly mixed sodium alginate solution A. Weigh 1.5 g of calcium chloride, add 10 g of distilled water to prepare a calcium chloride solution, shake well, and slowly add it to the above-prepared sodium alginate solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B. Pour the solution B obtained in the above step into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the sample performance.

[0060] After that, put the petri dish into an oven, set the temperature to 40 °C, and dry for 6 h to obtain a film-like sample. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, and then add 20 mL of 5% calcium chloride solution for single-sided mineralization. One side of the film-like substance is immersed in the calcium chloride solution, and the other side does not contact the calcium chloride solution. After treatment for 2 h, wash it with deionized water 2 - 3 times and dry it at room temperature to obtain the final product.

[0061] Example 8: Weigh 1.0 g of hydroxypropyl carboxymethyl cellulose, slowly pour it into a round-bottom flask containing 50 g of distilled water, and stir at a rotation speed of 700 rpm / min for 2 h until the solution is clear and transparent, obtaining a uniformly mixed hydroxypropyl carboxymethyl cellulose solution A. Weigh 0.01 g of calcium sulfate, add 10 g of distilled water to prepare a calcium sulfate solution, shake well, and slowly add it to the above-prepared hydroxypropyl carboxymethyl cellulose solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B; Pour the solution B obtained in the above step into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the performance of the sample.

[0062] Then place the petri dish in an oven, set the temperature to 40 °C, and dry for 6 h to obtain the film-like sample we need. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, add 20 mL of 0.2% calcium sulfate solution for single-sided mineralization, wash it with deionized water 2 - 3 times after 2 h of treatment, and dry it at room temperature to obtain the final product.

[0063] Example 9: Weigh 1.0 g of xanthan gum, slowly pour it into a round-bottom flask containing 50 g of distilled water, and stir at a rotation speed of 700 rpm / min for 2 h until the solution is clear and transparent, obtaining a uniformly mixed xanthan gum solution A; Weigh 0.01 g of calcium sulfate, add 10 g of distilled water to prepare a calcium sulfate solution, shake well, and slowly add it to the above-prepared xanthan gum solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B; Pour the solution B obtained in the above step into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the performance of the sample.

[0064] Then place the petri dish in an oven, set the temperature to 40 °C, and dry for 6 h to obtain the film-like sample we need. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, add 20 mL of 0.2% calcium sulfate solution for single-sided mineralization, wash it with deionized water 2 - 3 times after 2 h of treatment, and dry it at room temperature to obtain the final product.

[0065] Example 10: Weigh 1.0 g of xanthan gum, slowly pour it into a round-bottom flask containing 50 g of distilled water, and stir at a rotation speed of 700 rpm / min for 2 h until the solution is clear and transparent, obtaining a uniformly mixed xanthan gum solution A; Weigh 0.01 g of calcium sulfate, add 10 g of distilled water to prepare a calcium sulfate solution, shake well, and slowly add it to the above-prepared xanthan gum solution A and stir. Keep the initial rotation speed at 800 rpm / min, and then gradually reduce the rotation speed to 500 rpm / min to reduce the generation of bubbles, obtaining solution B; Pour the solution B obtained in the above steps into a petri dish, observe the bubble situation, and use a dropper to remove most of the bubbles to prevent affecting the performance of the sample.

[0066] Then, put the petri dish into an oven, set the temperature to 40 °C, and dry for 6 h to obtain the film-like sample we need. Scrape it off with a cutter, moisten it with 1 - 2 mL of water, add 20 mL of 0.1% calcium sulfate solution for single-sided mineralization. After treatment for 2 h, wash it 2 - 3 times with deionized water and dry it at room temperature to obtain the final product.

[0067] Change the concentration of the metal salt solution and the cation of the metal salt used in the mineralization of Examples 1 and 3. Test the mechanical properties of the periosteum prepared by mineralization and drying under different mineralization conditions. The data results of the tensile strength and elongation at break are shown in Table 1: Table 1

[0068] The results in Table 1 show that for the hydrogels prepared in Examples 1 and 3, after mineralization with the metal salt solution, the tensile strength and elongation at break are significantly improved compared with before mineralization.

[0069] When the concentration of the zinc sulfate solution increases from 1% to 5%, with the increase of the mineralization degree, the mechanical properties are improved. The tensile strength increases with the increase of the concentration, and reaches the maximum value at 5%. After 5% concentration, due to too high concentration resulting in uneven crosslinking, it will instead affect the mechanical properties. When the concentration increases from 5% to 7.5%, the tensile strength decreases with the increase of the concentration.

[0070] The comparison of Examples 1, 5, and 8 shows that the mechanical properties of the periosteum mineralized with the zinc salt solution are better than those of the calcium salt solution. And from the experimental process, calcium chloride has the fastest gelation speed. Although calcium sulfate has a low solubility and a low concentration, it can still form a mineralized layer and improve the mechanical properties.

[0071] In Example 3, the polysaccharide is xanthan gum. In its mineralization step, increasing the concentration of zinc sulfate improves the mechanical properties, and the mechanical properties of the periosteum mineralized with the zinc sulfate solution are not as good as those of calcium sulfate.

[0072] The comparison of Examples 1, 3, and 6 shows that different polysaccharide raw materials have an impact on the performance of the periosteum. The mechanical properties of the periosteum prepared with xanthan gum and sodium alginate as raw materials are not as good as those of hydroxypropyl carboxymethyl cellulose in Example 1.

[0073] By changing the mineralization time of Example 1, it can be seen that when the mineralization time is less than 1 h, the mineralization degree is insufficient, and the mechanical properties of the periosteum are still poor and do not meet the requirements; when the mineralization time is greater than 4 h, there will be over-mineralization and uneven mineralization phenomena, resulting in the formed film of the product being too brittle and the strength decreasing instead, affecting the clinical use effect.

[0074] SEM images of the network morphology of the membranous sample before mineralization and the final product after mineralization in Example 1, after freeze-drying, are as Figure 1 shown Figure 1 In the figure, Figure a is before mineralization, with a scale bar of 50 μm, and Figure b is after mineralization, with a scale bar of 100 μm. Figure 1 The results show that after mineralization, due to the complexation of metal ions, the network structure becomes denser.

[0075] Figure 2 The infrared comparison spectra of the periosteum in Example 1 before and after mineralization are Figure 2 shown, indicating that after complexation of Zn 2+ ions, the hydroxyl peak is enhanced and glycosidic bonds are formed; Figure 3 The photo of the mineralized hydrogel (before drying) prepared is shown. The left figure is the product of Example 1 (5% ZnSO 4 mineralization), and the right figure is the product of Example 1 with the mineralization concentration changed (7.5% ZnSO 4 mineralization, mineralization time 1 h).

[0076] Figure 4 SEM images of the microscopic morphology of the mineralized hydrogel (before drying) in Example 1 are Figure 4 shown, and the scale bars in the figures are all 100 μm. The left figure is the outer layer of the surface of the hydrogel mineralized by metal ions, and the right figure is the three-dimensional network structure inside the gel. Figure 3 , 4 shown, indicating that after mineralization with metal ions, the hydrogel forms a core-shell structure. The core-shell structure mainly means that the inner core and the outer shell are composed of substances with different morphologies. After mineralization, a relatively dense wrinkled mineralized layer is formed on the surface of the hydrogel film, and the inside is a three-dimensional network structure of hydroxypropyl carboxymethyl cellulose gel. The core-shell structure can achieve the coverage of the inner part by the shell layer and improve its mechanical strength.

[0077] The XRD spectra of the membranous sample before mineralization and the final product after mineralization in Example 1 are as Figure 5 shown. The left figure is before mineralization, and the right figure is after mineralization. Figure 5 The results show that new peaks appear after soaking in the metal salt solution for mineralization, and there are some differences in the crystal forms after surface mineralization, and there is a mixed phase, which proves the formation of mineralization.

[0078] In Example 1, 20 mL of 5% zinc sulfate solution (0.3 mol / L) was used for mineralization, and the zinc sulfate solution was changed to 0 (i.e., pure water), 0.1, 0.2, 0.4, 0.5, 0.6, 1.0, 1.5, 2.0 M zinc sulfate solutions respectively, and mineralization was carried out for 2 h.

[0079] SEM images of the surface microscopic morphology of the hydrogel after soaking and mineralization at different metal ion concentrations, after freeze-drying, are asFigure 6 as shown Figure 6 The scale bars in the figures are all 50 μm. Figure 6 The results show that the higher the metal ion concentration, the more obvious the wrinkles generated by mineralization, resulting in a more obvious difference in smoothness between the two sides, which in turn affects its hydrophilicity and hydrophobicity. Therefore, it is more appropriate to preferably select the metal ion concentration in the range of 3% - 5%. The higher the metal ion concentration, the more wrinkles will be formed, which will easily cause stress concentration points and make it brittle, resulting in poor mechanical properties. The physical photograph of the transparent high-strength hydrogel film (after drying) prepared in Example 2 is as Figure 7 shown. The thickness of the hydrogel film is 100 - 200 μm. Figure 7 It can be seen that the transparency of the hydrogel is very high, and the text under the film can be clearly seen.

[0080] The stress-strain curve of the hydrogel during the drying process is as Figure 8 shown, where the left figure is the data of the mechanical strength of gels with different water contents, and the right figure is the influence of mineralization with different concentrations of metal ions on the mechanical properties of the gels.

[0081] Figure 8 In the left figure of, the curve with a water content of 90% refers to the mechanical strength data detected when the water content of the hydrogel after mineralization and before drying is 90%.

[0082] The curve with a water content of 50% refers to the mechanical strength data detected when the hydrogel is mineralized, dried to a water content below 3% to obtain a dried periosteum, and then rehydrated to a water content of 50%.

[0083] In practical applications, for the periosteum material dried to below 3%, after being placed in the oral environment, the periosteum will gradually absorb water. According to the existing data, it will reach equilibrium at a water content of 50%. The mechanical strength at this water content state can represent the mechanical properties of the periosteum in practical applications. Therefore, a water content of 50% is used for comparison.

[0084] Figure 8 The left figure of shows that the mechanical properties of the gel will be significantly improved after drying and reformation. During the drying and reformation process, the inorganic phase introduced by mineralization will form a rigid inorganic network, restricting the swelling of polymer chains. At the same time, drying will affect the interface between the mineralized layer and the gel layer, causing irreversible deformation.

[0085] According to the experimental data, the mechanical properties of the periosteum material dried to below 3% are improved compared to the periosteum with a water content of 50%.

[0086] Therefore, in the present invention, drying after mineralization can improve the mechanical properties.

[0087] Figure 8The right figure shows the effect of mineralization with metal ions at different concentrations on the mechanical properties of the gel. Compared with Example 1 in the preparation method of the hydrogel, the concentration of zinc sulfate in the first step was changed to 0.1%, and the concentration of hydroxypropyl carboxymethyl cellulose was 0.5%. The prepared film-like substances were mineralized with 1%, 2.5%, 5%, and 7.5% zinc sulfate solutions for 2 h. Figure 8 The results in the right figure show that mineralization with different metal ion concentrations can maintain the mechanical properties of the gel at a relatively high level.

[0088] The compressive strength of the gel mineralized with different concentrations of metal ions is as Figure 9 shown, where the left figure is a line chart and the right figure is a bar chart. Figure 9 Among them, XG-Ca-27, XG-Ca-39, and XG-Ca-50 respectively represent that after mineralization with calcium ions, the mass fraction of calcium ions in the hydrogel (the ratio of the mass of calcium ions to the dry weight of the hydrogel after drying and removing water) is 27%, 39%, and 50%. The increase in calcium ion content indirectly reflects the degree of mineralization. Figure 9 It shows that before mineralization, the compressive modulus is very low. With the increase in the degree of mineralization, the compressive modulus can be increased to a strength of 200 - 700 kPa.

[0089] The degradation curve of the gel prepared in Example 1 over time is as Figure 10 shown. Figure 10 It shows that after 12 weeks, the remaining mass is about 55%. The treatment period of the periosteum is generally between 3 and 6 months. Therefore, the degradation period matches the treatment period.

[0090] In the present invention, mineralization with zinc ions shows a more obvious improvement in mechanical properties compared with calcium ions. Moreover, in the actual application scenario (bone defect repair), zinc ions have better properties than calcium ions. It is preferably to use zinc ions for mineralization to meet the clinical requirements, achieve the dual needs of tensile strength and toughness, and meet the material property requirements.

Claims

1. A method for preparing a hydrogel periosteum material for oral bone repair, characterized in that The method is: The natural polysaccharide solution and the metal salt react to obtain a gel-like substance, which is then dried to obtain a membrane-like substance, and the membrane-like substance is placed in a metal salt solution for mineralization and drying to obtain the oral bone repair hydrogel periosteum material; The natural polysaccharide is one or more of hydroxypropyl carboxymethyl cellulose, xanthan gum, hyaluronic acid and sodium alginate.

2. The method according to claim 1, characterized in that The metal salt is one or more of calcium salt, magnesium salt, zinc salt, copper salt, strontium salt, iron salt, ferrous salt and barium salt.

3. The method according to claim 2, characterized in that The calcium salt includes hydroxyapatite, calcium gluconate, calcium chloride, calcium sulfate, calcium carbonate or calcium phosphate; the zinc salt is zinc sulfate.

4. The method according to claim 1, characterized in that The mass concentration of the natural polysaccharide solution is 1-3%; The metal salt is configured into an aqueous solution, and the mass fraction of the metal salt solution is 0.1-15%.

5. The method according to claim 1, characterized in that The method is carried out according to the following steps: (1) Adding a metal salt solution to a natural polysaccharide solution with a mass concentration of 1-3%, stirring and mixing, removing bubbles, and drying to obtain a film-like substance; (2) The membrane-like substance is added to a metal salt solution for mineralization and drying to obtain the oral bone repair hydrogel periosteum material.

6. The method according to claim 5, characterized in that: In the step (1), the mass ratio of the natural polysaccharide to the metal salt is 1:0.01-5; the concentration of the metal salt solution is 0.1-15%; in the step (2), the metal salt solution is calcium chloride or zinc sulfate solution; the mass concentration is 1%-7.5%.

7. The method according to claim 5, characterized in that: In the step (2), the mineralization is single-sided mineralization, one side of the membrane material is immersed in the metal salt solution, and the other side is not in contact with the metal salt solution; the mineralization time is 1h~4h.

8. The oral bone repair hydrogel periosteum material prepared according to any one of claims 1 to 7.

9. The oral bone repair hydrogel periosteum material according to claim 8, wherein the oral bone repair hydrogel periosteum material has a thickness of 100 to 300 microns, a tensile strength of 60 to 90 MPa, and a degradation time of 3 to 6 months.

10. Use of the oral bone repair hydrogel periosteum material according to claim 8 or 9 in dental bone repair.

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