CN113171492B - Bone defect repair material and preparation method and application thereof - Google Patents
Bone defect repair material and preparation method and application thereof Download PDFInfo
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- CN113171492B CN113171492B CN202110560438.5A CN202110560438A CN113171492B CN 113171492 B CN113171492 B CN 113171492B CN 202110560438 A CN202110560438 A CN 202110560438A CN 113171492 B CN113171492 B CN 113171492B
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/43—Hormones, e.g. dexamethasone
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
The invention discloses a bone defect repair material and a preparation method and application thereof. The repair material comprises a ZIF-8 carrier and an osteogenesis promoter loaded on the carrier, wherein the osteogenesis promoter comprises at least one of trastuzumab and parathyroid hormone, simvastatin and sodium fluoride. The preparation method comprises preparing osteogenesis promoter into solution, soaking the carrier in osteogenesis promoter solution, and soaking the soaked carrier in polylactic acid solution. The bone repair material of the invention can slowly release Zn after being implanted into a body2+And osteogenesis promoter, can ensure that new bone is generated in a short time, can effectively repair bone defect, and has good repairing effect.
Description
Technical Field
The invention belongs to the technical field of medical materials, and particularly relates to a bone defect repairing material as well as a preparation method and application thereof.
Background
In recent years, implant repair is gradually the first choice for treating dentition loss or defect repair, and sufficient alveolar bone mass in an implant area is a precondition for ensuring successful implant repair. Clinicians and researchers have therefore sought various means of repairing alveolar bone defects, which are critical to restoring the bone microenvironment at the site of the bone defect. The microenvironment refers to the environment in which bone cells live in growth and development, including various mechanical stimuli during the growth process of the cells, and components such as stromal cells, extracellular matrix, various regulatory factors and the like.
At present, the "gold standard" for repairing alveolar bone defects and restoring the microenvironment of bone defect sites is autologous bone grafting. It has the disadvantages of limited bone mass source and local secondary injury to the donor. With the development of tissue engineering technology, bone tissue engineering scaffold materials are gradually applied to clinical repair of large alveolar bone defects, and can make up for the defects of autologous bone and allogeneic bone transplantation to a certain extent. However, the existing scaffold materials for bone tissue engineering still have the following defects: 1) the morphological design is not personalized enough, and the matching performance with the bone defect part is not good; 2) based on the design deficiency of the bone cell mechanical microenvironment and the biochemical microenvironment; 3) the bone induction is insufficient, and the bone regeneration cannot be sufficiently induced. Therefore, designing a bone defect repair material capable of promoting bone regeneration not only has important theoretical significance, but also has urgent clinical requirements.
Disclosure of Invention
Aiming at the prior art, the invention provides a bone defect repair material to solve the problem of insufficient bone inductivity of the existing bone repair material.
In order to achieve the purpose, the invention adopts the technical scheme that: providing a bone defect repair material, which comprises a carrier and an osteogenesis promoter loaded on the carrier; the carrier is ZIF-8, and the osteogenesis promoter comprises at least one of trastuzumab and parathyroid hormone, simvastatin and sodium fluoride.
The invention adopts the technical method and has the beneficial effects that: the bone repair material takes ZIF-8 as a carrier, and the ZIF-8 is Zn2+And imidazolyl ligand, and has regular pore diameter
The diameter of the cavity is
) High specific surface area, unsaturated metal sites and the like, can be used as a drug carrier to load small molecular drugs and play a role in drug slow release. The ZIF-8 has excellent three-level drug slow release power after carrying the drug, namely, drug molecules are directly released from the aperture, the drug molecules are released after the coordination action with the metal coordination center disappears, and the drug molecules are finally and completely released along with the degradation of the ZIF-8 and slowly release the components of the drug molecules.
The carrier is also loaded with an osteogenesis promoter which comprises parathyroid hormone, simvastatin and sodium fluoride besides the trastuzumab. Wherein, the Sintuzumab (SIM) can effectively promote the growth of bone fibers and promote the formation of new bones; parathyroid hormone is an important calcium regulation hormone for maintaining the balance of calcium and phosphorus metabolism of an organism, a bone is one of main target organs of the parathyroid hormone, and the parathyroid hormone can promote the proliferation and differentiation of osteoblast progenitor cells, directly inhibit the apoptosis of osteoblasts to prolong the osteogenesis action time, promote the transformation of lining cells to osteoblasts and stimulate the osteoblasts to generate IGF-1 and Transforming Growth Factor (TGF) to exert the bone synthesis effect; simvastatin can significantly improve the expression level of bone morphogenetic protein-2 (BMP-2) and increase the number of osteoblasts; the sodium fluoride releases fluoride ions which can promote the mitosis of osteoblasts, increase the number of osteoblasts and promote the formation of bones. The components are matched with each other, so that new bones can be generated in a short time, the bone defects can be effectively repaired, and the repairing effect is good. In addition, the components are loaded on a ZIF-8 carrier, and the release rate of the osteogenesis promoter can be effectively controlled through the three-stage slow release effect of the ZIF-8 carrier, so that the osteogenesis promoter can continuously play an osteogenesis promoting role for a long time.
On the basis of the technical scheme, the invention can be further improved as follows.
Furthermore, the osteogenesis promoter consists of the octatuzumab, the parathyroid hormone and the simvastatin, and the mass ratio of the octatuzumab, the parathyroid hormone and the simvastatin in the osteogenesis promoter is 2-5: 0.5-1.
Furthermore, the osteogenesis promoter consists of the octatuzumab, simvastatin and sodium fluoride, and the mass ratio of the octatuzumab to the simvastatin to the sodium fluoride in the osteogenesis promoter is 5-8: 2-4: 1-3.
Further, the osteogenesis promoter consists of the octatuzumab, the parathyroid hormone, the simvastatin and the sodium fluoride, and the mass ratio of the octatuzumab, the parathyroid hormone, the simvastatin and the sodium fluoride in the osteogenesis promoter is 8-12: 2-4: 1-3: 0.5 to 1.
The invention also relates to a preparation method of the bone defect repair material, which comprises the following steps:
s1: preparing a ZIF-8 carrier;
s2: dissolving the osteogenesis promoter in deionized water, adding a surfactant, and uniformly stirring to form an osteogenesis promoter solution;
s3: soaking a ZIF-8 carrier into an osteogenesis promoter solution, performing ultrasonic treatment for 1-3 h, and then continuously soaking for 1-2 days to obtain a bone defect repair material primary product;
s4: dissolving polylactic acid in an organic solvent to prepare a polylactic acid solution with the concentration of 1-3 wt%, then putting the primary bone defect repair material into the polylactic acid solution, soaking for 5-10 min, and then taking out and drying to obtain the bone defect repair material.
The preparation method has the beneficial effects that: soaking the ZIF-8 carrier in an osteogenesis promoter solution added with a surfactant, and uniformly attaching the osteogenesis promoter to the inside and the surface of the ZIF-8 carrier under the combined action of the surfactant and ultrasound; then the carrier is put into polylactic acid solution for soaking, and the polylactic acid forms a porous film on the surface of the carrier to wrap the osteogenesis promoter. The polylactic acid has biodegradability, and the polylactic acid is degraded after the prepared bone repair material is implanted into a body, so that the release rate of the osteogenesis promoter is further controlled, and the osteogenesis promoting effect is better.
The preparation method of the invention can be further improved on the basis of the technical scheme as follows.
Further, the ZIF-8 carrier is prepared by the following steps:
SS 1: dissolving zinc nitrate and 2-methylimidazole in deionized water according to the mass ratio of 1: 20-30, and uniformly stirring at room temperature to obtain a milky white solution;
SS 2: adding 1, 8-diazabicyclo [5.4.0] undec-7-ene into the milky white solution, and stirring at the speed of 45-60 rpm at the temperature of 30-35 ℃ for 45-60 min to obtain milky white suspension;
SS 3: and transferring the milky white suspension into a reaction kettle, carrying out centrifugal reaction at the centrifugal speed of 4000-4500 rpm for 4-8 min at 35-40 ℃, collecting the precipitate, and washing with deionized water to obtain the ZIF-8 carrier.
Further, the molar ratio of 1, 8-diazabicyclo [5.4.0] undec-7-ene to zinc nitrate added to SS2 is 1 to 3: 10.
Further, the surfactant is monolauryl phosphate, and the mass ratio of the monolauryl phosphate to the osteogenesis promoter is 1: 20-30.
Further, the organic solvent is dichloromethane.
The invention has the beneficial effects that: the bone defect repair material takes ZIF-8 as a carrier, has good drug-loading performance, and can release Zn2+The biochemical microenvironment for the growth of bone cells can be improved, and the bone regeneration is promoted; and ZIF-8 has excellent three-level drug slow release power, and the drug loaded by the repair material after being implanted into the body can be slowly released, so that the repair material can continuously play a role in promoting osteogenesis for a long time.
The osteogenesis promoter can ensure that new bone is generated in a short time, can effectively repair bone defects, and has a good repairing effect.
Detailed Description
The following examples are provided to illustrate specific embodiments of the present invention.
Example 1
A bone defect repair material, which comprises a ZIF-8 carrier and an osteogenesis promoter loaded on the carrier; the osteogenesis promoter consists of octatuzumab, parathyroid hormone, simvastatin and sodium fluoride, and the mass ratio of the octatuzumab, the parathyroid hormone, the simvastatin and the sodium fluoride in the osteogenesis promoter is 10:3:2: 1.
The bone defect repair material in the embodiment is prepared by the following steps:
s1: preparing a ZIF-8 carrier;
SS 1: adding zinc nitrate (Zn (NO)3)2·6H2O) and 2-methylimidazole are mixed and dissolved in deionized water according to the mass ratio of 1:25, and the mixture is stirred uniformly at room temperature to obtain a milky white solution; the concentration of zinc nitrate in the obtained milky white solution is 3.0 mg/mL;
SS 2: adding 1, 8-diazabicyclo [5.4.0] undec-7-ene into the milky white solution, and stirring at 30 ℃ and 50rpm for 60min to obtain milky white suspension; the molar ratio of the added 1, 8-diazabicyclo [5.4.0] undec-7-ene to zinc nitrate is 1: 5;
SS 3: transferring the milky white suspension into a reaction kettle, carrying out centrifugal reaction at 37 ℃ and at a centrifugal speed of 4000rpm for 5min, collecting the precipitate, and washing with deionized water for three times to obtain a ZIF-8 carrier;
s2: dissolving the osteogenesis promoter in deionized water to prepare a solution with the concentration of 0.1 g/mL; adding monolauryl phosphate into the solution, wherein the mass ratio of the added monolauryl phosphate to the osteogenesis promoter is 1:25, and uniformly stirring to form an osteogenesis promoter solution;
s3: immersing the ZIF-8 carrier into osteogenesis promoter solution, firstly carrying out ultrasonic treatment for 2 hours at the frequency of 100Hz, and then continuously immersing for 2 days to obtain a bone defect repair material primary product;
s4: dissolving polylactic acid in dichloromethane to prepare a polylactic acid solution with the concentration of 2 wt%, then putting the primary bone defect repair material into the polylactic acid solution, soaking for 8min, taking out and drying by blowing to obtain the bone defect repair material.
Example 2
A bone defect repair material, which comprises a ZIF-8 carrier and an osteogenesis promoter loaded on the carrier; the osteogenesis promoter consists of the octatuzumab ozogamicin, the parathyroid hormone and the simvastatin, and the mass ratio of the octatuzumab ozogamicin, the parathyroid hormone and the simvastatin in the osteogenesis promoter is 4:1: 0.5.
The bone defect repair material in the embodiment is prepared by the following steps:
s1: preparing a ZIF-8 carrier;
SS 1: adding zinc nitrate (Zn (NO)3)2·6H2O) and 2-methylimidazole are mixed and dissolved in deionized water according to the mass ratio of 1:20, and the mixture is stirred uniformly at room temperature to obtain a milky white solution; the concentration of zinc nitrate in the obtained milky white solution is 3.0 mg/mL;
SS 2: adding 1, 8-diazabicyclo [5.4.0] undec-7-ene into the milky white solution, and stirring at 35 ℃ at a speed of 45rpm for 60min to obtain milky white suspension; the molar ratio of the added 1, 8-diazabicyclo [5.4.0] undec-7-ene to zinc nitrate is 1: 10;
SS 3: transferring the milky white suspension into a reaction kettle, carrying out centrifugal reaction at the centrifugal speed of 4500rpm for 8min at 35 ℃, collecting the precipitate, and washing with deionized water for three times to obtain a ZIF-8 carrier;
s2: dissolving the osteogenesis promoter in deionized water to prepare a solution with the concentration of 0.1 g/mL; adding monolauryl phosphate into the solution, wherein the mass ratio of the added monolauryl phosphate to the osteogenesis promoter is 1:30, and uniformly stirring to form an osteogenesis promoter solution;
s3: immersing the ZIF-8 carrier into osteogenesis promoter solution, firstly carrying out ultrasonic treatment for 1h at the frequency of 100Hz, and then continuously immersing for 2 days to obtain a bone defect repair material primary product;
s4: dissolving polylactic acid in dichloromethane to prepare a polylactic acid solution with the concentration of 3 wt%, then putting the primary bone defect repair material into the polylactic acid solution, soaking for 5min, taking out and drying by blowing to obtain the bone defect repair material.
Example 3
A bone defect repair material, which comprises a ZIF-8 carrier and an osteogenesis promoter loaded on the carrier; the osteogenesis promoter consists of the octatuzumab, the simvastatin and the sodium fluoride, and the mass ratio of the octatuzumab, the simvastatin and the sodium fluoride in the osteogenesis promoter is 6:3: 2.
The bone defect repair material in the embodiment is prepared by the following steps:
s1: preparing a ZIF-8 carrier;
SS 1: adding zinc nitrate (Zn (NO)3)2·6H2O) and 2-methylimidazole are mixed and dissolved in deionized water according to the mass ratio of 1:30, and the mixture is stirred uniformly at room temperature to obtain a milky white solution; the concentration of zinc nitrate in the obtained milky white solution is 3.0 mg/mL;
SS 2: adding 1, 8-diazabicyclo [5.4.0] undec-7-ene into the milky white solution, and stirring at 40 ℃ at a speed of 60rpm for 45min to obtain milky white suspension; the molar ratio of the added 1, 8-diazabicyclo [5.4.0] undec-7-ene to zinc nitrate is 1: 3;
SS 3: transferring the milky white suspension into a reaction kettle, carrying out centrifugal reaction for 8min at the centrifugal speed of 4000rpm at 40 ℃, collecting the precipitate, and washing with deionized water for three times to obtain a ZIF-8 carrier;
s2: dissolving the osteogenesis promoter in deionized water to prepare a solution with the concentration of 0.1 g/mL; adding monolauryl phosphate into the solution, wherein the mass ratio of the added monolauryl phosphate to the osteogenesis promoter is 1:20, and uniformly stirring to form an osteogenesis promoter solution;
s3: soaking a ZIF-8 carrier into an osteogenesis promoter solution, performing ultrasonic treatment for 3 hours at the frequency of 100Hz, and then continuously soaking for 1 day to obtain a bone defect repair material primary product;
s4: dissolving polylactic acid in dichloromethane to prepare a polylactic acid solution with the concentration of 1 wt%, then putting the primary bone defect repair material into the polylactic acid solution, soaking for 8min, taking out and drying by blowing to obtain the bone defect repair material.
Comparative example 1
A bone defect repair material, a polyether-ether-ketone carrier and an osteogenesis promoter loaded on the carrier; the osteogenesis promoter consists of octatuzumab, parathyroid hormone, simvastatin and sodium fluoride, and the mass ratio of the octatuzumab, the parathyroid hormone, the simvastatin and the sodium fluoride in the osteogenesis promoter is 10:3:2: 1.
The bone defect repair material in the embodiment is prepared by the following steps:
s1: dissolving the osteogenesis promoter in deionized water to prepare a solution with the concentration of 0.1 g/mL; adding monolauryl phosphate into the solution, wherein the mass ratio of the added monolauryl phosphate to the osteogenesis promoter is 1:25, and uniformly stirring to form an osteogenesis promoter solution;
s3: soaking the ether-ketone carrier into osteogenesis promoter solution, firstly carrying out ultrasonic treatment for 2h at the frequency of 100Hz, and then continuously soaking for 2 days to obtain a bone defect repair material primary product;
s4: dissolving polylactic acid in dichloromethane to prepare a polylactic acid solution with the concentration of 2 wt%, then putting the primary bone defect repair material into the polylactic acid solution, soaking for 8min, taking out and drying by blowing to obtain the bone defect repair material.
Comparative example 2
A bone defect repair material comprises a ZIF-8 carrier and trastuzumab loaded on the carrier.
The bone defect repair material in the embodiment is prepared by the following steps:
s1: preparing ZIF-8 carrier by the same method as example 1;
s2: dissolving the octatuzumab in deionized water to prepare a solution with the concentration of 0.1 g/mL;
s3: immersing the ZIF-8 carrier into an octatuzumab solution, firstly carrying out ultrasonic treatment for 2h at the frequency of 100Hz, and then continuously immersing for 2 days to obtain a bone defect repair material primary product;
s4: dissolving polylactic acid in dichloromethane to prepare a polylactic acid solution with the concentration of 2 wt%, then putting the primary bone defect repair material into the polylactic acid solution, soaking for 8min, taking out and drying by blowing to obtain the bone defect repair material.
Comparative example 3
A bone defect repair material, which comprises a ZIF-8 carrier and an osteogenesis promoter loaded on the carrier; the osteogenesis promoter consists of octatuzumab, parathyroid hormone, simvastatin and sodium fluoride, and the mass ratio of the octatuzumab, the parathyroid hormone, the simvastatin and the sodium fluoride in the osteogenesis promoter is 10:3:2: 1.
The bone defect repair material in the embodiment is prepared by the following steps:
s1: preparing ZIF-8 carrier by the same method as example 1;
s2: dissolving the osteogenesis promoter in deionized water to prepare a solution with the concentration of 0.1 g/mL; adding monolauryl phosphate into the solution, wherein the mass ratio of the added monolauryl phosphate to the osteogenesis promoter is 1:25, and uniformly stirring to form an osteogenesis promoter solution;
s3: soaking ZIF-8 carrier in osteogenesis promoter solution, performing ultrasonic treatment at 100Hz for 2h, and soaking for 2 days.
Analysis of results
The bone defect repairing materials prepared in the above example 1 and each comparative example were tested for their performance by culturing mouse preosteoblasts (MC3T 3-E1). The proliferation assay results were as follows:
after 14 days of culture, the bone defect repair material in example 1 had a bone cell proliferation amount 3.4 times that of the material in comparative example 1, 4.2 times that of the material in comparative example 2, and 2.8 times that of the material in comparative example 3.
After 14 days of culture, the bone defect repair material in example 1 had two calcium nodule formations that were 6.8 times as much as the material in comparative example 1, 9.5 times as much as the material in comparative example 2, and 3.3 times as much as the material in comparative example 3.
While the present invention has been described in detail with reference to the embodiments, it should not be construed as limited to the scope of the patent. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.
Claims (7)
1. A bone defect repair material, characterized in that: comprises a carrier and an osteogenesis promoter loaded on the carrier; the carrier is ZIF-8; the osteogenesis promoter consists of octatuzumab, parathyroid hormone and simvastatin, and the mass ratio of the octatuzumab to the parathyroid hormone to the simvastatin in the osteogenesis promoter is 2-5: 0.5-1; or the osteogenesis promoter consists of the octatuzumab, simvastatin and sodium fluoride, and the mass ratio of the octatuzumab, the simvastatin and the sodium fluoride in the osteogenesis promoter is 5-8: 2-4: 1-3; or the osteogenesis promoter consists of octatuzumab, parathyroid hormone, simvastatin and sodium fluoride, and the mass ratio of the octatuzumab, the parathyroid hormone, the simvastatin and the sodium fluoride in the osteogenesis promoter is 8-12: 2-4: 1-3: 0.5 to 1.
2. The method for preparing a bone defect repair material according to claim 1, comprising the steps of:
s1: preparing a ZIF-8 carrier;
s2: dissolving the osteogenesis promoter in deionized water, adding a surfactant, and uniformly stirring to form an osteogenesis promoter solution;
s3: immersing a ZIF-8 carrier into the osteogenesis promoter solution, firstly carrying out ultrasonic treatment for 1-3 h, and then continuously immersing for 1-2 days to obtain a bone defect repair material primary product;
s4: dissolving polylactic acid in an organic solvent to prepare a polylactic acid solution with the concentration of 1-3 wt%, then putting the primary bone defect repair material into the polylactic acid solution, soaking for 5-10 min, and then taking out and drying to obtain the bone defect repair material.
3. The preparation method according to claim 2, wherein the ZIF-8 carrier is prepared by the following steps:
SS 1: dissolving zinc nitrate and 2-methylimidazole in deionized water according to the mass ratio of 1: 20-30, and uniformly stirring at room temperature to obtain a milky white solution;
SS 2: adding 1, 8-diazabicyclo [5.4.0] undec-7-ene into the milky white solution, and stirring at the speed of 45-60 rpm at the temperature of 30-35 ℃ for 45-60 min to obtain milky white suspension;
SS 3: and transferring the milky white suspension into a reaction kettle, carrying out centrifugal reaction at the centrifugal speed of 4000-4500 rpm for 4-8 min at 35-40 ℃, collecting the precipitate, and washing with deionized water to obtain the ZIF-8 carrier.
4. The production method according to claim 3, characterized in that: the molar ratio of 1, 8-diazabicyclo [5.4.0] undec-7-ene to zinc nitrate added to SS2 is 1-3: 10.
5. The method of claim 2, wherein: the surfactant is monolauryl phosphate, and the mass ratio of the monolauryl phosphate to the osteogenesis promoter is 1: 20-30.
6. The method of claim 2, wherein: the organic solvent is dichloromethane.
7. Use of a bone defect repair material according to claim 1 for the preparation of an alveolar bone defect repair scaffold.
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