CN111068109A - Method for constructing calcium biphosphate crystals on surface of composite support and product - Google Patents
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Abstract
The invention discloses a method for constructing calcium biphosphate crystals on the surface of a composite support and a product. The method is based on a recrystallization technology, and comprises the steps of firstly immersing the bioactive ceramic-biomedical polymer composite support into a bisphosphonate aqueous solution for incubation, and constructing calcium biphosphate crystals on the surface of the bioactive ceramic-biomedical polymer composite support. The invention effectively solves the problems that the bioactive ceramic-biomedical polymer composite scaffold lacks osteoinductivity and has cytotoxicity when high-concentration bisphosphonate is directly used, and has great research significance for the application of the bioactive ceramic-biomedical polymer composite scaffold in bone tissue engineering.
Description
Technical Field
The invention belongs to the field of preparation of biomedical bone repair materials, and particularly relates to a method for constructing calcium biphosphate crystals on the surface of a composite support and a product.
Background
Bioactive ceramic materials (such as calcium phosphate, hydroxyapatite, β -tricalcium phosphate, bioglass and the like) and mineral phases of natural bone tissues have similar chemical components, show good bioactivity, osteoconductivity and mechanical strength, are excellent choices for bone injury repair and regeneration and are used for bone tissue engineering for decades.
Bisphosphonates (BPs) bind specifically to bone matrix, inhibit osteoclast activity, and thus inhibit bone resorption, and are therefore widely used for the treatment of osteoporosis. Recent studies have found that low concentrations of bisphosphonates have some effect in inducing osteogenic differentiation of stem cells. However, the high-concentration bisphosphonate has strong cytotoxicity, and the clinical common administration mode has a plurality of problems, such as oral administration easily causes damage to oral cavity, esophagus, stomach and intestinal mucosa, and intravenous injection easily causes necrosis of mandible bone. It is therefore preferred to achieve local delivery of the bisphosphonate in situ. ElisaBoanii et al construct calcium biphosphate crystals on the surface of octacalcium phosphate in order to achieve in situ delivery of the biphosphate, and experimental results show that the material has the effect of promoting cell osteogenic differentiation, but still has certain cytotoxicity [ E.Boanii, P.Torricelli, M.Gazzano, M.Fini, A.Bigi, Crystalline calcium aluminate, beta. octacalcium phosphate derivative: a new chance for local treatment of bone diseases? Adv Mater 25(33) 4605-11 (2013). Researchers have studied the performance of other inorganic calcium phosphate materials such as amorphous calcium phosphate [ g.zhang, r.huang, z.li, x.yang, x.chen, w.xia, x.sun, g.yang, c.gao, z.gou, inversion of the flexibility on the morphology and phase transformation of adaptive precursors, j.inorg Biochem 113(2012)1-8 ], Hydroxyapatite [ r.bosco, m.iaf, a.tamperi, j.a.jansen, s.c.g.leewenburg, j.j.p.van, calcium phosphate nanoparticles, moisture calcium phosphate nanoparticles, calcium phosphate slurry, calcium phosphate. However, no report has been made on the research of constructing calcium biphosphate on bioactive ceramic-biomedical polymer composite material.
Disclosure of Invention
In order to solve the problems of constructing calcium biphosphate crystals on a composite material support and simultaneously considering biological properties such as material cytotoxicity, bone differentiation promoting property and the like, the invention provides a method for constructing calcium biphosphate crystals on the surface of the composite support and a product.
The object of the present invention is achieved by the following means.
A method for constructing calcium biphosphate crystals on the surface of a composite stent comprises the following steps:
immersing the bioactive ceramic-biomedical polymer composite bracket into a bisphosphonate aqueous solution for incubation, and constructing a calcium biphosphate crystal on the surface of the bioactive ceramic-biomedical polymer composite bracket.
Preferably, the concentration of the aqueous bisphosphonate solution is 1-10mg/mL, more preferably 5 mg/mL.
Preferably, the incubation time is 1-3d, more preferably 2 d.
Preferably, the incubation is carried out in a shaker, wherein the temperature of the shaker is between 35 ℃ and 40 ℃ and the speed of the shaker is between 75rpm and 120 rpm.
Preferably, the bioactive ceramic in the bioactive ceramic-biomedical polymer composite scaffold is hydroxyapatite.
Preferably, the biomedical polymer in the bioactive ceramic-biomedical polymer composite scaffold is modified gelatin introduced with double bonds.
Preferably, the bisphosphonate is alendronate sodium.
Preferably, the bisphosphonate aqueous solution is obtained by dissolving the bisphosphonate in ultrapure water with heating and stirring.
Preferably, the bioactive ceramic-biomedical polymer composite scaffold is a hydroxyapatite-modified gelatin (HAp-GelMA) composite scaffold, and the preparation process comprises the following steps:
the method comprises the following steps: synthesis of modified gelatin (GelMA)
(1) Stirring and dissolving gelatin in PBS under heating condition;
(2) adding methacrylic anhydride, and reacting under heating;
(3) transferring the reaction solution into a dialysis bag, and dialyzing until the reactant has no small molecular impurities;
(4) the dialysate was freeze-dried using a lyophilizer to give dried GelMA.
Step two: preparation of hydroxyapatite-modified gelatin (HAp-GelMA) composite scaffold
(1) Dissolving GelMA in deionized water under the heating condition;
(2) sequentially adding hydroxyapatite and a photoinitiator, and stirring until the mixture is uniformly mixed to obtain a pre-solution;
(3) and transferring the pre-solution into a mold, and performing crosslinking and curing under ultraviolet light to obtain the hydroxyapatite-modified gelatin (HAp-GelMA) composite scaffold.
Further preferably, the dialysis temperature is 40 ℃.
Further preferably, the synthesis conditions of the modified gelatin (GelMA) are that the dosage (g: mL) of the gelatin and methacrylic anhydride is 1:1-1:3, the reaction temperature is 50-60 ℃, the cut-off molecular weight of a dialysis membrane is 5000-10000, and the dialysis time is 3-5 d.
Further preferably, the HAp-GelMA composite scaffold is prepared under the following conditions: the mass concentration of the modified gelatin GelMA is 5-15%, the mass concentration of the hydroxyapatite is 5-15%, the mass concentration of the photoinitiator Irgacure 2959 is 0.5-1.5%, the ultraviolet light is irradiated for 5-15min, and the ultraviolet light wavelength is as follows: 365nm, intensity: 5-15 mW.
Preferably, modified gelatin GelMA with double bonds introduced is used as an organic phase, and hydroxyapatite with osteoconductivity is used as an inorganic phase; and (3) constructing calcium biphosphate on the surface of the composite support by taking the solution of biphosphonate as a reaction solution.
The composite bracket with the surface constructed by the calcium biphosphate crystals prepared by the method.
Compared with the prior art, the invention has the following advantages:
(1) the invention constructs the calcium biphosphate crystal on the bioactive ceramic-biomedical polymer composite bracket with the components and the structure closer to the natural bone tissue for the first time.
(2) By controlling the reaction conditions (bisphosphonate water solution concentration and incubation time), the prepared calcium biphosphate crystal has good cell osteogenesis and differentiation promoting effects while keeping good cell compatibility.
(3) Compared with the method for loading the growth factors commonly used by the composite scaffold, the method has longer action time and lower price.
Drawings
FIG. 1 shows the IR spectra of Gelatin (Gelatin) and modified Gelatin (GelMA) in example 1.
FIG. 2 is an electron microscope image of the HAp-GelMA composite scaffold of example 1.
FIG. 3 is an electron microscope picture (1mg/mL) of calcium biphosphate constructed on the surface of the HAp-GelMA composite scaffold in example 1.
FIG. 4 is an electron microscope picture (5mg/mL) of calcium biphosphate constructed on the surface of the HAp-GelMA composite scaffold in example 2.
FIG. 5 is an electron microscope picture (10mg/mL) of calcium biphosphate constructed on the surface of the HAp-GelMA composite scaffold in example 3.
FIG. 6 is EDS spectrum of calcium biphosphate constructed on the surface of HAp-GelMA composite scaffold in example 3.
FIG. 7 is a graph showing the effect of stem cells on the activity of HAp-GelMA composite scaffold (Control) and HAp-GelMA composite scaffold (ALC) with calcium biphosphate formed on the surface, cultured for 7 days in example 2.
FIG. 8 is a graph showing the effect of ALP activity of stem cells cultured in HAp-GelMA composite scaffolds (controls) and HAp-GelMA Composite Scaffolds (ALCs) with calcium biphosphate on the surface for 14 days in example 2.
Detailed Description
The invention will be further described with reference to the following examples for better understanding, but the scope of the invention as claimed is not limited to the scope shown in the examples.
Example 1
The method comprises the following steps: synthesis of modified gelatin (GelMA)
(1) Adding 5g of gelatin into 100mL of PBS solution, and stirring at 50 ℃ until the gelatin is dissolved;
(2) adding 5mL of methacrylic anhydride according to a feeding ratio (gelatin: methacrylic anhydride is 1g:1mL), and reacting for 3h at 50 ℃;
(3) transferring the reaction solution into a dialysis bag with molecular weight cutoff of 5000, and dialyzing for 7d at 40 ℃;
(4) the prefrozen dialysate was lyophilized using a lyophilizer to give dry modified gelatin GelMA. FIG. 1 shows the IR spectra of Gelatin (Gelatin) and modified Gelatin (gelMA), which showed characteristic peaks of double bonds at 5.3 and 5.6ppm compared to Gelatin, indicating successful introduction of double bonds into the Gelatin molecular chain to obtain modified Gelatin.
Step two: preparation of hydroxyapatite-modified gelatin (HAp-GelMA) composite scaffold
(1) Dissolving 0.5g of GelMA in 10mL of deionized water at 50 ℃ to obtain a GelMA solution;
(2) sequentially adding 0.5g of hydroxyapatite and 0.05g of photoinitiator Irgacure 2959, and stirring until the mixture is uniformly mixed;
(3) and transferring the pre-solution into a mold, and crosslinking for 15min under ultraviolet light (365nm,5mW) to obtain the HAp-GelMA composite scaffold.
Step three: construction of calcium biphosphate crystal on surface of HAp-GelMA composite support
(1) Adding 100mg alendronate sodium into 100mL of ultrapure water (final concentration is 1mg/mL), and stirring at 60 ℃ until the alendronate sodium is dissolved;
(2) cooling the bisphosphonate aqueous solution to room temperature, and transferring the cooled bisphosphonate aqueous solution into a plastic wide-mouth bottle;
(3) immersing the HAp-GelMA composite bracket into excessive bisphosphonate aqueous solution;
(4) the plastic jar was incubated for 3 days at 34 ℃ and 75rpm in a shaker to obtain calcium biphosphate crystals (as shown in FIG. 3). FIG. 2 is an SEM photograph showing the surface morphology of the HAp-GelMA composite scaffold, and only granular hydroxyapatite can be observed. FIG. 3 is an SEM photograph of a calcium biphosphate crystal constructed on the surface of the HAp-GelMA composite scaffold, and a rod-like calcium biphosphate crystal structure appears on the surface besides granular hydroxyapatite. The EDS characterization of the collected ALC crystals of this example is the same as in fig. 6, indicating that they contain the elements carbon (C), phosphorus (P), oxygen (O) and calcium (Ca), which are clearly distinguished from the elemental composition of hydroxyapatite.
Example 2
The method comprises the following steps: synthesis of modified gelatin (GelMA)
(1) Adding 10g of gelatin into 100mL of PBS solution, and stirring at 50 ℃ until the gelatin is dissolved;
(2) adding 20mL of methacrylic anhydride according to a feeding ratio (gelatin: methacrylic anhydride is 1g:2mL), and reacting for 2h at 55 ℃;
(3) transferring the reaction solution into a dialysis bag with the molecular weight cutoff of 7000, and dialyzing for 5d at 40 ℃;
(4) the prefrozen dialysate was lyophilized using a lyophilizer to give dry modified gelatin GelMA.
Step two: preparation of hydroxyapatite-modified gelatin (HAp-GelMA) composite scaffold
(1) Dissolving 1g of GelMA in 10mL of deionized water at 50 ℃ to obtain a GelMA solution;
(2) sequentially adding 1g of hydroxyapatite and 0.1g of photoinitiator Irgacure 2959, and stirring until the mixture is uniformly mixed;
(3) and transferring the pre-solution into a mold, and crosslinking for 10min under ultraviolet light (365nm,10mW) to obtain the HAp-GelMA composite scaffold.
Step three: construction of calcium biphosphate crystal on surface of HAp-GelMA composite support
(1) 500mg of alendronate sodium is added into 100mL of ultrapure water (with the final concentration of 5mg/mL), and stirred at 60 ℃ until the alendronate sodium is dissolved;
(2) cooling the bisphosphonate aqueous solution to room temperature, and transferring the cooled bisphosphonate aqueous solution into a plastic wide-mouth bottle;
(3) immersing the HAp-GelMA composite bracket into excessive bisphosphonate aqueous solution;
(4) the plastic jar was incubated for 2 days at 37 ℃ and 90rpm in a shaker to obtain calcium biphosphate crystals (as shown in FIG. 4). FIG. 2 is an SEM photograph showing the surface morphology of the HAp-GelMA composite scaffold, and only granular hydroxyapatite can be observed. FIG. 4 is an SEM photograph of a calcium biphosphate crystal constructed on the surface of the HAp-GelMA composite stent, wherein the surface of the stent has a filamentous calcium biphosphate crystal structure besides granular hydroxyapatite. The EDS characterization of the collected ALC crystals of this example is the same as in fig. 6, indicating that they contain the elements carbon (C), phosphorus (P), oxygen (O) and calcium (Ca), which are clearly distinguished from the elemental composition of hydroxyapatite.
Example 3
The method comprises the following steps: synthesis of modified gelatin (GelMA)
(1) Adding 15g of gelatin into 100mL of PBS solution, and stirring at 50 ℃ until the gelatin is dissolved;
(2) adding 45mL of methacrylic anhydride according to a feeding ratio (gelatin: methacrylic anhydride is 1g:3mL), and reacting for 1h at 60 ℃;
(3) transferring the reaction solution into a dialysis bag with the molecular weight cutoff of 10000, and dialyzing for 3d at 40 ℃;
(4) the prefrozen dialysate was lyophilized using a lyophilizer to give dry modified gelatin GelMA.
Step two: preparation of hydroxyapatite-modified gelatin (HAp-GelMA) composite scaffold
(1) Dissolving 1.5g of GelMA in 10mL of deionized water at 50 ℃ to obtain a GelMA solution;
(2) sequentially adding 1.5g of hydroxyapatite and 0.15g of photoinitiator Irgacure 2959, and stirring until the mixture is uniformly mixed;
(3) and transferring the pre-solution into a mold, and crosslinking for 5min under ultraviolet light (365nm,15mW) to obtain the HAp-GelMA composite scaffold.
Step three: construction of calcium biphosphate crystal on surface of HAp-GelMA composite support
(1) Adding 1000mg of alendronate sodium into 100mL of ultrapure water (the final concentration is 10mg/mL), and stirring at 60 ℃ until the alendronate sodium is dissolved;
(2) cooling the bisphosphonate aqueous solution to room temperature, and transferring the cooled bisphosphonate aqueous solution into a plastic wide-mouth bottle;
(3) immersing the HAp-GelMA composite bracket into excessive bisphosphonate aqueous solution;
(4) the plastic jar was incubated for 1 day at 40 ℃ and 120rpm in a shaker to obtain calcium biphosphate crystals (as shown in FIG. 5). FIG. 2 is an SEM photograph showing the surface morphology of the HAp-GelMA composite scaffold, and only granular hydroxyapatite can be observed. FIG. 5 is an SEM photograph of calcium biphosphate crystals constructed on the surface of the HAp-GelMA composite scaffold, and spherical calcium biphosphate crystal structures appear on the surface besides granular hydroxyapatite. Fig. 6 shows EDS characterization of collected ALC crystals containing carbon (C), phosphorus (P), oxygen (O), and calcium (Ca) elements, distinct from the elemental composition of hydroxyapatite.
The invention constructs the calcium biphosphate crystal on the surface of the bioactive ceramic-biomedical polymer composite material bracket for the first time. Compared with an unmodified composite scaffold, the scaffold can deliver bisphosphonate in situ at a bone defect, and enhances osteogenic inductivity while maintaining good cell compatibility. As shown in fig. 7, the CCK-8 test results of adipose-derived mesenchymal stem cells cultured on two scaffolds for 4 days show that there is no significant difference in absorbance between the Control group (composite scaffold group) and the ALC group (calcium biphosphate crystal group constructed on the surface of the composite scaffold), which indicates that the cell activities are similar and the two materials have similar cell compatibility. Meanwhile, fig. 8 shows the results of alkaline phosphatase (ALP) activity after adipose mesenchymal stem cells were cultured on both scaffolds for 14 d. Alkaline phosphatase is a marker for osteogenic differentiation of cells, and the quantitative results can be used to characterize the extent of osteogenic differentiation of cells. ALP activity of the ALC group is obviously higher than that of the Control group, which shows that the ALC group has more excellent effect of promoting osteogenic differentiation of stem cells.
Claims (10)
1. A method for constructing calcium biphosphate crystals on the surface of a composite stent is characterized by comprising the following steps:
immersing the bioactive ceramic-biomedical polymer composite bracket into a bisphosphonate aqueous solution for incubation, and constructing a calcium biphosphate crystal on the surface of the bioactive ceramic-biomedical polymer composite bracket.
2. The method of claim 1, wherein said aqueous bisphosphonate solution has a concentration of 1-10 mg/mL.
3. The method of claim 2, wherein said aqueous bisphosphonate solution has a concentration of 5 mg/mL.
4. The method of claim 1, wherein the incubation time is 1-3 days.
5. The method according to claim 4, wherein the incubation time is 2 d.
6. The method of claim 1, wherein the incubation is performed in a shaker, wherein the temperature of the shaker is between 35 ℃ and 40 ℃ and the speed of the shaker is between 75rpm and 120 rpm.
7. The method according to claim 1, wherein the bioactive ceramic in the bioactive ceramic-biomedical polymer composite scaffold is hydroxyapatite.
8. The method according to claim 1, wherein the biomedical polymer in the bioactive ceramic-biomedical polymer composite scaffold is a modified gelatin introduced with double bonds.
9. The method of claim 1, wherein the bisphosphonate is alendronate sodium.
10. A surface-structured composite scaffold of calcium biphosphate crystals prepared by the method of any one of claims 1 to 9.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111544655A (en) * | 2020-05-21 | 2020-08-18 | 中鼎凯瑞科技成都有限公司 | Bisphosphonate type self-coagulation composite bone graft and preparation method thereof |
| CN112724172A (en) * | 2020-12-30 | 2021-04-30 | 华南理工大学 | Risedronate calcium complex and preparation method thereof |
| WO2022142539A1 (en) * | 2020-12-30 | 2022-07-07 | 华南理工大学 | Minodronate calcium complex and preparation method therefor |
Citations (1)
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| WO2019048697A1 (en) * | 2017-09-11 | 2019-03-14 | Bone Support Ab | Macro- and microporous composite cryogel biomaterial for use in bone regeneration |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019048697A1 (en) * | 2017-09-11 | 2019-03-14 | Bone Support Ab | Macro- and microporous composite cryogel biomaterial for use in bone regeneration |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111544655A (en) * | 2020-05-21 | 2020-08-18 | 中鼎凯瑞科技成都有限公司 | Bisphosphonate type self-coagulation composite bone graft and preparation method thereof |
| CN112724172A (en) * | 2020-12-30 | 2021-04-30 | 华南理工大学 | Risedronate calcium complex and preparation method thereof |
| WO2022142539A1 (en) * | 2020-12-30 | 2022-07-07 | 华南理工大学 | Minodronate calcium complex and preparation method therefor |
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Application publication date: 20200428 |