CN115463250A - Gelatin-coated ferroferric oxide magnetic microsphere for promoting osteogenesis and preparation method and application thereof - Google Patents
Gelatin-coated ferroferric oxide magnetic microsphere for promoting osteogenesis and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an osteogenesis promoting gelatin coated ferroferric oxide magnetic microsphere, a preparation method and application thereof, wherein the microsphere comprises Fe 3 O 4 Inner core of, the Fe 3 O 4 The gelatin shell is wrapped outside the inner core, the particle size range is 10-100 mu m in a completely dry state, and the coating rate of the microspheres is 49% -83%. The bone marrow mesenchymal stem cell can promote proliferation, osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells, is beneficial to bone formation, and promotes bone regeneration and repair.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a preparation method and application of gelatin coated ferroferric oxide magnetic microspheres for promoting osteogenesis.
Background
More than 600 million patients with bone defects or dysfunction caused by factors such as sports injury, traffic and production safety accidents, bone tumor excision, natural disasters and the like in China each year bring serious influence and huge economic burden to the individuals, families and society of the patients. In addition, the problems of difficult bone regeneration, delayed bone repair and the like also bring great pain to patients. Magnetic thermal therapy is a new and efficient treatment method, and under the action of an Alternating Magnetic Field (AMF), magnetic materials convert magnetic energy into heat energy, so that the temperature of tissues at local lesion sites is increased, and a treatment effect is achieved. The promotion effect of different magnetic field intensity on the formation of bone tissues has specificity, the therapeutic effect is difficult to realize when the magnetic field intensity is too low, and negative effects can be generated on organisms when the magnetic field intensity is too high.
The ferroferric oxide nano particles have excellent magnetic response performance and tissue penetrability, can convert magnetic field energy into heat energy in an alternating magnetic field through relaxation effect, and are widely used in the fields of biomarker detection, magnetic thermal treatment, tumor imaging and the like. Studies have shown that heating to 42 ± 0.5 ℃ for a short period of time at the focal site of a local site promotes osteogenesis (Materials Today,2020, 36. Although ferroferric oxide nanoparticles and a magnetic hyperthermia technology have considerable application prospects, a plurality of challenging problems still exist and need to be solved: 1) How to regulate the intensity and action time of the magnetic field and the dosage of the magnetic particles; 2) How to improve and regulate the dispersibility, magnetic responsiveness and thermal conversion efficiency of the ferroferric oxide nano particles; 3) How to realize the treatment effect while avoiding or reducing the damage to normal cells and tissues. Therefore, it is an important difficult problem to be solved urgently to develop a magnetic material with low toxicity, high thermal conversion rate and controllable magnetic heating effect, and reduce or avoid damage to primary cells and tissues while giving consideration to treatment effect.
Disclosure of Invention
In view of the above, the invention aims to provide gelatin-coated ferroferric oxide magnetic microspheres for promoting osteogenesis and a preparation method and application thereof. The microsphere has good bioactivity and compatibility, accurate and controllable magneto-thermal responsiveness, can be heated to 39-43 ℃ under the action of a sine alternating magnetic field, can promote the proliferation, osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells, is favorable for bone formation, and promotes bone regeneration and repair.
The scheme adopted by the invention for solving the technical problems is as follows:
an osteogenesis promoting magnetic microsphere, said microsphere comprising Fe 3 O 4 Inner core of, the Fe 3 O 4 The gelatin shell is wrapped outside the inner core, the particle size range is 10-100 mu m in a completely dry state, and the coating rate of the microspheres is 49% -83%.
Preferably, the temperature of the microspheres can be raised to 39-43 ℃ for 1-5 min under the action of a sinusoidal alternating magnetic field.
Further preferably, the intensity of the sinusoidal alternating magnetic field is 0.5-5mT.
Further preferably, the frequency of the sinusoidal alternating magnetic field is 10-400Hz.
The invention also provides a preparation method of the magnetic microsphere capable of promoting bone formation, which comprises the following steps:
(1) Obtaining mesoporous Fe 3 O 4 Nanospheres;
(2) Gelatin is coated on the mesoporous Fe by an emulsification method 3 O 4 Obtaining gelatin coated Fe with a coating rate of 49-83% on the surface of the nanosphere 3 O 4 And (4) microspheres.
Preferably, the mesoporous Fe 3 O 4 The preparation method of the nanosphere comprises the following steps: feCl is added 3 ·6H 2 Adding O, sodium citrate, urea and polyacrylamide into deionized water, and stirring until the mixture is dissolvedPerforming decomposition, reacting the obtained mixed solution for 10-24h at 160-250 ℃, removing the solution, and drying to obtain the mesoporous Fe 3 O 4 And (4) nano microspheres.
Preferably, the emulsification method of step (2) comprises: the mesoporous Fe is added 3 O 4 Dispersing the nano-microspheres in gelatin solution, dropwise adding the gelatin solution into mixed emulsion of liquid paraffin and span 80, adding carbodiimide hydrochloride, stirring for 0.5-4h at a speed of 150-600r/min under the condition of ice-water bath, cleaning and drying the product to obtain gelatin-coated Fe 3 O 4 And (3) microspheres.
Preferably, feCl 3 ·6H 2 The mass portion ratio of O, sodium citrate, urea and polyacrylamide is (0.4-0.6): (0.8-2.5): (0.2-0.8): (0.05-0.4).
Preferably, fe 3 O 4 The ratio of the nano microspheres to the gelatin solution is (0.3-0.8) g:5ml, wherein the mass concentration of the gelatin in the gelatin solution is 5-50%.
Preferably, the volume ratio of the liquid paraffin to the span 80 is (5-15): 1.
preferably, the carbodiimide hydrochloride is added in an amount of 0.05% to 25% by mass of the gelatin.
The invention also provides application of the magnetic microsphere as a bone repair material. The microsphere has accurate and controllable magnetic-thermal response capability, and can promote osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells.
Furthermore, the microspheres can be used as a composition component of a bone repair material, and can promote cell proliferation and osteogenic differentiation of a defect area by applying a magnetic field for precise temperature rise after being applied to a human body, so that the bone repair effect is improved.
Furthermore, the microspheres can be used as a component of a bone repair material after being loaded with a medicament.
Iron is an essential trace element with the largest content in the human body and is an important component of hemoglobin. The ferroferric oxide nano particles have the advantages of high crystallinity, adjustable size, larger specific surface area, strong magnetic responsiveness and the like, and are widely applied to the biomedical fields of drug carriers, biological imaging, targeted therapy and the like. Gelatin is a natural macromolecular hydrophilic material, has good plasticity, bioactivity, biodegradability and biocompatibility, and is beneficial to cell growth. Therefore, based on the excellent performances of the ferroferric oxide nanoparticles and the gelatin, the gelatin is coated on the surfaces of the ferroferric oxide nanoparticles, and the temperature rise effect of the gelatin coated ferroferric oxide nanoparticles under the action of the sine alternating magnetic field can be realized by regulating and controlling the coating efficiency of the gelatin coated ferroferric oxide nanoparticles, so that the osteogenesis is promoted, and the gelatin coated ferroferric oxide nanoparticles can be used in the field of biomedicine.
According to the invention, gelatin is coated on the surfaces of the ferroferric oxide nanoparticles, so that the gelatin has an adjustable and controllable precise heating effect (39-43 ℃) under an alternating magnetic field compared with a single ferroferric oxide nanoparticle, so that the aim of promoting osteogenesis is fulfilled, the treatment efficiency is obviously improved, and the treatment effect is enhanced. In addition, the magnetic microsphere has good degradability, bioactivity and biocompatibility, can be flexibly and widely applied to the fields of drug loading, targeted therapy, bone defect filling and the like, improves the therapeutic effect, has a simple and easy preparation process, is accurate and controllable in magnetocaloric effect, and has a good application prospect in the field of biomedical materials.
Drawings
FIG. 1 is a graph showing the relationship between the amount of iron oxide and the coating rate obtained in examples 1 to 4;
FIG. 2 is a magnetocaloric temperature rise curve of the gelatin-coated ferroferric oxide magnetic microspheres prepared in examples 1-4 under the magnetic field condition of 200Hz and 2mT;
FIG. 3 is the effect of gelatin coated ferroferric oxide magnetic microspheres prepared in examples 1, 2 and 4 on the proliferation of mesenchymal stem cells;
FIG. 4 is the effect of gelatin coated ferroferric oxide magnetic microspheres prepared in examples 1, 2 and 4 on the expression level of bone marrow mesenchymal stem cell alkaline phosphatase;
FIG. 5 is an SEM image of gelatin-coated ferroferric oxide magnetic microspheres prepared in example 2.
Detailed Description
The following examples are provided to further illustrate the present invention for better understanding, but the present invention is not limited to the following examples.
Example 1
The preparation process of this example includes:
(1) 0.5g FeCl 3 ·6H 2 Adding O, 0.85g of sodium citrate, 0.7g of urea and 0.2g of polyacrylamide into 40ml of deionized water, continuously stirring at 40 ℃ until the materials are dissolved, then pouring the materials into a high-pressure reaction kettle, reacting at 200 ℃ for 12 hours, and naturally cooling to obtain mesoporous Fe 3 O 4 Nano microspheres are dried and stored in a vacuum drying oven;
(2) 0.15g of Fe prepared in the step (1) at room temperature 3 O 4 Ultrasonically dispersing the nano microspheres in 5ml of gelatin solution (the mass fraction of the gelatin is 42%), dropwise adding the obtained dispersion solution into 40ml of mixed emulsion of liquid paraffin and span 80 (the mass ratio of the two is 12.
After the gelatin is decomposed by reacting the obtained gelatin-coated ferroferric oxide microspheres with collagenase at 37 ℃ for 2 hours, the coating rate is 27.4% (the result is shown in figure 1), wherein: the coating rate = ferroferric oxide mass separated after gelatin is dissolved by enzyme/total mass of gelatin-coated ferroferric oxide microspheres.
The obtained magnetic microsphere can be heated from room temperature (20 deg.C) to 33.7 deg.C (FIG. 2) under the action of sinusoidal alternating magnetic field (200Hz, 2mT) for 5 min.
The magnetic microsphere can be heated from room temperature (20 ℃) to 30.2 ℃ under the action of a sinusoidal alternating magnetic field (200Hz, 0.5 mT) for 5 min.
The obtained magnetic microsphere can be heated to 36.7 ℃ from room temperature (20 ℃) after being acted for 5min in a sine alternating magnetic field (200Hz, 5 mT).
The obtained magnetic microspheres and bone marrow mesenchymal stem cells were co-cultured and stimulated by the same sinusoidal alternating magnetic field, and it was found that the magnetic microspheres had no significant effect on the proliferation (fig. 3) and osteogenic differentiation (fig. 4) of the cells compared to the control group.
Example 2
The preparation method differs from example 1 in that: fe in step (2) 3 O 4 The mass of the nano microsphere is 0.3g.
The obtained gelatin-coated ferroferric oxide magnetic microspheres are shown in figure 5, and the coating rate is 61.1% (figure 1).
The temperature can be raised from room temperature (20 ℃) to 39.2 ℃ by applying sinusoidal alternating magnetic field (200Hz, 2mT) for 5min (FIG. 2).
The microspheres and bone marrow mesenchymal stem cells are co-cultured and stimulated by a sine alternating magnetic field, so that the cell proliferation can be remarkably promoted (figure 3), and the expression level of alkaline phosphatase is improved (figure 4).
Example 3
The preparation method differs from example 1 in that: fe in step (2) 3 O 4 The mass of the nano microsphere is 0.5g.
The coating rate of the obtained gelatin-coated ferroferric oxide magnetic microspheres is 82.1 percent (figure 2).
The temperature can be raised from room temperature (20 deg.C) to 42.5 deg.C (FIG. 2) by applying sinusoidal alternating magnetic field (200Hz, 2mT) for 5 min.
The microsphere and the bone marrow mesenchymal stem cells are co-cultured and stimulated by a sine alternating magnetic field, and the cell proliferation and osteogenic differentiation can be remarkably promoted.
Example 4
The preparation method differs from example 1 in that: fe in step (2) 3 O 4 The mass of the nano microsphere is 1g.
The coating rate of the obtained gelatin-coated ferroferric oxide magnetic microspheres is 91.5 percent (figure 1).
It can be heated from room temperature (20 deg.C) to 55 deg.C (FIG. 2) by applying sinusoidal alternating magnetic field (200Hz, 2mT) for 5 min.
The microspheres were co-cultured with mesenchymal stem cells and stimulated by sinusoidal alternating magnetic field, which was found to be detrimental to cell proliferation (fig. 3) and osteogenic differentiation (fig. 4).
The obtained magnetic microsphere can be acted on a sine alternating magnetic field (200Hz, 0.5 mT) for 5min, and the temperature can be raised from room temperature (20 ℃) to 43.9 ℃.
The obtained magnetic microsphere can be acted on a sine alternating magnetic field (200Hz, 5 mT) for 5min, and the temperature can be raised to 64.4 ℃ from room temperature (20 ℃).
Example 5
The preparation process of this example includes:
(1) 0.6g FeCl 3 ·6H 2 Adding O, 2g of sodium citrate, 0.5g of urea and 0.4g of polyacrylamide into 40ml of deionized water, continuously stirring at 40 ℃ until the materials are dissolved, then pouring the materials into a high-pressure reaction kettle, reacting at 180 ℃ for 14h, and naturally cooling to obtain mesoporous Fe 3 O 4 Nano microspheres are dried and stored in a vacuum drying oven;
(2) 0.5g of Fe prepared in the step (1) at room temperature 3 O 4 Ultrasonically dispersing the nano microspheres in 5ml of gelatin solution (the mass fraction of the gelatin is 30%), dropwise adding the gelatin solution into 40ml of mixed emulsion of liquid paraffin and span 80 (8:1), adding 1ml of carbodiimide hydrochloride (1M), mechanically stirring for 1h at the speed of 350r/min after ice-water bath change, and cleaning and drying to obtain the gelatin-coated ferroferric oxide magnetic microspheres.
The coating rate of the obtained gelatin-coated ferroferric oxide microspheres is 74.3%.
The obtained gelatin-coated ferroferric oxide microspheres act in a sinusoidal alternating magnetic field (200Hz, 2mT) for 5min, and can be heated to 41.7 ℃ from room temperature (20 ℃).
The microsphere and the bone marrow mesenchymal stem cells are co-cultured and are stimulated by a sinusoidal alternating magnetic field, and the cell proliferation and the osteogenic differentiation can be remarkably promoted.
Example 6
The preparation method differs from example 5 in that: the mechanical stirring speed in the step (2) is 500r/min.
The coating rate of the obtained gelatin-coated ferroferric oxide magnetic microspheres is 49.4 percent.
The temperature can be raised from room temperature (20 ℃) to 40.8 ℃ by acting on a sine alternating magnetic field (100Hz, 3mT) for 5 min.
The microsphere and the bone marrow mesenchymal stem cells are co-cultured and stimulated by a sine alternating magnetic field, and the cell proliferation and osteogenic differentiation can be remarkably promoted.
Example 7
The preparation method differs from the example 3 in that: the concentration of the diimine hydrochloride in step (2) was 0.5M.
The coating rate of the obtained gelatin-coated ferroferric oxide magnetic microspheres is 78.4%.
Acting in sinusoidal alternating magnetic field (200Hz, 2mT) for 5min, and heating from room temperature (20 deg.C) to 42 deg.C.
The microsphere and the bone marrow mesenchymal stem cells are co-cultured and stimulated by a sine alternating magnetic field, and the cell proliferation and osteogenic differentiation can be remarkably promoted.
Example 8
The preparation method differs from example 3 in that: the concentration of the diimine hydrochloride in step (2) was 0.1M.
The coating rate of the obtained gelatin-coated ferroferric oxide magnetic microspheres is 67.1 percent.
The temperature can be raised from room temperature (20 ℃) to 41.5 ℃ by acting on a sine alternating magnetic field (100Hz, 4mT) for 5 min.
The microsphere and the bone marrow mesenchymal stem cells are co-cultured and stimulated by a sine alternating magnetic field, and the cell proliferation and osteogenic differentiation can be remarkably promoted.
Example 9
The preparation process of this example includes:
(1) 0.55g FeCl 3 ·6H 2 Adding O, 2.3g of sodium citrate, 0.4g of urea and 0.35g of polyacrylamide into 40ml of deionized water, continuously stirring at 40 ℃ until the materials are dissolved, then pouring the materials into a high-pressure reaction kettle, reacting at 180 ℃ for 24 hours, and naturally cooling to obtain mesoporous Fe 3 O 4 Nano microspheres are dried and stored in a vacuum drying oven;
(2) 0.3g of Fe prepared in the step (1) at room temperature 3 O 4 The nano-microspheres are ultrasonically dispersed in 5ml of gelatin solution (the mass fraction of the gelatin is 20%), dropwise added into 40ml of mixed emulsion of liquid paraffin and span 80 (the volume ratio is 10.
The coating rate of the obtained gelatin-coated ferroferric oxide magnetic microspheres is 45.7 percent.
The temperature can be raised from room temperature (20 ℃) to 38.2 ℃ by acting on a sine alternating magnetic field (100Hz, 3mT) for 5 min.
The microsphere and the bone marrow mesenchymal stem cells are co-cultured and stimulated by a sine alternating magnetic field, and the microsphere is found to have no promotion effect on cell proliferation, osteogenic differentiation and mineralization.
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.
Claims (10)
1. An osteogenesis promoting magnetic microsphere, said microsphere comprising Fe 3 O 4 Inner core of, the Fe 3 O 4 The gelatin shell is wrapped outside the inner core, the particle size range is 10-100 mu m in a completely dry state, and the coating rate of the microspheres is 49% -83%.
2. The microsphere of claim 1, wherein the microsphere can be heated to 39-43 ℃ within 1-5 min under the action of a sinusoidal alternating magnetic field.
3. Microspheres according to claim 2, wherein the sinusoidal alternating magnetic field strength is between 0.5 and 5mT.
4. A preparation method of magnetic microspheres capable of promoting bone growth is characterized by comprising the following steps:
(1) Obtaining mesoporous Fe 3 O 4 Nanospheres;
(2) Gelatin is coated on the mesoporous Fe by an emulsification method 3 O 4 Obtaining gelatin coated Fe with a coating rate of 49-83% on the surface of the nanosphere 3 O 4 And (3) microspheres.
5. The method according to claim 4, wherein the mesoporous Fe is 3 O 4 The preparation method of the nanosphere comprises the following steps: will be provided withFeCl 3 ·6H 2 Adding O, sodium citrate, urea and polyacrylamide into deionized water, stirring until the O, the sodium citrate, the urea and the polyacrylamide are dissolved, reacting the obtained mixed solution for 10-24 hours at the temperature of 160-250 ℃, removing the solution, and drying to obtain the mesoporous Fe 3 O 4 And (4) nano microspheres.
6. The method according to claim 4, wherein the emulsification process of step (2) comprises: subjecting the mesoporous Fe 3 O 4 Dispersing the nano-microspheres in gelatin solution, dropwise adding the gelatin solution into mixed emulsion of liquid paraffin and span 80, adding carbodiimide hydrochloride, stirring for 0.5-4h at a speed of 150-600r/min under the condition of ice-water bath, cleaning and drying the product to obtain gelatin-coated Fe 3 O 4 And (3) microspheres.
7. The method of claim 5, wherein FeCl 3 ·6H 2 The mass portion ratio of O, sodium citrate, urea and polyacrylamide is (0.4-0.6): (0.8-2.5): (0.2-0.8): (0.05-0.4).
8. The method according to claim 6, wherein Fe 3 O 4 The ratio of the nano microspheres to the gelatin solution is (0.3-0.8) g:5ml, wherein the mass concentration of the gelatin in the gelatin solution is 5-50%.
9. The method according to claim 6, wherein the volume ratio of the liquid paraffin to the span 80 is (5-15): 1; the addition amount of the carbodiimide hydrochloride is 0.05 to 25 percent of the mass of the gelatin.
10. Use of the magnetic microspheres according to claims 1-3 or the magnetic microspheres obtained by the preparation method according to claims 4-9 as bone repair material.
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