CN115400265A - Biochemical-like gradient scaffold and preparation method thereof - Google Patents
Biochemical-like gradient scaffold and preparation method thereof Download PDFInfo
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Abstract
The invention provides a bionic gradient support and a preparation method thereof, the bionic gradient support comprises an inner filler block, a supporting layer, a drug-loaded layer and an adhesion layer which are arranged from inside to outside in sequence, nano-hydroxyapatite is mixed in the inner filler block and the supporting layer, the content of the nano-hydroxyapatite in the inner filler block is greater than that in the supporting layer, aspirin is mixed in the drug-loaded layer, and the adhesion layer is used for reducing the release rate of the aspirin. The biomimetic gradient scaffold and the preparation method thereof provided by the invention have a synergistic effect to highly simulate a microenvironment, so that the bone regeneration rate can be improved; the thickness of each layer is flexibly adjusted according to the actual bone defect area, the mechanical stimulation is improved, and the bone regeneration process is not influenced; the outer layer is softer and can attract cells to climb, the inner layer can provide enough mechanical support, and the mechanical and pharmacological requirements of bone regeneration are integrated; the long-term slow release of the medicine is realized; can realize the unidirectional release of the drug-loaded layer.
Description
Technical Field
The invention belongs to the technical field of biological scaffolds, and particularly relates to a bionic gradient scaffold and a preparation method thereof.
Background
The hydrogel biological scaffold material is used as a research and development hotspot for promoting bone regeneration and repairing bone defects at present, can highly simulate a natural extracellular microenvironment and promote bone tissue regeneration and mineralization. The existing hydrogel biological scaffold is a single homogeneous grid structure, and the structure has the following defects:
(1) The inner pore diameter is the same, the structure is single, the multi-cell and blood vessel co-implantation cannot be actively coped with, and the synergistic growth effect is poor. Along with the degradation and swelling processes of the hydrogel, the pore diameter of the ideal bone which is constructed in advance is increased, so that the ideal bone can not be maintained for a long time, and the effect of promoting the bone is short;
(2) The medicine loaded inside is released suddenly in the early stage, namely a large amount of medicine is released in a short period, and the risk of toxic and side effects of the medicine exists; the medicine is directly contacted with enzymes in the body, so the utilization rate is low; the drug release is too fast, the dosage of the drug is large, the cost is increased, and the drug administration cannot be accurate;
(3) The degradation rate is not adjustable, and the optimal degradation rate can not be adjusted arbitrarily according to individual difference so as to accurately achieve the ideal goal of giving mechanical stimulation to bone defects and simultaneously not blocking the bone regeneration process;
(4) The mechanical strength of the stent is single, and the implanted stent cannot meet the requirements of anisotropic complex mechanical environment in the oral cavity and cannot simultaneously have higher mechanical strength to support stress and softer support surface to attract cell adhesion.
Disclosure of Invention
The embodiment of the invention provides a bionic gradient scaffold and a preparation method thereof, aiming at promoting the regeneration of bone tissues, realizing the controllability of degradation rate, improving the utilization rate of medicines and optimizing the mechanical supporting effect.
In a first aspect, an embodiment of the present invention provides a biomimetic gradient stent, including an inner lining block, a support layer, a drug-loaded layer, and an adhesion layer, which are sequentially disposed from inside to outside, where the inner lining block and the support layer are both mixed with nano-hydroxyapatite, a content of the nano-hydroxyapatite of the inner lining block is greater than a content of the nano-hydroxyapatite in the support layer, the drug-loaded layer is mixed with aspirin, and the adhesion layer is configured to reduce a release rate of the aspirin.
Compared with the prior art, the scheme shown in the embodiment of the application has the following effects:
(1) The inner lining block, the supporting layer, the drug-loaded layer and the adhesion layer are sequentially arranged from the inner ring to the outer ring, wherein the content of nano-hydroxyapatite in the inner lining block is greater than that of nano-hydroxyapatite in the supporting layer, gradient degression is realized from inside to outside, the porosity is increased, multiple cells can be simultaneously supported to grow in, angiogenesis is accompanied, the porous structures allow molecular diffusion, the microenvironment is highly simulated by the synergistic effect of the porous structures, and the bone regeneration rate can be improved;
(2) The controllable degradation rate can be realized by adjusting the thickness of each layer and the integral height, the thickness of each layer can be flexibly adjusted according to the actual bone defect area, and the mechanical stimulation is improved without influencing the bone regeneration process;
(3) The content of the nano hydroxyapatite is gradually decreased from inside to outside, the mechanical strength is weakened layer by layer from inside to outside, the outer layer is softer and attracts cells to climb, the inner layer provides enough mechanical support, and the mechanical and pharmacological requirements of bone regeneration are integrated;
(4) The adhesion layer is positioned at the periphery of the drug-loaded layer and is used as a protective layer of the drug-loaded layer, so that the internal and external concentration difference is reduced at the initial stage of implantation of the bionic gradient stent in the embodiment, the phenomenon of suddenly releasing a large amount of drugs is avoided, the action time of the drugs (aspirin) at the absorption part is prolonged, and the long-term slow release is realized; meanwhile, due to the structural characteristics of multiple layers, the unidirectional release of the drug-loaded layer can be realized, and the utilization rate of the drug is further improved.
With reference to the first aspect, in one possible implementation manner, each of the inner pad block and the support layer is formed by mixing polyvinyl alcohol, sodium alginate, gelatin, nano hydroxyapatite and ultrapure water.
In some embodiments, the mass ratio of the nano-hydroxyapatite adopted by the inner filler block and the supporting layer is 2.
With reference to the first aspect, in one possible implementation manner, the drug-loaded layer is formed by mixing polyvinyl alcohol, sodium alginate, aspirin, gelatin and ultrapure water;
and/or the adhesion layer is formed by mixing polyvinyl alcohol, sodium alginate, gelatin and ultrapure water.
With reference to the first aspect, in a possible implementation manner, the inner pad, the support layer, the drug-loaded layer, and the adhesion layer are coaxially disposed and have equal heights.
With reference to the first aspect, in a possible implementation manner, the cross-sectional shape of the biomimetic gradient scaffold is one of a circle, a rectangle and an ellipse.
In a second aspect, an embodiment of the present invention further provides a method for preparing a biomimetic gradient scaffold, which is used for preparing the above biomimetic gradient scaffold, and includes the following steps:
s10: mixing polyvinyl alcohol, sodium alginate, gelatin and nano hydroxyapatite to prepare a lining solution;
s20: repeating the step S10 to prepare a supporting solution, a medicine carrying solution and an adhesion solution, wherein the content of nano-hydroxyapatite in the supporting solution is greater than that of nano-hydroxyapatite in the lining solution, aspirin is further mixed in the medicine carrying solution, and the content of nano-hydroxyapatite in the medicine carrying solution and the content of nano-hydroxyapatite in the adhesion solution are 0;
s30: selecting a first mold, wherein the first mold is provided with a first molding cavity, the volume of the first molding cavity is equal to that of the inner filler block, pouring the lining solution into the first molding cavity, and forming the inner filler block after solidification;
s40: selecting a second mold, wherein the second mold is provided with a second molding cavity, the difference value between the diameter of the second molding cavity and the diameter of the first molding cavity is equal to the thickness of the supporting layer, placing the lining block in the middle of the second molding cavity, pouring the supporting solution into the second molding cavity, forming the supporting layer on the periphery of the lining block after solidification, and the lining block and the supporting layer form a first entity;
s50: selecting a third mold, wherein the third mold is provided with a third molding cavity, the difference value between the diameter of the third molding cavity and the diameter of the second molding cavity is equal to the thickness of the drug-loaded layer, placing the first entity obtained in the step S40 in the middle of the third molding cavity, pouring the drug-loaded solution into the third molding cavity, and forming the drug-loaded layer on the periphery of the first entity after solidification to form a second entity;
s60: selecting a fourth mold, wherein the fourth mold is provided with a fourth molding cavity, the difference between the diameter of the fourth molding cavity and the diameter of the third molding cavity is equal to the thickness of the adhesion layer, placing the second entity in the middle of the fourth molding cavity, pouring the adhesion solution into the fourth molding cavity, and forming the adhesion layer on the periphery of the second entity after solidification to form the biomimetic gradient support.
With reference to the second aspect, in a possible implementation manner, the S10 step includes:
s11: taking a certain amount of polyvinyl alcohol, pouring into ultrapure water heated to 95 ℃, stirring uniformly until the polyvinyl alcohol is completely dissolved, and cooling to 37 ℃ to obtain a polyvinyl alcohol solution;
s12: putting a certain amount of sodium alginate into the polyvinyl alcohol solution, and stirring the sodium alginate and the polyvinyl alcohol solution uniformly;
s13: adding a certain amount of gelatin into ultrapure water, and stirring uniformly at 37 ℃;
s14: adding a certain amount of nano hydroxyapatite into ultrapure water, and stirring at room temperature until the nano hydroxyapatite is uniform;
s15: mixing the solutions prepared in the steps S11, S12, S13 and S14 to obtain the lining solution.
In some embodiments, the mass ratio of the polyvinyl alcohol, the sodium alginate, the gelatin and the nano hydroxyapatite is 1.
With reference to the second aspect, in a possible implementation manner, after the step S60, the method further includes:
and circularly freezing and thawing the bionic gradient scaffold for multiple times, soaking the bionic gradient scaffold in an anhydrous calcium chloride solution, freeze-drying, finishing the shape, and sterilizing.
Drawings
Fig. 1 is a schematic perspective view of a biomimetic gradient scaffold provided in an embodiment of the present invention.
Description of reference numerals:
10-inner pads;
20-a support layer;
30-drug-loaded layer;
40-adhesion layer.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
Referring to FIG. 1, the present invention provides a biochemical-simulating gradient scaffold. The biomimetic gradient stent comprises an inner lining block 10, a supporting layer 20, a drug-loaded layer 30 and an adhesion layer 40 which are sequentially arranged from inside to outside, wherein nano-hydroxyapatite is mixed in the inner lining block 10 and the supporting layer 20, the content of the nano-hydroxyapatite in the inner lining block 10 is greater than that in the supporting layer 20, aspirin is mixed in the drug-loaded layer 30, and the adhesion layer 40 is used for reducing the release rate of the aspirin.
The preparation process of the biomimetic gradient scaffold provided in this embodiment is as follows:
(1) Preparing a lining solution: stirring polyvinyl alcohol, sodium alginate, gelatin and 2 parts of nano hydroxyapatite in ultrapure water until the mixture is uniform;
(2) Preparing a supporting solution: stirring polyvinyl alcohol, sodium alginate, gelatin and 1 part of nano hydroxyapatite in ultrapure water until the mixture is uniform;
(3) Preparing a drug-loaded solution: taking polyvinyl alcohol, sodium alginate, aspirin and gelatin, and stirring in ultrapure water until the polyvinyl alcohol, the sodium alginate, the aspirin and the gelatin are uniform;
(4) Preparing an adhesion solution: taking polyvinyl alcohol, sodium alginate and gelatin, and stirring in ultrapure water until the polyvinyl alcohol, the sodium alginate and the gelatin are uniform;
(5) Pouring the lining solution into the first molding cavity to solidify to form the lining block 10, placing the lining block 10 in the second molding cavity, pouring the supporting solution into the second molding cavity, placing the lining block 10 in the third molding cavity after solidification, pouring the drug-loaded solution into the third molding cavity, placing the lining block in the fourth molding cavity after solidification, pouring the adhesion solution into the fourth molding cavity, and forming the biomimetic gradient scaffold of the embodiment after solidification.
It should be noted that the diameter of the fourth molding cavity > the diameter of the third molding cavity > the diameter of the second molding cavity > the diameter of the first molding cavity.
Compared with the prior art, the bionic gradient scaffold has the following effects:
(1) The inner lining block 10, the supporting layer 20, the drug-loaded layer 30 and the adhesion layer 40 are sequentially arranged from the inner ring to the outer ring, wherein the content of nano-hydroxyapatite in the inner lining block 10 is larger than that of nano-hydroxyapatite in the supporting layer 20, gradient decrease is realized from inside to outside, the porosity is increased, multiple cells can be supported to grow in simultaneously, angiogenesis is accompanied, the porous structure allows molecular diffusion, the microenvironment is highly simulated through the synergistic effect of the porous structure, and the bone regeneration rate can be increased;
(2) The controllable degradation rate can be realized by adjusting the thickness of each layer and the integral height, the thickness of each layer can be flexibly adjusted according to the actual bone defect area, and the mechanical stimulation is improved without influencing the bone regeneration process;
(3) The content of the nano hydroxyapatite is gradually decreased from inside to outside, the mechanical strength is weakened layer by layer from inside to outside, the outer layer is softer and attracts cells to climb, the inner layer provides enough mechanical support, and the mechanical and pharmacological requirements of bone regeneration are integrated;
(4) The adhesion layer 40 is positioned at the periphery of the drug-loaded layer 30 and serves as a protective layer of the drug-loaded layer 30, so that the internal and external concentration difference is reduced at the initial stage of the implantation of the biomimetic gradient stent in the embodiment, the phenomenon of suddenly releasing a large amount of drugs is avoided, the action time of the drugs (aspirin) at the absorption part is prolonged, and the long-term slow release is realized; meanwhile, due to the structural characteristics of multiple layers, the unidirectional release of the drug-loaded layer 30 can be realized, and the utilization rate of the drug is further improved.
In some embodiments, a specific implementation of the inner pad 10 and the supporting layer 20 may be configured as follows. The inner pad 10 and the support layer 20 are formed by mixing polyvinyl alcohol, sodium alginate, gelatin, nano hydroxyapatite and ultrapure water. The inner lining block 10 and the supporting layer 20 formed after mixing have proper degradation rate, and the nano-hydroxyapatite can release calcium ions to promote proliferation and differentiation of bone cells, and the mechanical supporting performance from the inner lining block 10 to the supporting layer 20 is sequentially reduced by adjusting the content of the nano-hydroxyapatite of the inner lining block 10 and the content of the nano-hydroxyapatite of the supporting layer 20, so that the required mechanical supporting effect is ensured, the hardness of an outer ring is reduced, and the stimulation to tissues around a bone defect area is reduced.
In some embodiments, a modified embodiment of the inner pad 10 and the supporting layer 20 may adopt the following structure. The mass ratio of the nano-hydroxyapatite adopted by the inner filler block 10 and the support layer 20 is 2, for example, the mass of the nano-hydroxyapatite adopted by the inner filler block 10, the support layer 20 and the drug-loaded layer 30 is 20g, 10g and 0g in sequence, so that an equal difference gradient is formed and gradually decreased, the gradual decrease of the support strength is realized, and the overall mechanical support effect is optimized.
In some embodiments, a specific embodiment of the drug-loaded layer 30 and the adhesion layer 40 can be as follows. The drug-loaded layer 30 is formed by mixing polyvinyl alcohol, sodium alginate, aspirin, gelatin and ultrapure water; and/or, the adhesion layer 40 is formed by mixing polyvinyl alcohol, sodium alginate, gelatin and ultrapure water. The nano-hydroxyapatite is removed from the drug-loaded layer 30, and the aspirin is added, so that the aspirin can be slowly released for a long time in the using process, and the immune and inflammatory microenvironment of a bone defect area can be regulated and controlled; the adhesion layer 40 is soft in structure, can attract cells to climb, and is beneficial to bone regeneration, the adhesion layer 40 wraps the periphery of the medicine-carrying layer 30, the concentration difference between the inside and the outside is adjusted, the release duration of aspirin is prolonged, and the utilization rate of the medicine is improved.
In some embodiments, a specific embodiment of the biomimetic gradient scaffold described above may be configured as shown in FIG. 1. Referring to fig. 1, the lining blocks 10, the support layer 20, the drug-loaded layer 30 and the adhesion layer 40 are coaxially arranged and have the same height. It should be noted that the thicknesses of the supporting layer 20, the drug-loaded layer 30 and the adhesion layer 40 are consistent along the circumferential direction, so that the release rate and the supporting effect of the drug at each position in the circumferential direction are consistent.
In a modified embodiment, the heights of the lining block 10, the supporting layer 20, the drug-loaded layer 30 and the adhesion layer 40 may be different, and may be processed to conform to the shape of the bone defect region, thereby forming a height difference.
In some embodiments, a specific embodiment of the biomimetic gradient scaffold described above may be configured as shown in FIG. 1. Referring to fig. 1, the cross-sectional shape of the biomimetic gradient scaffold is one of circular, rectangular and elliptical. The bionic gradient scaffold with the shape is convenient to produce and low in manufacturing cost.
Alternatively, when the shape of the cross section of the bionic gradient stent is circular, the cross section of the inner lining block 10 is also circular, and the cross sections of the support layer 20, the drug-loaded layer 30 and the adhesion layer 40 are circular rings.
Specifically, the cross-sectional shape of the biomimetic gradient scaffold can also be irregular, specifically based on the fit with the bone defect region.
Based on the same inventive concept, the embodiment of the application also provides a preparation method of the biomimetic gradient scaffold, which comprises the following steps:
s10: mixing polyvinyl alcohol, sodium alginate, gelatin and nano hydroxyapatite to prepare lining solution;
s20: repeating the step S10 to prepare a supporting solution, a medicine carrying solution and an adhesion solution, wherein the content of the nano-hydroxyapatite in the supporting solution is greater than that of the nano-hydroxyapatite in the lining solution, aspirin is further mixed in the medicine carrying solution, and the content of the nano-hydroxyapatite in the medicine carrying solution and the content of the nano-hydroxyapatite in the adhesion solution are 0;
s30: selecting a first mold, wherein the first mold is provided with a first molding cavity, the volume of the first molding cavity is equal to that of the inner filler block 10, pouring the lining solution into the first molding cavity, and solidifying to form the inner filler block 10;
s40: selecting a second mold, wherein the second mold is provided with a second molding cavity, the difference between the diameter of the second molding cavity and the diameter of the first molding cavity is equal to the thickness of the supporting layer 20, placing the inner lining block 10 in the middle of the second molding cavity, pouring a supporting solution into the second molding cavity, forming the supporting layer 20 on the periphery of the inner lining block 10 after solidification, and forming a first entity by the inner lining block 10 and the supporting layer 20;
s50: selecting a third mold, wherein the third mold is provided with a third molding cavity, the difference value between the diameter of the third molding cavity and the diameter of the second molding cavity is equal to the thickness of the drug-loaded layer 30, placing the first entity obtained in the step S40 in the middle of the third molding cavity, pouring a drug-loaded solution into the third molding cavity, and forming the drug-loaded layer 30 on the periphery of the first entity after solidification to form a second entity;
s60: selecting a fourth mold, wherein the fourth mold is provided with a fourth molding cavity, the difference between the diameter of the fourth molding cavity and the diameter of the third molding cavity is equal to the thickness of the adhesion layer 40, placing the second entity in the middle of the fourth molding cavity, pouring an adhesion solution into the fourth molding cavity, and forming the adhesion layer 40 on the periphery of the second entity after solidification to form the biomimetic gradient support.
Compared with the prior art, the preparation method of the bionic gradient scaffold has the following effects:
(1) The inner lining block 10, the supporting layer 20, the drug-loaded layer 30 and the adhesion layer 40 are sequentially arranged from the inner ring to the outer ring, wherein the content of nano-hydroxyapatite in the inner lining block 10 is greater than that of nano-hydroxyapatite in the supporting layer 20, gradient decrease is realized from inside to outside, the porosity is increased, multiple cells can be simultaneously supported to grow in, angiogenesis is accompanied, the porous structure allows molecular diffusion, the microenvironment is highly simulated through the synergistic effect of the porous structure, and the bone regeneration rate can be improved;
(2) The controllable degradation rate can be realized by adjusting the thickness of each layer and the overall height, the thickness of each layer can be flexibly adjusted according to the actual bone defect area, the mechanical stimulation is improved, and the bone regeneration process is not influenced;
(3) The content of the nano hydroxyapatite is gradually decreased from inside to outside, the mechanical strength is weakened layer by layer from inside to outside, the outer layer is softer and attracts cells to climb, the inner layer provides enough mechanical support, and the mechanical and pharmacological requirements of bone regeneration are integrated;
(4) The adhesion layer 40 is positioned at the periphery of the drug-loaded layer 30 and serves as a protective layer of the drug-loaded layer 30, so that the internal and external concentration difference is reduced at the initial stage of the implantation of the biomimetic gradient stent in the embodiment, the phenomenon of suddenly releasing a large amount of drugs is avoided, the action time of the drugs (aspirin) at the absorption part is prolonged, and the long-term slow release is realized; meanwhile, due to the structural characteristics of multiple layers, the unidirectional release of the drug-loaded layer 30 can be realized, and the utilization rate of the drug is further improved.
In some embodiments, the S10 step comprises:
s11: taking a certain amount of polyvinyl alcohol, pouring the polyvinyl alcohol into ultrapure water heated to 95 ℃, stirring the polyvinyl alcohol uniformly until the polyvinyl alcohol is completely dissolved, and cooling the polyvinyl alcohol to 37 ℃ to obtain a polyvinyl alcohol solution;
s12: putting a certain amount of sodium alginate into a polyvinyl alcohol solution, and stirring the sodium alginate and the polyvinyl alcohol solution uniformly;
s13: adding a certain amount of gelatin into ultrapure water, and stirring uniformly at 37 ℃;
s14: adding a certain amount of nano hydroxyapatite into ultrapure water, and stirring at room temperature until the nano hydroxyapatite is uniform;
s15: the solutions prepared in the steps S11, S12, S13, and S14 are mixed together to obtain a lining solution.
The first solution is prepared in the step S11 and the step S12, the second solution is prepared in the step S13, the third solution is prepared in the step S14, the multiple substances are prepared into the multiple solutions, and then the prepared three solutions are uniformly mixed to obtain the lining solution, so that the uniform mixing of the multiple solutions can be ensured, the uniformity of the distribution of the substances in the lining solution is improved, and the mechanical supporting effect of the inner lining block 10 formed after solidification is favorably improved.
Specifically, the method further comprises the following steps between the step S14 and the step S15: ultrasonically shaking to remove bubbles and shattering the nano-hydroxyapatite. The ultrasonic oscillation can remove bubbles in the mixing process of the nano-hydroxyapatite and the ultrapure water, and the nano-hydroxyapatite is broken up through the ultrasonic oscillation, so that the sufficient mixing of the nano-hydroxyapatite and the ultrapure water is facilitated, and the subsequent mixing with other solutions is facilitated.
In some embodiments, the mass ratio of polyvinyl alcohol, sodium alginate, gelatin and nano hydroxyapatite is 1.
For example: 2g of polyvinyl alcohol is put into 50ml of ultrapure water, and 2g of sodium alginate is added after uniform stirring; 4g of gelatin is added into 30ml of ultrapure water and stirred evenly; 20g of nano-hydroxyapatite is added into 20ml of ultrapure water and stirred evenly.
The mechanical support effect of the inner lining block 10 after solidification is ensured by blending according to a certain proportion and configuring according to the proportion according to the size of the bone defect area.
In some embodiments, the step S60 is followed by:
and (3) circularly freezing and thawing the bionic gradient scaffold for multiple times, soaking the bionic gradient scaffold in an anhydrous calcium chloride solution, freeze-drying, finishing the shape and sterilizing.
Through circulating freeze thawing and soaking of anhydrous calcium chloride, the method is favorable for realizing physical crosslinking modes of organic matters and medicines in the bionic gradient scaffold through hydrogen bonds, electrostatic attraction and the like, and the anhydrous calcium chloride and sodium alginate are chemically crosslinked to form compact structures such as 'egg shells' in the bionic gradient scaffold, so that the stability of the structure in the subsequent use process is ensured, and the layering probability of the bionic gradient scaffold is reduced.
In some embodiments, a specific embodiment of the first mold may have the following structure. The first molding cavities are provided with a plurality of molding cavities and are distributed in an array. The first mould is a porous plate structure, hole sites on the porous plate form a first molding cavity, and a proper porous plate is selected according to the size of the required inner lining block 10; each porous plate can be used for preparing a plurality of bionic gradient supports at the same time, so that mass production is realized, and the production efficiency is improved.
Specifically, the second mold, the third mold and the fourth mold may all adopt the same structure as the first mold.
A specific implementation manner of the embodiment of the present application is:
(1) Preparing a lining solution:
weighing 2.0g of polyvinyl alcohol, pouring the polyvinyl alcohol into 50ml of ultrapure water heated to 95 ℃, stirring for 2h under a magnetic stirrer until the polyvinyl alcohol is completely dissolved, standing, weighing 2g of sodium alginate when the solution is cooled to 37 ℃, adding the sodium alginate into the polyvinyl alcohol solution, and continuously stirring for 2h under the magnetic stirrer;
weighing 4g of gelatin, adding into 30ml of ultrapure water, and continuously stirring for 2h at 37 ℃ by using a magnetic stirrer;
weighing 20g of nano-hydroxyapatite, adding the nano-hydroxyapatite into 20ml of ultrapure water, continuously stirring for 2h at room temperature, ultrasonically treating for 2h to remove bubbles, and fully shaking and crushing the nano-hydroxyapatite.
The above obtained solutions were mixed together, respectively, to form a lining solution.
(2) Preparing a supporting solution:
weighing 2.0g of polyvinyl alcohol, pouring the polyvinyl alcohol into 50ml of ultrapure water heated to 95 ℃, stirring for 2h under a magnetic stirrer until the polyvinyl alcohol is completely dissolved, standing, weighing 2g of sodium alginate when the solution is cooled to 37 ℃, adding the sodium alginate into the polyvinyl alcohol solution, and continuously stirring for 2h under the magnetic stirrer;
weighing 4g of gelatin, adding into 30ml of ultrapure water, and continuously stirring for 2h at 37 ℃ by using a magnetic stirrer;
weighing 10g of nano-hydroxyapatite, adding the nano-hydroxyapatite into 20ml of ultrapure water, continuously stirring for 2h at room temperature, ultrasonically treating for 2h to remove bubbles, and fully shaking and crushing the nano-hydroxyapatite.
The resulting solutions were mixed together separately to form the supporting solution.
(3) Preparing a drug-loaded solution:
weighing 2.0g of polyvinyl alcohol, pouring the polyvinyl alcohol into 50ml of ultrapure water heated to 95 ℃, stirring for 2h under a magnetic stirrer until the polyvinyl alcohol is completely dissolved, standing, weighing 2g of sodium alginate when the solution is cooled to 37 ℃, adding the sodium alginate into the polyvinyl alcohol solution, and continuously stirring for 2h under the magnetic stirrer;
weighing 200 mu g of aspirin and 4g of gelatin, adding the aspirin and the gelatin into 30ml of ultrapure water, and continuously stirring the mixture for 2 hours at 37 ℃ by using a magnetic stirrer;
the solutions obtained above are mixed together to form a drug-loaded solution.
(4) Preparing an adhesion solution:
weighing 2.0g of polyvinyl alcohol, pouring the polyvinyl alcohol into 50ml of ultrapure water heated to 95 ℃, stirring for 2h under a magnetic stirrer until the polyvinyl alcohol is completely dissolved, standing, weighing 2g of sodium alginate when the solution is cooled to 37 ℃, adding the sodium alginate into the polyvinyl alcohol solution, and continuously stirring for 2h under the magnetic stirrer;
weighing 4g of gelatin, adding into 30ml of ultrapure water, and continuously stirring for 2h at 37 ℃ by using a magnetic stirrer;
the resulting solutions are mixed together separately to form a coherent solution.
(5) The lining solution is poured into a hole groove with the diameter of 0.8cm and the height of 1cm, and the lining block 10 is formed after the lining solution is cooled, crosslinked and changed into a solid state.
(6) The inner pad 10 is immersed in an anhydrous sodium chloride solution with a mass of 2%, immersed for 30 minutes, taken out and placed in the center of a hole groove with a diameter of 1.2cm and a height of 1cm, a supporting solution is injected, and after being cooled, the supporting solution becomes a solid and is removed to form a first entity.
(7) And (3) immersing the first entity in an anhydrous sodium chloride solution with the mass of 2%, soaking for 30 minutes, taking out, placing in the center of a pore groove with the diameter of 1.6cm and the height of 1cm, injecting a drug-carrying solution, cooling to form a solid state, and removing to form a second entity.
(8) And (3) immersing the second entity in an anhydrous sodium chloride solution with the mass of 2%, soaking for 30 minutes, taking out and placing in the center of a pore groove with the diameter of 2cm and the height of 1cm, injecting an adhesion solution, cooling to form a solid state, and removing to form the biomimetic gradient scaffold.
(9) Placing the bionic gradient scaffold at-20 deg.C for 18h, placing at room temperature for 4h, circularly freezing and thawing for 3 times, soaking in 2% anhydrous calcium chloride solution for 24h, freeze drying, shaping, and sterilizing.
The above description is intended to be illustrative of the preferred embodiment of the present invention and should not be taken as limiting the invention, but rather, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
Claims (10)
1. The bionic gradient stent is characterized by comprising an inner filler block, a supporting layer, a drug-loaded layer and an adhesion layer which are sequentially arranged from inside to outside, wherein nano-hydroxyapatite is mixed in the inner filler block and the supporting layer, the content of the nano-hydroxyapatite of the inner filler block is greater than that of the nano-hydroxyapatite in the supporting layer, aspirin is mixed in the drug-loaded layer, and the adhesion layer is used for reducing the release rate of the aspirin.
2. The biomimetic gradient scaffold of claim 1, wherein the inner backing block and the support layer are formed from a blend of polyvinyl alcohol, sodium alginate, gelatin, nano-hydroxyapatite, and ultra pure water.
3. The biomimetic gradient scaffold according to claim 2, wherein the inner backing block and the support layer respectively employ nano-hydroxyapatite in a mass ratio of 2.
4. The biomimetic gradient scaffold according to any of claims 1-3, wherein the drug-loaded layer is formed by mixing polyvinyl alcohol, sodium alginate, aspirin, gelatin, and ultra-pure water;
and/or the adhesion layer is formed by mixing polyvinyl alcohol, sodium alginate, gelatin and ultrapure water.
5. The biomimetic gradient stent of claim 1, wherein the inner backing block, the support layer, the drug-loaded layer, and the adhesion layer are coaxially disposed and are of equal height.
6. The biomimetic gradient scaffold according to claim 1 or 5, wherein the cross-sectional shape of the biomimetic gradient scaffold is one of circular, rectangular and elliptical.
7. A method for preparing a biomimetic gradient scaffold, wherein the method is used for preparing the biomimetic gradient scaffold according to any one of claims 1-6, and comprises the following steps:
s10: mixing polyvinyl alcohol, sodium alginate, gelatin and nano hydroxyapatite to prepare a lining solution;
s20: repeating the step S10 to prepare a supporting solution, a medicine carrying solution and an adhesion solution, wherein the content of nano-hydroxyapatite in the supporting solution is greater than that of nano-hydroxyapatite in the lining solution, aspirin is further mixed in the medicine carrying solution, and the content of nano-hydroxyapatite in the medicine carrying solution and the content of nano-hydroxyapatite in the adhesion solution are 0;
s30: selecting a first mold, wherein the first mold is provided with a first molding cavity, the volume of the first molding cavity is equal to that of the inner filler block, pouring the lining solution into the first molding cavity, and solidifying to form the inner filler block;
s40: selecting a second mold, wherein the second mold is provided with a second molding cavity, the difference value between the diameter of the second molding cavity and the diameter of the first molding cavity is equal to the thickness of the supporting layer, placing the lining block in the middle of the second molding cavity, pouring the supporting solution into the second molding cavity, forming the supporting layer on the periphery of the lining block after solidification, and the lining block and the supporting layer form a first entity;
s50: selecting a third mold, wherein the third mold is provided with a third molding cavity, the difference value between the diameter of the third molding cavity and the diameter of the second molding cavity is equal to the thickness of the drug-loaded layer, placing the first entity obtained in the step S40 in the middle of the third molding cavity, pouring the drug-loaded solution into the third molding cavity, and forming the drug-loaded layer on the periphery of the first entity after solidification to form a second entity;
s60: selecting a fourth mold, wherein the fourth mold is provided with a fourth molding cavity, the difference value between the diameter of the fourth molding cavity and the diameter of the third molding cavity is equal to the thickness of the adhesion layer, placing the second entity in the middle of the fourth molding cavity, pouring the adhesion solution into the fourth molding cavity, and forming an adhesion layer on the periphery of the second entity after solidification to form the biomimetic gradient support.
8. The method for preparing a biomimetic gradient scaffold according to claim 7, wherein the S10 step comprises:
s11: taking a certain amount of polyvinyl alcohol, pouring into ultrapure water heated to 95 ℃, stirring uniformly until the polyvinyl alcohol is completely dissolved, and cooling to 37 ℃ to obtain a polyvinyl alcohol solution;
s12: putting a certain amount of sodium alginate into the polyvinyl alcohol solution, and stirring the sodium alginate and the polyvinyl alcohol solution uniformly;
s13: adding a certain amount of gelatin into ultrapure water, and stirring uniformly at 37 ℃;
s14: adding a certain amount of nano hydroxyapatite into ultrapure water, and stirring at room temperature until the nano hydroxyapatite is uniform;
s15: mixing the solutions prepared in the steps S11, S12, S13 and S14 to obtain the lining solution.
9. The method for preparing the biomimetic gradient scaffold, according to claim 8, wherein the mass ratio of the polyvinyl alcohol, the sodium alginate, the gelatin and the nano hydroxyapatite is 1.
10. The method for preparing a biomimetic gradient scaffold according to claim 7, wherein the step S60 is followed by further comprising:
and circularly freezing and thawing the bionic gradient scaffold for multiple times, soaking the bionic gradient scaffold in an anhydrous calcium chloride solution, freeze-drying, finishing the shape, and sterilizing.
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