Construction of a drug delivery system for bone defects and a method for constructing the delivery body

Abstract

This application discloses the construction of a drug delivery system for bone defects and a method for constructing the delivery body, relating to the technical field of medical and health materials. The materials include: polyetherimide, tricalcium phosphate, calcium sulfate hemihydrate, graphene oxide, and adiponectin; wherein the mass ratio of polyetherimide, tricalcium phosphate, and calcium sulfate hemihydrate is 1:0.05-0.3:0.1-0.5; the concentration of graphene oxide is 5-10 μg / mL, and the concentration of adiponectin is 2-20 μg / mL; graphene oxide can carry adiponectin through physical adsorption to construct a graphene oxide-adiponectin complex. The complex is bound to the surface of the polyetherimide-calcium scaffold through a bio-coating, and then applied to the prosthesis-bone repair area for diabetes. The adiponectin delivery body for the bone defect site uses graphene oxide as a sustained-release carrier, exhibiting high drug loading and easy release at the prosthesis-bone interface without affecting biocompatibility.

Description

Technical Field

[0001] This invention relates to the technical field of medical and health materials, and in particular to the construction of a drug delivery system for bone defects and a method for constructing the delivery body. Background Technology

[0002] With the continuous advancement of tissue engineering technology, 3D-printed tissue engineering scaffolds are gradually replacing traditional autologous and allogeneic bone grafting methods, and have made significant progress in addressing the shortcomings of traditional bone grafting methods. The advantage of 3D printing technology lies in its ability to precisely control the pore structure and surface properties of the scaffold, including porosity, pore size, pore volume, and spatial arrangement. These factors are crucial for the biocompatibility and cell growth of the scaffold, thus promising the creation of high-performance bone tissue engineering scaffolds.

[0003] Nevertheless, current 3D-printed bone repair scaffolds are primarily designed for bone filling in normal physiological microenvironments, with relatively limited applications in addressing specific pathological microenvironments such as those associated with diabetes. Bone repair in diabetic settings faces unique challenges, mainly due to mitochondrial dysfunction in the tissues surrounding the implant under hyperglycemic conditions, which affects osseointegration and the long-term stability of the implant.

[0004] Currently, although surface modification technology for tissue engineering scaffolds has made some progress in improving osseointegration and has been optimized using materials such as calcium phosphate, biomolecules, hydroxyapatite, and tantalum, these technologies still cannot fully meet the needs of the special pathological microenvironment in the field of diabetes treatment. Summary of the Invention

[0005] This application provides a method for constructing a drug delivery system for bone defects and a delivery body, which solves the problem in the prior art that the treatment of diabetes does not meet the needs of special pathological microenvironments, and achieves the technical effect of treating bone injuries in the field of diabetes.

[0006] This application provides a method for constructing a drug delivery system for bone defects, the materials of which include: polyetherimide, tricalcium phosphate, calcium sulfate hemihydrate, graphene oxide, and adiponectin;

[0007] The mass ratio of polyetherimide, tricalcium phosphate, and calcium sulfate hemihydrate is 1:0.05-0.3:0.1-0.5; the concentration of graphene oxide is 2-10 μg / mL; and the concentration of adiponectin is 2-50 μg / mL.

[0008] The above-mentioned method for constructing a drug delivery system at bone defects includes the following specific steps:

[0009] S1: Prepare a 3D-printed polyetherimide-calcium scaffold by using polyetherimide, tricalcium phosphate, and calcium sulfate hemihydrate;

[0010] S2: Prepare a graphene oxide-adiponectin complex by thoroughly mixing graphene oxide and adiponectin at the concentrations described above;

[0011] S3: Graphene oxide-adiponectin complex is loaded onto the surface of a 3D-printed polyetherimide-calcium scaffold via a polydopamine coating;

[0012] S4: The graphene oxide-adiponectin complex is repeatedly loaded onto the scaffold surface 3-5 times, rinsed with ultrapure water 2-3 times, and dried to obtain the local adiponectin delivery body for diabetic bone defects.

[0013] The drying conditions are as follows: drying temperature 30-37℃, drying time 12-24 hours.

[0014] Furthermore, the preparation method of the 3D printed polyetherimide-calcium scaffold in step S1 is as follows:

[0015] S11: Take calcium hydroxide, dissolve it in water to obtain a solution with 2% water content by mass, then add 1.5 mol / L dilute sulfuric acid solution, and stir the reaction at 20-60℃ for 0.5-5 h; filter the solution after reaction and wash it repeatedly, dry it and dehydrate it at 140-160℃ to obtain calcium sulfate hemihydrate;

[0016] S12: Polyetherimide powder, tricalcium phosphate and calcium sulfate hemihydrate are mixed to obtain polyetherimide-calcium mixed powder;

[0017] The specific mixing conditions are: 10000-25000 rpm, 5-15 min;

[0018] S13: Add polyetherimide-calcium mixed powder to the feed port of a twin-screw extruder, and after extrusion, obtain polyetherimide-calcium filament with a diameter of 1.50-2.00 mm;

[0019] The diameter of the polyetherimide-calcium filament is 1.50-2.00 mm; the feed parameters of the twin-screw extruder are 20-25 r / min, and the forming extrusion temperature is 330-350℃.

[0020] S14: Place the filament into the 3D printer, adjust the printer temperature to 370-390℃, and obtain a polyetherimide-calcium scaffold after 3D printing.

[0021] Furthermore, the preparation method of the graphene oxide-adiponectin complex in step S2 comprises the following steps:

[0022] S21: Prepare an adiponectin solution with a concentration of 2-10 μg / mL using phosphate buffer solution;

[0023] S22: Place graphene oxide into an adiponectin solution with a graphene oxide concentration of 5-10 μg / mL, at a temperature of 30-37℃, and stir at 300-500 rpm for 6-8 hours to obtain mixture 1.

[0024] S23: After the reaction is complete, centrifuge mixture 1 at 3000-4000 rpm for 15-20 min, discard the supernatant, and obtain precipitate 1;

[0025] S24: Add precipitate 1 back to the adiponectin solution and repeat 3 times. After the reaction is complete, centrifuge at 3000-4000 rpm for 15-20 min, discard the supernatant, and the precipitate is graphene oxide-adiponectin complex.

[0026] Furthermore, in step S3, the graphene oxide-adiponectin delivery body is loaded onto the scaffold surface, which comprises the following steps:

[0027] S31: Polyetherimide-calcium was surface modified using a polydopamine solution with pH=8.5 and a concentration of 2 mg / mL under aeration conditions. The stirring speed was 600-800 rpm for 12-24 hours to obtain polydopamine-modified polyetherimide-calcium scaffold.

[0028] S32: Place the graphene oxide-adiponectin complex and the polydopamine-modified polyetherimide-calcium scaffold in ultrapure water and stir at 300-400 rpm for 2-4 hours.

[0029] Furthermore, the method for preparing the 3D-printed polyetherimide-calcium scaffold in step S1 also includes step S15:

[0030] S15: Add the polyetherimide-calcium scaffold to a 0.5 mol / L dilute sulfuric acid solution, and slowly add zinc hydroxide powder. Stir and react at 60-80℃ for 0.5-2 hours to make the polyetherimide-calcium scaffold contain zinc. The molar ratio of zinc hydroxide to calcium hydroxide is 2-5:18-19.

[0031] Furthermore, in the preparation of the 3D printed polyetherimide-calcium scaffold in step S1, the prepared 3D printed polyetherimide-calcium scaffold has a grid print inside and a complete exterior. The printed grid has liquid channels inside, which exist inside the grid scaffold.

[0032] Furthermore, after obtaining the polydopamine-modified polyetherimide-calcium scaffold in step S31, an intermediate layer loading is performed again.

[0033] Specifically, the mixture of polyetherimide-calcium and graphene oxide-adiponectin and the polydopamine-modified polyetherimide-calcium scaffold are placed in ultrapure water and stirred at 300-400 rpm for 1-2 hours; and when loaded, the liquid channels of the scaffold are opened to allow the mixture of polyetherimide-calcium and graphene oxide-adiponectin to be poured in.

[0034] Furthermore, the mass ratio of polyetherimide-calcium powder to graphene oxide-adiponectin is 1:5-10.

[0035] Furthermore, the 3D-printed scaffold is divided into a through module and a main module. The liquid channels in the main module scaffold are filled with a mixture of polyetherimide-calcium and graphene oxide-adiponectin. The through module scaffold is filled only with graphene oxide-adiponectin and completely penetrates the main module scaffold. The main module also includes inner, middle and outer modules, each loaded with zinc. The amount of drug loaded in each module is different, specifically decreasing from the inside to the outside.

[0036] One or more technical solutions provided in the embodiments of this application have at least the following technical effects or advantages:

[0037] Firstly, graphene oxide can carry adiponectin through physical adsorption to construct a graphene oxide-adiponectin complex. The complex is then bound to the surface of a polyetherimide-calcium scaffold through a bio-coating and applied to the prosthesis-bone repair area in diabetic patients. The local adiponectin delivery system for bone defects uses graphene oxide as a sustained-release carrier, which has a high drug loading rate and is easy to release at the prosthesis-bone interface without affecting biocompatibility.

[0038] Secondly, when zinc hydroxide is added to an acidic environment, zinc ions quickly combine with sulfate ions, accelerating the formation of crystal nuclei. Due to the sudden introduction of zinc ions, more crystal nuclei are formed in the solution, resulting in an increase in the number of crystal nuclei during the nucleation stage. More crystal nuclei will compete for ions in the solution for growth, resulting in smaller final crystals.

[0039] Thirdly, the additional intermediate load layer can increase the overall thickness and strength of the scaffold, making it more robust and durable. The coating can fill small pores or uneven surfaces that may be generated during the 3D printing process, making the scaffold structure more uniform and dense. Both polyetherimide and calcium materials have good biocompatibility. The additional coating promotes cell adhesion and proliferation on the scaffold surface. The smooth surface coating can reduce friction and irritation to surrounding tissues, reducing the risk of inflammatory reactions. The coating contains drugs or bioactive substances, acting as a drug release reservoir to achieve slow and continuous drug release. The coating can provide a more suitable surface environment for bone cell growth, promoting bone tissue regeneration and repair. The chemical composition and surface properties of the coating can simulate the microenvironment of natural bone tissue, thereby accelerating the bone healing process. Furthermore, it makes the connection between the coating and the scaffold more compact.

[0040] Fourthly, by setting up an internal main module, during the initial callus formation period, the bone injury site contains a large amount of calcium, zinc, adiponectin, and other substances that promote osteocyte proliferation, thus promoting the formation of callus and bone tissue and accelerating calcification healing. During the callus remodeling and shaping period, the main module scaffold is basically completely metabolized, and the only material penetrating the module scaffold is graphene oxide-adiponectin. The amount of drug released is reduced, and the medication is gradually reduced in preparation for the healing period. It no longer contains a large amount of calcium and zinc elements, promoting the removal of callus outside the stress axis. The calcium sulfate and tricalcium phosphate penetrating the module scaffold are sufficient to restore the callus calcification to its original form. When entering the healing period, the scaffold is basically completely metabolized, and the amount of adiponectin released is initially high and then gradually decreases until it is no longer present, preventing damage to human pancreatic function due to large changes in adiponectin concentration. Attached Figure Description

[0041] Figure 1 This is a schematic diagram of the 3D printing module of Embodiment 4 of the present invention. Detailed Implementation

[0042] It should be noted that the terms "vertical," "horizontal," "up," "down," "left," "right," and similar expressions used in this article are for illustrative purposes only and do not represent the only possible implementation.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to limit the invention; the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0044] Example 1

[0045] Construction of a drug delivery system for bone defects, the materials of which include: polyetherimide, tricalcium phosphate, calcium sulfate hemihydrate, graphene oxide, and adiponectin;

[0046] The mass ratio of polyetherimide, tricalcium phosphate, and calcium sulfate hemihydrate is 1:0.05-0.3:0.1-0.5.

[0047] The concentration of graphene oxide is 5-10 μg / mL, and the concentration of adiponectin is 2-20 μg / mL;

[0048] The method for constructing the drug delivery system at the bone defect site includes the following specific steps:

[0049] S1: Prepare a 3D-printed polyetherimide-calcium scaffold by using polyetherimide, tricalcium phosphate, and calcium sulfate hemihydrate;

[0050] S2: Prepare a graphene oxide-adiponectin complex by thoroughly mixing graphene oxide and adiponectin at the concentrations described above;

[0051] S3: Graphene oxide-adiponectin complex is loaded onto the surface of a 3D-printed polyetherimide-calcium scaffold via a polydopamine coating;

[0052] S4: The graphene oxide-adiponectin complex is repeatedly loaded onto the scaffold surface 3-5 times, rinsed with ultrapure water 2-3 times, and dried to obtain the local adiponectin delivery body for diabetic bone defects.

[0053] The drying conditions are as follows: drying temperature 30-37℃, drying time 12-24 hours;

[0054] The preparation method of the 3D printed polyetherimide-calcium scaffold in step S1 is as follows:

[0055] S11: Take calcium hydroxide, dissolve it in water to obtain a solution with 2% water content by mass, then add 1.5 mol / L dilute sulfuric acid solution, and stir the reaction at 20-60℃ for 0.5-5 h; filter the solution after reaction and wash it repeatedly, dry it and dehydrate it at 140-160℃ to obtain calcium sulfate hemihydrate;

[0056] S12: Polyetherimide powder, tricalcium phosphate and calcium sulfate hemihydrate are mixed to obtain polyetherimide-calcium mixed powder;

[0057] The specific mixing conditions are: 10000-25000 rpm, 5-15 min;

[0058] S13: Add polyetherimide-calcium mixed powder to the feed port of a twin-screw extruder, and after extrusion, obtain polyetherimide-calcium filament with a diameter of 1.50-2.00 mm;

[0059] The diameter of the polyetherimide-calcium filament is 1.50-2.00 mm; the feed parameters of the twin-screw extruder are 20-25 r / min, and the forming extrusion temperature is 330-350℃.

[0060] S14: Place the filament into the 3D printer, adjust the printer temperature to 370-390℃, and obtain a polyetherimide-calcium scaffold after 3D printing.

[0061] The preparation method of the graphene oxide-adiponectin complex in step S2 includes the following steps:

[0062] S21: Prepare an adiponectin solution with a concentration of 2-10 μg / mL using phosphate buffer solution;

[0063] S22: Place graphene oxide into an adiponectin solution with a graphene oxide concentration of 5-10 μg / mL, at a temperature of 30-37℃, and stir at 300-500 rpm for 6-8 hours to obtain mixture 1.

[0064] S23: After the reaction is complete, centrifuge mixture 1 at 3000-4000 rpm for 15-20 min, discard the supernatant, and obtain precipitate 1;

[0065] S24: Add precipitate 1 back to the adiponectin solution and repeat 3 times. After the reaction is complete, centrifuge at 3000-4000 rpm for 15-20 min, discard the supernatant, and the precipitate is graphene oxide-adiponectin complex.

[0066] In step S3, the graphene oxide-adiponectin delivery system is loaded onto the scaffold surface, which involves the following steps:

[0067] S31: Polyetherimide-calcium was surface modified using a polydopamine solution with pH=8.5 and a concentration of 2 mg / mL under aeration conditions. The stirring speed was 600-800 rpm for 12-24 hours to obtain polydopamine-modified polyetherimide-calcium scaffold.

[0068] S32: Place the graphene oxide-adiponectin complex and the polydopamine-modified polyetherimide-calcium scaffold in ultrapure water and stir at 300-400 rpm for 2-4 hours.

[0069] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages:

[0070] Graphene oxide can carry adiponectin through physical adsorption to construct a graphene oxide-adiponectin complex. The complex is bound to the surface of a polyetherimide-calcium scaffold through a bio-coating and then applied to the prosthesis-bone repair area in diabetes. The local adiponectin delivery system for bone defects uses graphene oxide as a sustained-release carrier, which has a high drug loading rate and is easy to release at the prosthesis-bone interface without affecting biocompatibility.

[0071] Artificial bone materials prepared by using a mixture of tricalcium phosphate and calcium sulfate hemihydrate exhibit good biocompatibility. Osteoblasts can adhere and grow on this composite material, and the number of cells adhering to the material increases over time, promoting cell adhesion and proliferation. Over time, the implanted tricalcium phosphate and calcium sulfate hemihydrate composite material is gradually surrounded by new bone tissue, and the material begins to degrade. Adiponectin in graphene is gradually released and forms synchronously with the new bone tissue, ensuring the gradual healing and repair of bone defects.

[0072] Graphene oxide has good biocompatibility and can physically adsorb adiponectin. Its high porosity and high specific surface area can provide good drug release and adsorption sites. Polyetherimide-calcium scaffolds can be 3D printed and have good osteoinductive properties, which can provide space for bone tissue regeneration. The added adiponectin has anti-diabetic effects, can promote mitochondrial biogenesis, correct cell function, and promote osteogenic differentiation.

[0073] 3D printing allows for more controllable shape of the entire delivery system, better meeting individualized medication needs.

[0074] Example 2

[0075] Example 1 involves attaching an adiponectin coating to the surface of a polyetherimide-calcium scaffold using graphene oxide to promote osteoblast growth and differentiation. To reduce osteoclast growth, zinc is incorporated into the polyetherimide-calcium scaffold, representing a further improvement on Example 1.

[0076] The preparation method of 3D printed polyetherimide-calcium scaffold in step S1 also includes step S15:

[0077] S15: Add the polyetherimide-calcium scaffold to a 0.5 mol / L dilute sulfuric acid solution, and slowly add zinc hydroxide powder. Stir and react at 60-80℃ for 0.5-2 hours to make the polyetherimide-calcium scaffold contain zinc.

[0078] The molar ratio of zinc hydroxide to calcium hydroxide is 2-5:18-19.

[0079] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages:

[0080] When zinc hydroxide is added to an acidic environment, zinc ions combine with sulfate ions. The introduction of zinc ions accelerates the formation of crystal nuclei, resulting in more crystal nuclei in the solution. This increases the number of crystal nuclei during the nucleation stage. More crystal nuclei compete for ions in the solution for growth, resulting in smaller and more numerous final crystals. Because calcium hydroxide reacts first, calcium sulfate crystallizes, causing zinc ions to partially replace calcium ions in the calcium sulfate lattice. Some zinc ions also crystallize into small crystals, which are adsorbed and surround the polyetherimide-calcium scaffold main module, filling some of the large pores. This slows down the formation of large voids in the bone defect area after the material is completely degraded due to the rapid degradation of hemihydrate calcium sulfate, which can lead to fibrous tissue ingrowth and affect the healing effect of bone defects. Furthermore, it increases the specific surface area of ​​the scaffold, improves its contact sites, and enhances the binding degree with the graphene oxide-adiponectin main module.

[0081] Zinc has certain antibacterial properties, which can inhibit bacterial growth. In the process of bone defect repair, it can also reduce the growth of osteoclasts and improve the efficiency of bone repair.

[0082] Example 3

[0083] To prevent performance degradation of the stent due to chemical corrosion in the in vivo environment, a multi-layer coating is used, which is a further improvement on Example 2.

[0084] In step S31 of S3, polydopamine solution with pH=8.5 and a concentration of 2 mg / mL is used to modify the surface of polyetherimide-calcium under aeration conditions. The stirring speed is 600-800 rpm for 12-24 hours. After obtaining the polydopamine-modified polyetherimide-calcium scaffold, an intermediate layer loading is performed. That is, a mixture of polyetherimide-calcium and graphene oxide-adiponectin is used to load the surface of the polyetherimide-calcium scaffold. The mass ratio of polyetherimide-calcium powder to graphene oxide-adiponectin is 1:5-10.

[0085] Furthermore, in step S1, during the preparation of the 3D-printed polyetherimide-calcium scaffold, the prepared 3D-printed polyetherimide-calcium scaffold has an internal mesh printing structure and an externally complete structure. Liquid channels are left inside the printed mesh, and these channels exist within the mesh scaffold.

[0086] The specific loading steps are as follows: place the mixture of polyetherimide-calcium and graphene oxide-adiponectin and the polydopamine-modified polyetherimide-calcium scaffold in ultrapure water, and stir at 300-400 rpm for 1-2 hours; connect the liquid channel of the scaffold to the outside before loading; so that the mixture of polyetherimide-calcium and graphene oxide-adiponectin can be poured in.

[0087] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages:

[0088] The additional intermediate load layer increases the overall thickness and strength of the scaffold, making it more robust and durable. The coating fills small pores or uneven surfaces generated during 3D printing, making the scaffold structure more uniform and dense. When the intermediate load layer is loaded onto the scaffold in ultrapure water, the high hydrophilicity of the zinc layer in water improves surface wettability. Even with a high degree of graphene oxide oxidation, the improved surface wettability allows the intermediate load layer to spread across the scaffold surface and penetrate into the gaps. Furthermore, the infusion of the mixture ensures a large amount of effective therapeutic substances within the scaffold. Simultaneously, the presence of polyetherimide-calcium powder in the intermediate load layer provides support. The intermediate load layer acts as a support and adhesive layer within the scaffold, ensuring that the scaffold structure retains significant support and compressive strength even after degradation. Moreover, the pharmacologically effective graphene oxide-adiponectin infiltrates the scaffold, allowing the adiponectin in the main module to retain its therapeutic effect for diabetes.

[0089] Both polyetherimide and calcium materials exhibit good biocompatibility. The additional coating promotes cell adhesion and proliferation on the scaffold surface. The smooth surface coating reduces friction and irritation to surrounding tissues, lowering the risk of inflammatory responses. The coating contains drugs or bioactive substances, acting as a drug reservoir for slow and sustained drug release. The coating provides a more suitable surface environment for osteoblast growth, promoting bone tissue regeneration and repair. The chemical composition and surface properties of the coating mimic the microenvironment of natural bone tissue, thereby accelerating the bone healing process and ensuring a tighter bond between the coating and the surrounding tissue.

[0090] The additional intermediate load layer improves the wear resistance of the scaffold, enabling it to maintain structural integrity during long-term use; the coating also enhances the corrosion resistance of the scaffold, preventing performance degradation due to chemical corrosion in the body environment; and the polyetherimide-calcium scaffold is further encapsulated with graphene oxide, making the degradation time of hemihydrate calcium sulfate crystals controllable, which can synchronize the drug release rate, so that the degradation rate of the scaffold is balanced with drug treatment and bone injury recovery.

[0091] Example 4

[0092] To improve the individualized application, further improvements were made based on Example 3.

[0093] In step S1, during the preparation of the 3D-printed polyetherimide-calcium scaffold, the prepared 3D-printed polyetherimide-calcium scaffold has an internal mesh printout and a smooth, complete exterior. Liquid channels are present within the printed mesh scaffold.

[0094] The 3D-printed scaffold is divided into a through-module and a main module. The main module scaffold is filled with a mixture of polyetherimide-calcium and graphene oxide-adiponectin. The through-module scaffold is filled only with graphene oxide-adiponectin and completely penetrates the main module scaffold. This allows the through-module scaffold to participate in the degradation process when the scaffold begins to degrade, and it can still function after the main module scaffold has completely degraded, releasing graphene oxide-adiponectin. The main module also includes inner, middle and outer modules, each loaded with zinc. The drug loading of each module is different, specifically decreasing from the inside to the outside. Furthermore, scaffolds with different modules can be printed separately to meet the needs of different patients.

[0095] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages:

[0096] By setting up a main module and a through module, during the initial callus formation period, the bone injury site contains a large amount of substances that promote osteocyte proliferation, such as calcium, zinc, and adiponectin, which promote the formation of callus and bone tissue and accelerate calcification healing. During the callus remodeling and shaping period, the main module scaffold is basically completely metabolized, while the through module scaffold contains only graphene oxide-adiponectin, with reduced drug release. The drug is gradually reduced to prepare for the healing period, and it no longer contains a large amount of calcium and zinc, promoting the removal of callus outside the stress axis. The calcium sulfate and tricalcium phosphate in the through module scaffold are sufficient to restore the callus calcification to its original shape. When entering the healing period, the scaffold is basically completely metabolized, and the release of adiponectin is initially high and then gradually decreases until it is zero, preventing damage to human pancreatic function due to large changes in adiponectin concentration. Since the through module participates in the release throughout the process, the overall type and release rate of the drug can also be adjusted by adjusting the through module.

[0097] By setting up a main module and a through module, during the initial callus formation period, the bone injury site contains a large amount of calcium, zinc, adiponectin, and other substances that promote osteocyte proliferation, thus promoting the formation of callus and bone tissue and accelerating calcification healing. During the callus remodeling and shaping period, the through module scaffold is basically completely metabolized, and the main module scaffold only contains graphene oxide-adiponectin, with reduced drug release. The drug is gradually reduced to prepare for the healing period, and it no longer contains a large amount of calcium and zinc elements, promoting the removal of callus outside the stress axis. The calcium sulfate and tricalcium phosphate in the main module scaffold are sufficient to restore the callus calcification to its original form. When entering the healing period, the scaffold is basically completely metabolized, and the release of adiponectin is initially high and then gradually decreases until it is zero, preventing damage to human pancreatic function due to large changes in adiponectin concentration.

[0098] The main module design allows for individualized drug delivery design based on the patient's condition, individual status, and bone injury healing. Individualized drug delivery scaffolds are constructed using different modules, and different drug release strategies are achieved through combination.

[0099] By setting up internal, external, and through modules, the drug release concentration can be controlled and the drug release strategy can be adjusted to meet the medication needs of various patients.

[0100] The bone defect drug delivery systems prepared according to Examples 1 to 4 and application number CN202210212530.7 as comparative examples were subjected to performance testing, and the test results are shown in Table 1:

[0101] Table 1

[0102]

[0103] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for constructing a drug delivery system for bone defects, characterized in that, The materials and dosages of adiponectin delivery systems for bone defects include: a mass ratio of polyetherimide, tricalcium phosphate, and calcium sulfate hemihydrate of 1:0.05-0.3:0.1-0.5; a graphene oxide concentration of 2-10 µg / mL; and an adiponectin concentration of 2-50 µg / mL. The specific preparation method includes the following steps: S1: Prepare a 3D-printed polyetherimide-calcium scaffold by using polyetherimide, tricalcium phosphate, and calcium sulfate hemihydrate; S2: Prepare a graphene oxide-adiponectin complex by thoroughly mixing graphene oxide and adiponectin at the concentrations described above; S3: Graphene oxide-adiponectin complex is loaded onto the surface of a 3D-printed polyetherimide-calcium scaffold via a polydopamine coating; S4: The graphene oxide-adiponectin complex is repeatedly loaded onto the scaffold surface 3-5 times, rinsed with ultrapure water 2-3 times, and dried to obtain the local adiponectin delivery body for bone defects. The drying conditions are as follows: drying temperature 30-37℃, drying time 12-24 hours; In step S1, during the preparation of the 3D printed polyetherimide-calcium scaffold, the prepared 3D printed polyetherimide-calcium scaffold has a grid printed inside and a complete outside. The printed grid has liquid channels inside, which exist inside the grid scaffold. In step S3, the graphene oxide-adiponectin delivery system is loaded onto the scaffold surface, which involves the following steps: S31: Polyetherimide-calcium was surface modified using a polydopamine solution with pH=8.5 and a concentration of 2 mg / mL under aeration conditions. The stirring speed was 600-800 rpm for 12-24 hours to obtain polydopamine-modified polyetherimide-calcium scaffold. S32: Place the graphene oxide-adiponectin complex and the polydopamine-modified polyetherimide-calcium scaffold in ultrapure water and stir at 300-400 rpm for 2-4 hours. After obtaining the polydopamine-modified polyetherimide-calcium scaffold in step S31, an intermediate layer loading is performed again. Specifically, the mixture of polyetherimide-calcium and graphene oxide-adiponectin, along with a polydopamine-modified polyetherimide-calcium scaffold, is placed in ultrapure water and stirred at 300-400 rpm for 1-2 hours. During loading, the liquid channels of the polydopamine-modified polyetherimide-calcium scaffold are traversed to allow the mixture of polyetherimide-calcium and graphene oxide-adiponectin to be injected.

2. The method for constructing a drug delivery system for bone defects as described in claim 1, characterized in that, The preparation method of the 3D printed polyetherimide-calcium scaffold in step S1 is as follows: S11: Take calcium hydroxide, dissolve it in water to make a 2% (w / w) solution, then add 1.5 mol / L dilute sulfuric acid solution, stir the reaction at 20-60℃ for 0.5-5 h; filter the solution after the reaction and wash it repeatedly, dry it and dehydrate it at 140-160℃ to obtain calcium sulfate hemihydrate; S12: Polyetherimide powder, tricalcium phosphate and calcium sulfate hemihydrate are mixed to obtain polyetherimide-calcium mixed powder; The specific mixing conditions are: 10000-25000 rpm, 5-15 min; S13: Add polyetherimide-calcium mixed powder to the feed port of a twin-screw extruder, and after extrusion, obtain polyetherimide-calcium filament with a diameter of 1.50-2.00 mm; The diameter of the polyetherimide-calcium filament is 1.50-2.00 mm; the feed parameters of the twin-screw extruder are 20-25 r / min, and the forming extrusion temperature is 330-350℃. S14: Place the filament into the 3D printer, adjust the printer temperature to 370-390℃, and obtain a polyetherimide-calcium scaffold after 3D printing.

3. The method for constructing a drug delivery system for bone defects as described in claim 1, characterized in that, The method for preparing the graphene oxide-adiponectin complex in step S2 includes the following steps: S21: Prepare an adiponectin solution with a concentration of 2-10 µg / mL using phosphate buffer solution; S22: Place graphene oxide into an adiponectin solution with a graphene oxide concentration of 5-10 µg / mL, at a temperature of 30-37℃, and stir at 300-500 rpm for 6-8 hours to obtain mixture 1. S23: After the reaction is complete, centrifuge mixture 1 at 3000-4000 rpm for 15-20 min, discard the supernatant, and obtain precipitate 1; S24: Add precipitate 1 back to the adiponectin solution and repeat 3 times. After the reaction is complete, centrifuge at 3000-4000 rpm for 15-20 min, discard the supernatant, and the precipitate is graphene oxide-adiponectin complex.

4. The method for constructing a drug delivery system for bone defects as described in claim 2, characterized in that, The method for preparing the 3D-printed polyetherimide-calcium scaffold in step S1 also includes step S15: S15: Add the polyetherimide-calcium scaffold to a 0.5 mol / L dilute sulfuric acid solution, and slowly add zinc hydroxide powder. Stir and react at 60-80℃ for 0.5-2 hours to make the polyetherimide-calcium scaffold contain zinc. The molar ratio of zinc hydroxide to calcium hydroxide is 2-5:18-19.

5. The method for constructing a drug delivery system for bone defects as described in claim 4, characterized in that, The mass ratio of polyetherimide-calcium powder to graphene oxide-adiponectin is 1:5-10.

6. The method for constructing a drug delivery system for bone defects as described in claim 1, characterized in that, The 3D-printed scaffold is divided into a through module and a main module. The liquid channels in the main module scaffold are filled with a mixture of polyetherimide-calcium and graphene oxide-adiponectin. The through module scaffold is filled only with graphene oxide-adiponectin and completely penetrates the main module scaffold. The main module also includes inner, middle and outer modules, each loaded with zinc. The amount of drug loaded in each module is different, specifically decreasing from the inside to the outside.

Images