A photothermal bone tumor scaffold with controlled drug release, and its preparation method and application

Abstract

The present invention discloses a photothermal bone tumor scaffold with controlled drug release, as well as its preparation method and application. The scaffold has two sets of curved, independently connected channels, with the outer channel being open and connected, and the inner channel being closed and connected. The scaffold is made of a Ca2MgSi2O7 / ZTA composite ceramic material. The preparation process involves adding ceramic slurry to a photocuring printing device, performing photocuring printing based on a photothermal bone tumor scaffold model to produce a ceramic blank, performing secondary curing on the blank to produce a ceramic green body, and sintering the green body to obtain the photothermal bone tumor scaffold. The scaffold provided by the present invention has high porosity and strength, possesses an independent dual-channel structure, and integrates multiple functions: osteogenesis, controlled release of chemotherapy drugs, and photothermal killing of bone tumor cells.

Description

Technical Field

[0001] The present invention relates to a photothermal bone tumor stent with controllable drug release, a preparation method and application thereof, and belongs to the technical field of photothermal stent preparation. Background Art

[0002] Bone cancer is a general term for malignant bone tumors, which are tumors that occur in bones or their appendages. They include osteosarcoma, chondrosarcoma, fibrosarcoma, etc., and can be benign or malignant. Patients usually suffer from a variety of complications such as osteolysis, bone defects, and bone pain, which cause a significant decline in the body's motor function and bring great pain to patients. Photothermal therapy uses photothermal materials to convert light energy into heat energy under the irradiation of external light sources such as near-infrared light, rapidly raising the temperature of the tumor site and killing tumor cells. As an emerging non-invasive therapy, photothermal therapy has the advantages of few adverse reactions, high specificity, and repeatable treatment. It can achieve targeted treatment while reducing the damage of drugs or radiation to normal tissues. It has fewer toxic side effects on the human body and has significant advantages over traditional tumor treatments. Therefore, photothermal stents have become a new approach to bone tumor treatment.

[0003] Currently, photothermal stent materials include polymers, metals, and ceramics. However, the functions that photothermal stents must meet place demands on the material's properties, such as biocompatibility, mechanical properties, and osteoinduction. Due to the low mechanical strength of polymer materials, the mechanical properties of the stent itself are insufficient to match those of the body's own bone. The degradation products of metal materials can be excreted through metabolism, causing less harm to the human body. However, metals are susceptible to corrosion in the body and cannot induce bone formation. At the same time, their modulus does not match that of human bone, causing stress shielding. After implantation into the body, bioceramic bone repair materials can form a hydroxyapatite-like layer on their surface that is similar in composition to bone tissue and chemically bonds to bone tissue, thereby inducing ectopic osteogenesis. Among them, ceramic materials such as hydroxyapatite (HA) and tricalcium phosphate (TCP) are commonly used for non-load-bearing bones in the human body. In addition, the current drug loading methods for photothermal stents suitable for bone tumor treatment are relatively simple, usually using encapsulation or surface modification, and the drug loading capacity is limited; at the same time, the drug is attached to the surface of the stent pores, and after implantation into the body, it comes into direct contact with the tissue and is prone to explosive release. The chemotherapy effect cycle is short, and the controllable sustained release of the drug cannot meet the long-term clinical treatment needs. Summary of the Invention

[0004] In response to the shortcomings of the existing technology, the first purpose of the present invention is to provide a photothermal bone tumor scaffold with high porosity, high strength, an independent dual-channel structure, and integrated osteogenesis, controlled release of chemotherapy drugs, and photothermal effect to kill bone tumor cells.

[0005] The second object of the present invention is to provide a method for preparing a photothermal bone tumor scaffold that can controllably obtain a fine structure.

[0006] The third object of the present invention is to provide an application of a photothermal bone tumor scaffold with controlled drug release.

[0007] The present invention provides a photothermal bone tumor stent with controllable drug release. The photothermal bone tumor stent has two sets of curved independent connecting channels, wherein the outer channels are open and connected, and the inner channels are closed and connected; the material of the photothermal bone tumor stent is Ca2MgSi2O7 / ZTA composite ceramic material.

[0008] The photothermal bone tumor scaffold provided by the present invention features a dual-channel structure to meet the functional requirements of a photothermal bone tumor scaffold. The open, interconnected outer channel allows for cell adhesion and provides a pathway for bone and blood vessel growth; the closed, interconnected inner channel is used to load photothermal materials and chemotherapy drugs. Furthermore, the photothermal bone tumor scaffold provided by the present invention is a Ca2MgSi2O7 / ZTA composite ceramic material. The ZrO2-toughened Al2O3 composite ceramic (ZTA) exhibits excellent wear resistance, compressive strength, and bioreactivity. The Ca2MgSi2O7 bioceramic material can serve as a bioactive additive to enhance the bioactivity of ZTA and promote osteogenesis. At the same time, Ca2MgSi2O7 has a low melting point of 1450°C, which is lower than the sintering temperature range of ZTA (1450-1600°C). Therefore, it can be used as a sintering aid to improve the sintering performance of ZTA, reduce the sintering temperature, and increase the sintering density. The Ca2MgSi2O7 / ZTA composite ceramic material enables the photothermal bone tumor scaffold to meet good mechanical properties and biocompatibility while having good biological activity to promote osteogenesis.

[0009] In a preferred embodiment, the porosity of the photothermal bone tumor scaffold is 40% to 90%, preferably 50% to 80%.

[0010] For photothermal bone tumor scaffolds, the greater the porosity, the higher the scaffold permeability, which is conducive to cell adhesion, promotes osteogenesis, and provides sufficient space for tissue filling and nutrient flow. Since the photothermal bone tumor scaffold used in the present invention is based on ZTA ceramics and is doped with Ca2MgSi2O7 to improve sintering density, a photothermal bone tumor scaffold with a porosity of up to 90% can be prepared.

[0011] The photothermal stent provided by the present invention has high porosity, and the high porosity provides sufficient space for bone growth and loading of drugs and photothermal materials.

[0012] In a preferred embodiment, the pore size of the photothermal bone tumor scaffold is 0.1 to 1.00 mm, and the wall thickness of the independent communicating channels is 10 to 60 mm.

[0013] The inventors found that by controlling the pore size and wall thickness of the photothermal bone tumor scaffold within the above range, the photothermal bone tumor scaffold ultimately has the best effect.

[0014] In a preferred embodiment, the structure of the photothermal bone tumor scaffold is a plane formed by the basic function equation of the G-type minimal surface, which divides the space into two sets of curved independent connecting channels, and then the plane is obtained by thickening treatment. The basic function equation is F(x, y, z) = cos(x)*sin(y)+cos(y)*sin(z)+cos(z)*sin(x)+k, where k is -1.35~1.35, and the thickness of the thickening treatment is 10~60mm, preferably 10~45mm, and more preferably 10~30mm.

[0015] The structure of the photothermal bone tumor scaffold provided by the present invention can control two sets of pore sizes by changing the k value of the surface equation, thickening the surface to obtain a solid, and controlling the pore size and porosity of the final photothermal scaffold through the thickness of the coordinated thickening process. The inventors found that when k is -1.35 to 1.35 and the thickened thickness is 10 to 60 mm, the pore size range is 0.1 to 1.00 mm, the porosity is 40% to 90%, and the thickened thickness forms the wall thickness of the independent connecting channels.

[0016] In the present invention, the k value and the thickness of the thickening treatment need to be effectively controlled. If the k value and the thickness of the thickening treatment (wall thickness) are set unreasonably, the porosity may be too large or too small. Excessive porosity will reduce the mechanical properties of the scaffold; too small porosity cannot provide sufficient growth space for bones and blood vessels, and it is also difficult to infuse drugs and photothermal materials into the scaffold.

[0017] In a preferred embodiment, the mass fraction of Ca2MgSi2O7 in the photothermal bone tumor scaffold is 1.25-10%.

[0018] The inventors found that controlling the mass fraction of Ca2MgSi2O7 within the above range achieves the best final effect. If the added amount is too large, it will affect the stability of the slurry. At the same time, during sintering, due to the increase in the amount of high-temperature liquid phase of Ca2MgSi2O7 and sufficient sintering of the liquid phase, the Al2O3 grains will grow abnormally, resulting in many micropores and reducing the mechanical properties of the stent.

[0019] The present invention also provides a method for preparing a photothermal bone tumor scaffold with controlled drug release. Ceramic powder, pore-forming agent powder, and photosensitive raw materials are prepared in a designed ratio and mixed to obtain a ceramic slurry. The ceramic slurry is then added to a photocuring printing device. Photocuring printing is performed based on a photothermal bone tumor scaffold model to obtain a ceramic blank. The ceramic blank undergoes secondary curing to obtain a ceramic green body. The green body is then degreased and sintered to obtain the photothermal bone tumor scaffold. The ceramic powder comprises ZrO2 powder, Al2O3 powder, and Ca2MgSi2O7 powder.

[0020] In a preferred embodiment, the particle sizes of the ZrO2 powder, Al2O3 powder and Ca2MgSi2O7 powder are all submicron.

[0021] The inventors found that when ZrO2 powder, Al2O3 powder, and Ca2MgSi2O7 powder all have submicron particle sizes, the final composite material has the best performance. If the particle size is too small, agglomeration will occur, which is not conducive to dispersion in the ceramic slurry.

[0022] In a preferred embodiment, in the ceramic powder, the mass fraction of Ca2MgSi2O7 is 1.25% to 10%, preferably 1.25 to 5%, and the mass ratio of ZrO2 powder to Al2O3 powder is 1:3 to 6.

[0023] In a preferred embodiment, the pore-forming agent in the pore-forming agent powder is selected from polymethyl methacrylate (PMMA).

[0024] In a preferred embodiment, the particle size of the pore-forming agent powder is 0.1-5 μm, and the amount of the pore-forming agent powder added is 5-30% of the total mass of the ceramic powder and the pore-forming agent powder.

[0025] Since the present invention provides a photothermal bone tumor scaffold, adding PMMA as a pore-forming agent will form many micropores on the surface of the scaffold after volatilization at high temperature, providing channels for chemotherapy drugs to penetrate through the micropores.

[0026] In a preferred embodiment, the photosensitive raw materials are calculated by mass percentage as follows: Solsperse 41000 2-6%, Sago-8810 0.1-2%, Rad 2550 0.1-2%, TEGO foamex N 0.1-2%, polyethylene glycol (PEG 200) 1-10%, 2,4,6-diphenylphosphine oxide (TPO) 0.1-2%, trimethylolpropane triacrylate (TMPTA) 20-40%, hexanediol diacrylate (HDDA) 10-50%, and 2-hydroxyethyl acrylate (HEA) 10-30%.

[0027] The photosensitive raw material in the present invention uses HDDA, TMPTA, and HEA as a photosensitive resin. The inventors have discovered that the ceramic particles of the present invention have the best dispersibility in the HDDA, TMPTA, and HEA mixed resin, minimizing electrostatic attraction between the powders and reducing particle agglomeration. This allows for flow at a low initial yield stress, which facilitates spreading of the slurry by the roller cutter and improves the printing quality of the green blank. Furthermore, the present invention uses Solsperse 41000 as a dispersant. The inventors have discovered that Solsperse 41000 can convert the hydrophilic surface of submicron Al2O3 and ZrO2 powders to hydrophobicity, preventing agglomeration of the Al2O3 and ZrO2 powders due to the presence of a large number of hydrophilic hydroxyl groups on their surfaces. It also improves the wettability of the HDDA+TMPTA+HEA resin on the Al2O3 and ZrO2 powders, creating a stable ceramic slurry by generating a steric hindrance effect. The addition of Sago-8810 as an anti-settling agent imparts excellent thixotropic properties to the slurry. After the shearing action is removed, the weak cross-linking effect between the slurries is restored, and the viscosity recovers with an appropriate hysteresis, so that it has good leveling and anti-sagging properties. Finally, the slurry returns to its original thixotropic state. With the synergistic effect of the above components, a ceramic slurry with good dispersibility, good fluidity and high solid content can be obtained. At the same time, under the combination of the photosensitive trees of the present invention, 2,4,6-diphenylphosphine oxide (TPO) is used as a photoinitiator, and under low energy density ultraviolet light irradiation, a high-precision and high-performance photocured blank is prepared.

[0028] In addition, to improve the quality of the printed body, the present invention also adds Rad2550 as a release agent, which can form an isolation film on the surface of the mold and the platform, facilitating the separation of the printed model from the platform. TEGO foamex N is used as a defoaming agent, which can quickly spread on the foam surface and penetrate quickly, causing the foam to quickly burst and discharge the gas in the slurry, eliminating bubbles. Polyethylene glycol (PEG 200) is used as a plasticizer. When the plasticizer is mixed with the resin, the small molecules of the plasticizer will be inserted between the polymer molecular chains, weakening the attraction between the polymer molecular chains and increasing the distance between them. As a result, the possibility of polymer molecular chain movement is increased, the entanglement between polymer molecular chains is reduced, the plasticity is increased, and the mechanical properties of the scaffold can be enhanced.

[0029] In a preferred embodiment, the mixing is performed under vacuum conditions, with the mixing process being: first, mixing at 800-1500 rpm for 30 seconds to 2 minutes, then mixing at 1600-2200 rpm for 3-5 minutes, and finally mixing at 800-1000 rpm for 30 seconds to 2 minutes. The inventors have found that stirring under these conditions results in the best dispersion of the resulting slurry.

[0030] The present invention adopts a vacuum high-speed stirring process to prepare a ceramic slurry with high solid content (40-55 vol%) and low viscosity (<2 Pa·s).

[0031] In a preferred embodiment, the solid content of the ceramic slurry is 40-55 vol%. In the present invention, the solid content of the ceramic slurry refers to the total volume percentage of the ceramic powder and the pore-forming agent powder in the ceramic slurry.

[0032] In a preferred embodiment, the process of obtaining the photothermal bone tumor scaffold model is as follows: first, a plane model is formed by the basic function equation of the G-type minimal surface, and then the plane is thickened to obtain the photothermal bone tumor scaffold model. The basic function equation is F(x, y, z) = cos(x)*sin(y)+cos(y)*sin(z)+cos(z)*sin(x)+k, where k is -1.35~1.35, and the thickness of the thickening treatment is 10~60mm, preferably 10~45mm, and more preferably 10~30mm.

[0033] The plane formed by the above basic function equations divides the space into two sets of curved independent connected channels, the outer channel is open and connected, and the inner channel is closed and connected.

[0034] The preferred solution is that the parameters of the light-curing printing are: the exposure power density is 10-15 mW / cm 2 , exposure time is 0.5-2s, slice thickness is 10-50μm, temperature is 30-80℃, preferably 50-70℃.

[0035] In the present invention, the process parameters are precisely controlled within the above range to ensure that the designed pores in the model are consistent and high-precision green bodies can be obtained in a controllable manner. It can be seen that the process window of the present invention is small. This is because the inventors found that the scattering of ultraviolet light by powder particles in the ceramic slurry will seriously reduce the forming accuracy of the aperture, resulting in a significant deviation of the processed pore structure from the model design. When the exposure energy is too high, the aperture size is reduced compared to the design value, and even pore blockage occurs; when the exposure energy is too low, the interlayer bonding strength is low, and even the laminated manufacturing fails. The present invention uses a single-layer curing thickness experiment to establish the relationship between the photocuring forming parameters (surface exposure energy density) and the curing thickness, and determines the forming parameters that are 1 to 2 times thicker than the layer thickness to preliminarily determine the process window; on this basis, using the precision model test experiment, the relationship between the surface exposure energy density, exposure time, layer thickness and additional scattering width is established, and the minimum energy density parameter that can produce a precision model is selected as the optimal process parameter, that is, the manufacturing error of the precision model formed is small and the precision is the highest.

[0036] In addition, the present invention is carried out in a temperature field of 30 to 80°C, preferably 50 to 70°C during the photocuring process. The inventors found that introducing a temperature field during the curing process can not only increase the solid content of the ceramic slurry, but also increase the curing rate of the ceramic slurry, thereby increasing the cured thickness. While increasing the solid content, high-precision and high-performance ceramic samples can be printed without changing the exposure power and exposure time.

[0037] In a preferred embodiment, the exposure power density during the secondary curing is 10 to 15 mW / cm 2 , the secondary curing time is 30s~60s,

[0038] The inventors discovered that the mechanical properties of the model can be enhanced through secondary curing.

[0039] In a preferred embodiment, the degreasing is performed in a vacuum environment, the degreasing temperature is 400-600° C., and the degreasing time is 2500-3000 min.

[0040] In a preferred embodiment, the sintering process is to first heat the temperature to 400-500°C at a heating rate of 0.5-1°C / min, keep the temperature for 2-6 hours, then heat the temperature to 1450-1600°C at a heating rate of 5-10°C / min, keep the temperature for 1-3 hours, and cool to room temperature in the furnace.

[0041] The sintering process of the present invention first adopts a very slow heating rate, and then increases the heating rate after keeping warm at 400-500°C, and then sintering is carried out at 1450-1600°C. The slow heating in the early stage can avoid the problem of cracking during sintering and improve the yield. At the same time, the present invention sinters densely at a lower temperature. This is because Ca2MgSi2O7 is added to the ceramic powder in the present invention. Its melting point is 1450°C, which is close to the ZTA sintering temperature range (1450-1600°C). It can be used as a sintering aid to reduce the sintering temperature of ZTA, increase the density of the ceramic, and thus improve the mechanical properties of the ceramic material.

[0042] The present invention also provides an application of a photothermal bone tumor scaffold with controllable drug release, and the photothermal bone tumor scaffold is used to prepare bone tumor drugs.

[0043] In a preferred embodiment, the preparation process of the bone tumor drug is as follows: dissolving MXene in dichloromethane (CH2Cl2) to obtain a MXene / CH2Cl2 solution, dissolving polycaprolactone (PCL) and doxorubicin (DOX) in dichloromethane (CH2Cl2) to obtain a PCL / DOX / CH2Cl2 solution, and then sequentially filling the MXene / CH2Cl2 solution and the PCL / DOX / CH2Cl2 solution into a photothermal bone tumor scaffold. In the MXene / CH2Cl2 solution, the concentration of DOX is 0.5 mg / ml to 10 mg / ml, the concentration of MXene is 0.1 mg / ml to 2.5 mg / ml, the concentration of PCL is 10 mg / ml to 24 mg / ml, and the mass ratio of DOX to PCL is 1:10 to 30.

[0044] Principles and advantages

[0045] ①Structural design of photothermal support

[0046] By manipulating the structural parameters of a G-type minimal surface, this paper designs a dual-channel biomimetic scaffold with high porosity, high permeability, and excellent mechanical properties. This dual-channel structure meets the functional requirements of a photothermal scaffold. The open, interconnected outer channels facilitate cell adhesion and provide pathways for bone and blood vessel growth; the closed, interconnected inner channels are used to load photothermal materials and chemotherapy drugs. The high porosity provides ample space for bone growth and drug and photothermal material loading, while the high permeability ensures effective drug release within the closed inner channels.

[0047] ② Photothermal materials and drug loading methods

[0048] This stent is designed with a set of closed channels to load photothermal materials and chemotherapy drugs separately, which can effectively avoid direct contact with the human body, thereby avoiding foreign body reactions and explosive drug release. At the same time, the chemotherapy drugs loaded in the closed inner channel can only be slowly released through the inner wall after the polycaprolactone (PCL) that wraps it is degraded. Polycaprolactone (PCL) has good biodegradability, biocompatibility and non-toxicity. It is widely used in medical biodegradable materials and drug controlled release systems, and can be used in tissue engineering as a drug sustained-release system. When near-infrared light irradiates the stent, the photothermal material generates heat to degrade PCL. Due to the addition of PMMA microspheres to the ceramic slurry and the artificial increase in the porosity of the bionic stent, the inner wall becomes permeable, and the drug is slowly released from the inner wall of the closed inner channel, which prolongs the action cycle and can effectively eliminate residual cancer cells in the body and prevent cancer recurrence in the later stage.

[0049] ③ Selection of stent materials

[0050] The addition of Ca2MgSi2O7 bioceramic material to ZTA is innovative. Currently, bioceramic materials are the mainstream bone repair materials, but common HA and TCP can only be applied to non-load-bearing bones of the human body and have low mechanical strength, which greatly limits the application range of the scaffold. The ZrO2-toughened Al2O3 composite ceramic (ZTA) used in this scaffold is a highly promising bioceramic material for orthopedic load-bearing implants. The ZTA bioceramic exhibits excellent mechanical properties and bioactivity, with a relative density, Vickers hardness, and fracture toughness of up to 99.09%, 16.66GPa, and 6.88MPa·m, respectively. 1 / 2 In addition, bone marrow mesenchymal stem cells exhibit strong adhesion and proliferation capabilities on the surface of the ZTA ceramic, making it well suited for various bone repair scenarios. Ca2MgSi2O7 bioceramic material not only has good osteoinductive properties, but also has a melting point of 1450°C, which is close to the ZTA sintering temperature range (1450-1600°C). It can be used as a sintering aid to reduce the sintering temperature of ZTA.

[0051] ④ Selection of photothermal materials

[0052] During the application process, the scaffold is loaded with MXene photothermal material, which has good photothermal performance, biocompatibility and osteoinduction properties. Ultra-thin MXene nanosheets, as a new type of transition metal carbide / nitride / carbonitride, enrich the 2D material system with large specific surface area and adjustable physical and chemical properties. In this system, 2DTi3C2T X MXenes have been shown to exhibit excellent biocompatibility and ideal photothermal conversion efficiency in the near-infrared (NIR) biological window. In particular, under the combined action of water and oxygen, Ti3C2 degrades to release a Ti-based phase, which is expected to promote new bone growth. Unlike carbon nanomaterials, transition metal sulfides, and oxides, MXene nanosheets possess excellent biocompatibility and good degradation properties, and their degradation products can accelerate bone tissue repair. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 Models with different porosities obtained by controlling the k value and thickening thickness.

[0054] Figure 2 Print the process diagram. DETAILED DESCRIPTION

[0055] The printing equipment in the following examples are all from Shenzhen Mofang New Materials Technology Co., Ltd. S240 large-format, high-precision ceramic 3D printer.

[0056] Example 1

[0057] Design of photothermal bone tumor scaffold model:

[0058] First, a plane model is formed by the basic function equation of the G-type minimal surface, and then the plane is thickened to obtain a photothermal bone tumor scaffold model. The basic function equation is F(x,y,z)=cos(x)*sin(y)+cos(y)*sin(z)+cos(z)*sin(x)+k, where k is =0.5, the thickness of the thickening treatment is 13.1mm, and the designed photothermal bone tumor scaffold model with a porosity of 80% is obtained.

[0059] Composition of ceramic slurry:

[0060] The photosensitive raw materials are prepared, calculated by mass percentage: Solsperse 41000 3.63%, 8810 0.51%, Rad2550 0.51%, TEGOfoamexN 0.51%, trimethylolpropane triacrylate (TMPTA) 28.31%, hexanediol diacrylate (HDDA) 37.75%, 2-hydroxyethyl acrylate (HEA) 23.59%, polyethylene glycol (PEG 200) 4.72%, and 2,4,6-diphenylphosphine oxide (TPO) 0.47%.

[0061] The ceramic powder is 100 g, the mass ratio of ZrO2 powder to Al2O3 powder is 1:3, the mass fraction of Ca2MgSi2O7 powder in the ceramic powder is 1.25%, and the added amount of 0.8 μm PMMA powder is 10% of the total mass of the ceramic powder and PMMA powder.

[0062] The solid content of the ceramic slurry is 45 vol%

[0063] Preparation of ceramic slurry:

[0064] Ceramic powder and photosensitive raw materials were mixed under vacuum conditions. The mixing process was first at 800 rpm for 30 seconds, then at 1800 rpm for 3 minutes, and finally at 800 rpm for 30 seconds. After the mixing was completed, a ceramic slurry with a viscosity of 0.98 Pa·s and a solid content of 45 vol% was obtained. The ceramic slurry was then poured into the material tank. After the model was imported into the printer, the temperature was 13.31 mW / cm 2 The photocuring was performed under the conditions of exposure power density, 1.4s exposure time, 30μm slice thickness, and 50°C.

[0065] After the secondary curing of the ZTA ceramic green body formed by photocuring, the exposure power density during the secondary curing was 13.31mW / cm 2 , time is 40s.

[0066] The scaffold was placed in a vacuum muffle furnace for debinding, and the temperature was gradually increased from 0°C to 600°C. The sintering process used a temperature increase rate of 1°C / min to 200°C, and then a temperature increase rate of 5°C / min to 1500°C, which was maintained for 1 hour. After that, the scaffold was cooled to room temperature in the furnace to obtain a photothermal bone tumor scaffold.

[0067] The scaffold has a porosity of 80%, with micropore porosity increasing by 1.51%. The two sets of pore diameters are 760μm and 660μm, respectively, with a wall thickness of 13.1mm. The scaffold's compressive strength and elastic modulus are 246.12MPa and 2.745GPa, respectively.

[0068] Application of photothermal bone tumor stents

[0069] The MXene photothermal material and PCL / doxorubicin (DOX) were dissolved in the organic solvent dichloromethane (CH2Cl2) to obtain MXene / CH2Cl2 solutions and PCL / DOX / CH2Cl2 solutions, respectively. The concentration of MXene was 1mg / ml, the concentration of DOX was 0.5mg / ml, and the concentration of PCL was approximately 10mg / ml. Finally, 0.5ml of MXene / CH2Cl2 solution and 0.5ml of PCL / DOX / CH2Cl2 solution were sequentially filled into the pores of the biomimetic scaffold. The scaffold was placed in deionized water and irradiated with NIR (808nm, 0.2W) at room temperature. After 15 days, the total DOX release was measured to be 26%.

[0070] Example 2

[0071] Design of photothermal bone tumor scaffold model:

[0072] First, a plane model is formed by the basic function equation of the G-type minimal surface, and then the plane is thickened to obtain a photothermal bone tumor scaffold model. The basic function equation is F(x,y,z)=cos(x)*sin(y)+cos(y)*sin(z)+cos(z)*sin(x)+k, where k is =0.5, the thickness of the thickening treatment is 19.9mm, and a photothermal bone tumor scaffold model with a porosity of 70% is designed.

[0073] Composition of ceramic slurry:

[0074] The photosensitive raw materials are prepared, calculated by mass percentage: Solsperse 41000 3.63%, 8810 0.51%, Rad2550 0.51%, TEGOfoamexN 0.51%, trimethylolpropane triacrylate (TMPTA) 28.31%, hexanediol diacrylate (HDDA) 37.75%, 2-hydroxyethyl acrylate (HEA) 23.59%, polyethylene glycol (PEG 200) 4.72%, and 2,4,6-diphenylphosphine oxide (TPO) 0.47%.

[0075] The ceramic powder is 100 g, the mass ratio of ZrO2 powder to Al2O3 powder is 1:3, the mass fraction of Ca2MgSi2O7 powder in the ceramic powder is 5%, and the added amount of 0.8 μm PMMA powder is 20% of the total mass of the ceramic powder and PMMA powder.

[0076] The solid content of the ceramic slurry is 45 vol%.

[0077] Preparation of ceramic slurry:

[0078] Ceramic powder and photosensitive raw materials were mixed under vacuum conditions. The mixing process was first at 800 rpm for 30 seconds, then at 1800 rpm for 3 minutes, and finally at 800 rpm for 30 seconds. After the mixing was completed, a ceramic slurry with a viscosity of 0.56 Pa·s and a solid content of 45 vol% was obtained. The ceramic slurry was then poured into the material tank. After the model was imported into the printer, the temperature was 13.31 mW / cm 2 The photocuring was performed under the conditions of exposure power density, 1.4s exposure time, 30μm slice thickness, and 50°C.

[0079] After the secondary curing of the ZTA ceramic green body formed by photocuring, the exposure power density during the secondary curing was 13.31mW / cm 2 , time is 40s.

[0080] The scaffold was placed in a vacuum muffle furnace for debinding, and the temperature was gradually increased from 0°C to 600°C. The sintering process used a temperature increase rate of 1°C / min to 200°C, and then a temperature increase rate of 5°C / min to 1500°C, which was maintained for 1 hour. After that, the scaffold was cooled to room temperature in the furnace to obtain a photothermal bone tumor scaffold.

[0081] The scaffold has a porosity of 70%, with micropore porosity increasing by 2.21%. The two sets of pore diameters are 660μm and 640μm, respectively, and the wall thickness is 19.9mm. The scaffold's compressive strength and elastic modulus are 215.98MPa and 2.476GPa, respectively.

[0082] Application of photothermal bone tumor stents

[0083] The MXene photothermal material and PCL / doxorubicin (DOX) were dissolved in the organic solvent dichloromethane (CH2Cl2) to obtain MXene / CH2Cl2 solutions and PCL / DOX / CH2Cl2 solutions, respectively. The MXene concentration was 1mg / ml, the DOX concentration was 0.5mg / ml, and the PCL concentration was approximately 10mg / ml. Finally, 0.5ml of the MXene / CH2Cl2 solution and 0.5ml of the PCL / DOX / CH2Cl2 solution were sequentially filled into the pores of the biomimetic scaffold. The scaffold was placed in deionized water and irradiated with NIR (808nm, 0.6W) at room temperature. After 15 days, the total DOX release was measured to be 65%.

[0084] Example 3

[0085] Design of photothermal bone tumor scaffold model:

[0086] First, a plane model is formed by the basic function equation of the G-type minimal surface, and then the plane is thickened to obtain a photothermal bone tumor scaffold model. The basic function equation is F(x,y,z)=cos(x)*sin(y)+cos(y)*sin(z)+cos(z)*sin(x)+k, where k is =0.5, the thickness of the thickening treatment is 26.9mm, and the designed photothermal bone tumor scaffold model with a porosity of 60% is obtained.

[0087] Composition of ceramic slurry:

[0088] The photosensitive raw materials are prepared, calculated by mass percentage: Solsperse 41000 3.63%, 8810 0.51%, Rad2550 0.51%, TEGOfoamexN 0.51%, trimethylolpropane triacrylate (TMPTA) 28.31%, hexanediol diacrylate (HDDA) 37.75%, 2-hydroxyethyl acrylate (HEA) 23.59%, polyethylene glycol (PEG 200) 4.72%, and 2,4,6-diphenylphosphine oxide (TPO) 0.47%.

[0089] The ceramic powder is 100 g, the mass ratio of ZrO2 powder to Al2O3 powder is 1:3, the mass fraction of Ca2MgSi2O7 powder in the ceramic powder is 10%, and the added amount of 0.8 μm PMMA powder is 30% of the total mass of the ceramic powder and PMMA powder.

[0090] The solid content of the ceramic slurry is 45 vol%.

[0091] Preparation of ceramic slurry:

[0092] Ceramic powder and photosensitive raw materials were mixed under vacuum conditions. The mixing process was first at 800 rpm for 30 seconds, then at 1800 rpm for 3 minutes, and finally at 800 rpm for 30 seconds. After the mixing was completed, a ceramic slurry with a viscosity of 0.278 Pa·s and a solid content of 45 vol% was obtained. The ceramic slurry was then poured into the material tank. After the model was imported into the printer, the temperature was 13.31 mW / cm 2 The photocuring was performed under the conditions of exposure power density, 1.4s exposure time, 30μm slice thickness, and 50°C.

[0093] After the secondary curing of the ZTA ceramic green body formed by photocuring, the exposure power density during the secondary curing was 13.31mW / cm 2 , time is 40s.

[0094] The scaffold was placed in a vacuum muffle furnace for debinding, and the temperature was gradually increased from 0°C to 600°C. The sintering process used a temperature increase rate of 1°C / min to 200°C, and then a temperature increase rate of 5°C / min to 1500°C, which was maintained for 1 hour. After that, the scaffold was cooled to room temperature in the furnace to obtain a photothermal bone tumor scaffold.

[0095] The scaffold porosity is 60%, the micropore porosity increases by 2.96%, the two sets of pore diameters are 650μm and 560μm respectively, and the wall thickness is 26.9mm. The compressive strength and elastic modulus of the bracket are 194.38MPa and 2.248GPa respectively.

[0096] Application of photothermal bone tumor stents

[0097] The MXene photothermal material and PCL / doxorubicin (DOX) were dissolved in the organic solvent dichloromethane (CH2Cl2) to obtain MXene / CH2Cl2 solutions and PCL / DOX / CH2Cl2 solutions, respectively. The MXene concentration was 1mg / ml, the DOX concentration was 0.5mg / ml, and the PCL concentration was approximately 10mg / ml. Finally, 0.5ml of the MXene / CH2Cl2 solution and 0.5ml of the PCL / DOX / CH2Cl2 solution were sequentially filled into the pores of the biomimetic scaffold. The scaffold was placed in deionized water and irradiated with NIR (808nm, 1W) at room temperature. After 15 days, the total DOX release was measured to be 80%.

[0098] Comparative Example 1:

[0099] Other conditions are the same as those in Example 1, except that the k value in the basic function equation is set to 1.5. Nodes appear in one set of holes, which are intermittently connected and cause faults in the model.

[0100] Comparative Example 2

[0101] Other conditions were the same as those in Example 1, except that the exposure power density was set to 4.2 mW / cm 2 This makes it difficult for the cured layers to bond firmly together, and the curing platform cannot pull the complete model off the film, resulting in a successful print.

[0102] Comparative Example 3

[0103] Other conditions were the same as those in Example 1, except that the PMMA powder particle size was changed to 10 μm, which resulted in the micropores formed on the scaffold being too large, and the photothermal material Mxenes leaked out.

[0104] Comparative Example 4

[0105] Other conditions were the same as those in Example 1, except that the sintering temperature was set to 1650° C., which was close to the melting point of ZTA, causing the model to partially melt on the platform during sintering.

[0106] Comparative Example 5

[0107] All other conditions were identical to those in Example 1, except that the mass fraction of Ca₂MgSi₂Oₐ in the ceramic powder was 11.25%. After one day of stabilization, the slurry had a sedimentation rate of 5%. Furthermore, the number of micropores in the scaffold increased, and the scaffold's compressive strength and elastic modulus were 191.65 MPa and 2.19 GPa, respectively.

Claims

1. A photothermal bone tumor scaffold with controlled drug release, characterized by: The photothermal bone tumor stent has two sets of curved independent communication channels, wherein the outer channel is open and connected, and the inner channel is closed and connected; the material of the photothermal bone tumor stent is Ca2MgSi2O7 / ZTA composite ceramic material; The structure of the photothermal bone tumor stent is obtained by dividing the space into two sets of curved independent connecting channels by a plane formed by the basic function equation of the G-type minimal surface, and then the plane is thickened. The basic function equation is F(x, y, z) = cos(x)*sin(y) + cos(y)*sin(z) + cos(z)*sin(x) + k, where k is -1.35 to 1.35, and the thickness of the thickening treatment is 10 to 60 mm.

2. The photothermal bone tumor scaffold with controlled drug release according to claim 1, characterized in that: The porosity of the photothermal bone tumor scaffold is 40% to 90%, the pore size of the photothermal bone tumor scaffold is 0.1 to 1.00 mm, and the wall thickness of the independent communicating channels is 10 to 60 mm.

3. A photothermal bone tumor scaffold with controlled drug release according to claim 1 or 2, characterized in that: In the photothermal bone tumor scaffold, the mass fraction of Ca2MgSi2O7 is 1.25-10%.

4. The method for preparing a photothermal bone tumor scaffold with controlled drug release according to any one of claims 1 to 3, characterized in that: Ceramic powder, pore-forming agent powder, and photosensitive raw material are prepared according to the designed proportion, and the mixture is obtained into ceramic slurry. The ceramic slurry is added into a photocuring printing device, and photocuring printing is performed based on the photothermal bone tumor stent model to obtain a ceramic blank. The ceramic blank is subjected to secondary curing to obtain a ceramic green body. The ceramic green body is degreased and sintered to obtain a photothermal bone tumor stent. The ceramic powder is composed of ZrO2 powder, Al2O3 powder, and Ca2MgSi2O7 powder.

5. The method for preparing a photothermal bone tumor scaffold with controlled drug release according to claim 4, characterized in that: The particle sizes of the ZrO2 powder, Al2O3 powder, and Ca2MgSi2O7 powder are submicron-sized. In the ceramic powder, the mass fraction of Ca2MgSi2O7 is 1.25% to 10%, and the mass ratio of ZrO2 powder to Al2O3 powder is 1:3 to 6. The pore-forming agent in the pore-forming agent powder is selected from PMMA, the particle size of the pore-forming agent powder is 0.1-5 μm, and the amount of the pore-forming agent powder added is 5-30% of the total mass of the ceramic powder and the pore-forming agent powder.

6. The method for preparing a photothermal bone tumor scaffold with controlled drug release according to claim 4, characterized in that: The photosensitive raw materials include, by mass percentage: Solsperse 41000 2-6%, Sago-8810 0.1-2%, Rad2550 0.1-2%, TEGO foamex N 0.1-2%; PEG 200 1-10%, TPO 0.1-2%; TMPTA 20-40%, HDDA 10-50%, HEA 10-30%.

7. The method for preparing a photothermal bone tumor scaffold according to claim 4, characterized in that: The mixing is carried out under vacuum conditions, and the mixing process is first mixing at 800-1500 rpm for 30 seconds to 2 minutes, then mixing at 1600-2200 rpm for 3-5 minutes, and finally mixing at 800-1000 rpm for 30 seconds to 2 minutes; the solid phase content in the ceramic slurry is 40-55 vol%.

8. The method for preparing a photothermal bone tumor scaffold with controlled drug release according to claim 4, characterized in that: The process of obtaining the photothermal bone tumor stent model is as follows: first, a plane model is formed by using the basic function equation of the G-type minimal surface, and then the plane is thickened to obtain the photothermal bone tumor stent model. The basic function equation is F(x, y, z) = cos(x)*sin(y) + cos(y)*sin(z) + cos(z)*sin(x) + k, where k is -1.35 to 1.35, and the thickness of the thickening process is 10 to 60 mm. The parameters of the light-curing printing are: exposure power density is 10-15mW / cm 2 , exposure time is 0.5-2s, slice thickness is 10-50μm, temperature is 30-80℃, The exposure power density during the secondary curing is 10-15 mW / cm 2 , the secondary curing time is 30s-60s.

9. The method for preparing a photothermal bone tumor scaffold with controlled drug release according to claim 4, characterized in that: The degreasing is carried out in a vacuum environment, the degreasing temperature is 400-600°C, and the degreasing time is 2500-3000min; The sintering process is to first heat the material to 400-500°C at a heating rate of 0.5-1°C / min, keep the temperature for 2-6 hours, then heat the material to 1450-1600°C at a heating rate of 5-10°C / min, keep the temperature for 1-3 hours, and then cool the material to room temperature.

10. Use of a photothermal bone tumor scaffold with controlled drug release according to any one of claims 1 to 3, characterized in that: The photothermal bone tumor scaffold is used to prepare bone tumor drugs.

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