Method for the production of ceramic / polymer continuous gradient porous scaffolds

Abstract

The application claims a preparation method of a ceramic / polymer continuous gradient porous scaffold, and belongs to the technical field of biological tissue engineering bone scaffold. The porous scaffold structure adopts a three-period minimal surface (TPMS) design, and the scaffold structure and volume fraction are controllable. The continuous gradient material adopts a mixed slurry of different volume fractions of hydroxyapatite powder and photosensitive PLA resin as the material, and a gradient polylactic acid layer containing 0% to 30% of nano-hydroxyapatite is sequentially arranged from inside to outside. The high volume fraction of HA / PLA on the outside promotes cell adhesion and improves the bone ingrowth ability. The pure PLA scaffold is prepared by a 3D printing stereolithography forming method, the scaffold surface is activated by using a plasma cleaning process, the slurry with the ceramic material composition on the outer layer is attached to the scaffold surface by using a solution immersion method, the excess slurry in the pores is removed by using a centrifugal device, and ultraviolet light (wavelength range 360-410 nm) is used for irradiation and curing. The application uses a continuous gradient to overcome the shortcoming of the sharp change of the performance of the traditional composite material at the material interface, which leads to stratification.

Description

Technical Field

[0001] This invention relates to the field of biological bone scaffolds, particularly bone scaffolds with material gradients, specifically a method for fabricating porous scaffolds using ceramic / polymer functionally graded materials. Background Technology

[0002] For bone tissue engineering, scaffolds, in addition to good biocompatibility and sufficient mechanical strength, should also possess a porous, interconnected structure to facilitate cell adhesion, proliferation, and tissue growth, controllable geometric dimensions, good biodegradability, and ease of customization. These properties of the scaffold largely depend on its matrix material and preparation method. Scaffolds prepared using different matrix materials and methods exhibit different structural characteristics, directly affecting biological properties such as cell adhesion, proliferation, and differentiation.

[0003] Currently, research on continuous gradient material scaffold preparation methods mainly includes vapor deposition, thermal spraying, laser additive manufacturing, powder metallurgy, and centrifugal casting. The main materials are metal / ceramic composite materials, which have complex elements, and the process forms intermetallic compounds. The large-scale formation of intermetallic compounds seriously affects the bonding strength of the materials. At the same time, due to the limitations of the manufacturing methods, the gradient of the scaffold only exists in radial variation and it is impossible to form complex pore structures.

[0004] Biopolymers such as polylactic acid (PLA) and polycaprolactone (PCL) possess excellent biocompatibility and biodegradability. PLA is FDA-approved for use in medical surgical sutures, injectable capsules, microspheres, and implants. The final metabolic products of PLA in vivo are carbon dioxide and water, while the intermediate product, lactic acid, is also a product of normal glucose metabolism. PLA has good molding properties and can be made into various structures such as films, porous scaffolds, or tubular scaffolds. These structures all exhibit good biocompatibility and can guide osteogenesis when used as bone repair materials. When combined with other materials, it can serve as a load-bearing component in composite materials. However, it also has several drawbacks. Firstly, it has poor hydrophilicity and weak cell adhesion; secondly, it can easily cause aseptic inflammation, as the degradation products of PLA are acidic and can cause local pH changes. Ceramic materials such as hydroxyapatite (HA), tricalcium phosphate, and bioglass are the main inorganic salt components in bone tissue, possessing high biocompatibility and osteoinductive properties, making them the most ideal bone repair materials. However, hydroxyapatite has low fracture toughness (<1.0 MPa·m1 / 2) and flexural strength (50–100 MPa), and a single HA scaffold cannot meet the mechanical requirements of human bone scaffolds. Developing implantable composite materials that combine biopolymers and ceramics to achieve both good mechanical properties and bioactivity is a current focus of bone tissue engineering research. This invention utilizes 3D printing photopolymerization technology and ultraviolet light curing to prepare a continuous gradient material scaffold with hydrophilicity, multiphase gradient changes, controllable pore connectivity, and excellent mechanical properties.

[0005] CN107311654A discloses a method for preparing a zirconia-based nano-hydroxyapatite gradient functional material. The method includes the following steps: preparation of gradient functional material powder; preparation of green specimens; and sintering of the specimens. The material of this invention fully utilizes the advantages of n-HA's good biocompatibility and biological activity, as well as the high mechanical strength of the bioinert material ZrO2, and has strong practical and theoretical significance.

[0006] 1. This patent still uses the traditional high-temperature sintering method to prepare continuous gradient materials. Zirconia powder typically contains impurities such as iron, cadmium, and nickel, which form oxides during the sintering process. This patent uses photocuring to prepare the gradient layer, thus avoiding the generation of various oxide impurities.

[0007] 2. The thermal expansion coefficients of HA and zirconium oxide differ significantly, which can cause cracks to form inside the scaffold during sintering, affecting its usability. In this patent, the exothermic cross-linking of molecular bonds during curing is minimal and negligible.

[0008] 3. The mold used in this patent is a simple cylindrical steel mold, and the scaffold does not form a connected porous structure, making it impossible to form a complex scaffold, and its porosity and volume fraction are uncontrollable. This patent uses a combination of methods to prepare a porous scaffold with continuous gradient materials, which not only allows for personalized and rapid prototyping for lesions, but also allows for control of porosity, scaffold structure, and volume fraction, enabling rapid and low-cost adjustment of multiple scaffold parameters. Summary of the Invention

[0009] This invention aims to solve the problems of the prior art mentioned above. A method for fabricating a ceramic / polymer continuous gradient porous scaffold is proposed. The technical solution of this invention is as follows:

[0010] A method for fabricating a ceramic / polymer continuous gradient porous scaffold includes the following steps:

[0011] PLA photosensitive resin preparation steps: modified polylactic acid raw material preparation steps: gradient porous structure design steps: scaffold preparation steps: and gradient layer fabrication steps.

[0012] Furthermore, the PLA photosensitive resin preparation steps specifically include:

[0013] Step 1: In a reaction flask, add the following amounts of the formula: methacrylic anhydride modified 1,6-hexanediol carboxyl-terminated polylactic acid condensate, methacrylic anhydride modified glycerol carboxyl-terminated polylactic acid condensate, and methacrylic anhydride modified polyethylene glycol (600) carboxyl-terminated polylactic acid condensate to obtain a primary mixture.

[0014] Step 2: Add the free radical initiator (TPO) and ultraviolet absorber to the primary mixture in sequence, then heat to 40℃-50℃, turn on the mechanical stirrer to 500 rpm-800 rpm, stir at a constant speed for 1 hour to obtain a homogeneous mixed liquid, store it in the dark, and it is PLA photosensitive resin.

[0015] Furthermore, the raw materials for preparing the PLA photosensitive resin are as follows:

[0016] Raw material 1: The methacrylic anhydride-modified 1,6-hexanediol-terminated carboxyl polylactic acid condensate requires L-lactic acid, 1,6-hexanediol, stannous chloride, p-hydroxyanisole, and methacrylic anhydride with a mass concentration of 88% in a molar ratio of (2-8):1:(0.01-0.1):(0.01-0.1):(1.5-2.0).

[0017] Raw material 2: The methacrylic anhydride-modified glycerol-terminated polylactic acid condensate requires L-lactic acid, glycerol, stannous chloride, p-hydroxyanisole, and methacrylic anhydride with a mass concentration of 88% in a molar ratio of (1-6):1:(0.01-0.1):(0.01-0.1):(1.5-2.0).

[0018] Raw material 3: The methacrylic anhydride modified polyethylene glycol (600) carboxyl-terminated polylactic acid condensate requires a molar ratio of (3-9):1:(0.01-0.1):(0.01-0.1):(1.5-2.0) with an L-lactic acid mass concentration of 88%, polyethylene glycol (600), stannous chloride, p-hydroxyanisole, and methacrylic anhydride as raw materials.

[0019] Furthermore, the preparation steps of the modified polylactic acid raw material are as follows: All three raw materials are prepared according to this process. An 88% L-lactic acid aqueous solution is added to a 250 mL three-necked flask, magnetically stirred and heated. The temperature is gradually increased to 120°C under normal pressure, and dehydrated for 2 hours. Then, the second solution and the catalyst stannous chloride are added, and the mixture is stirred magnetically until homogeneous. Then, the mixture is further prepared at 2×10⁻⁶ mm². 4 The product was dehydrated at 130°C for 2 hours under Pa, followed by dehydration at 150°C for 1 hour under 1000 Pa. It was then cooled to 100°C under vacuum, and the polymerization inhibitors p-hydroxyanisole and methacrylic anhydride were added. The temperature was then raised to 120°C and reacted at atmospheric pressure for 3 hours. Excess methacrylic anhydride was then removed under reduced pressure at 120°C, and the product was cooled to room temperature to obtain three different products.

[0020] Furthermore, the design steps of the gradient porous structure are as follows: using MATLAB to process the three-period minimum surface function to generate a porous model of a unit cell structure, and using Diamond, Gyroid, and I-WP structures, which have good comprehensive mechanical properties and facilitate liquid outflow, for design. and These represent the functions of the Diamond, Gyroid, and I-WP structures on the coordinate axes, respectively.

[0021] t is a constant, used to control the relative density (ρ) of each lattice structure. * The parameters of ) can be assigned different values ​​to generate different sizes of solid regions, resulting in porous structures with different relative densities.

[0022] The unit cell configuration of a gradient porous scaffold is generated. A suitable unit cell structure is selected according to the design requirements. The unit cell configuration of the porous scaffold can be generated using a function. After selecting the unit cell configuration, the function can be modified and controlled to generate porous structures with varying volume fractions. The relative density of the structure can be adjusted by adjusting the value of t in the formula for the lattice structure. The gradient porous scaffold with G, D, and I unit cell configurations can be generated using a function.

[0023] Furthermore, the function formulas for the three designed structures are as follows:

[0024] and These represent the functions of the Diamond, Gyroid, and I-WP structures on the coordinate axes, respectively.

[0025]

[0026]

[0027]

[0028] Parameter t and relative density ρ * The specific relationship between them is as follows:

[0029]

[0030]

[0031]

[0032] Furthermore, the specific steps for preparing the stent are as follows:

[0033] The pure polylactic acid core inside the support was printed using a formulated photocurable PLA. The final model generated by MSlattice was imported into the 3D printer, the model infill rate was set to 100%, the initial layer thickness was set to 0.05mm, the exposure time was 3.5s to 7.5s, and the initial exposure duration was 35s to 45s. A base plate and a bottom support were added. After printing, the sample was cleaned with methanol and cured a second time to complete the fabrication of the core.

[0034] The outer gradient layer solution is a mixture of hydroxyapatite powder with an average particle size of 10μm to 20μm and photosensitive resin. The mass fraction of hydroxyapatite powder varies in each layer. The rod-shaped structure in the scaffold is extracted, and the gradient layer is attached in this way. The multi-layered material is photocured to encapsulate the inner core, and the material composition changes layer by layer from the inside out.

[0035] Furthermore, the gradient layer preparation method is as follows:

[0036] (1) Impregnation with HA / PLA solution; (2) Centrifuge drying; (3) UV curing; (4) Interlayer surface activation treatment;

[0037] Furthermore, the specific steps of the interlayer surface activation treatment (4) are as follows:

[0038] ① Pretreatment: Before activation, large particles and other impurities on the surface of the support are removed to ensure the plasma can effectively act on the surface. ② Processing device: The support to be processed is placed in the plasma processing equipment, and then the processing chamber is sealed and evacuated to a low pressure. ③ Plasma injection: An arc discharge is generated through the electrodes to convert inert gases (such as oxygen, argon, nitrogen, etc.) into plasma in an inert gas converter and inject it into the processing chamber. ④ Discharge treatment: After the plasma is discharged using a high-voltage excitation power supply, high-temperature, high-pressure, and high-energy plasma is generated. The organic and inorganic substances on the surface of the support are activated through plasma reactants and chemical reactions. ⑤ Gas flow exhaust: After plasma activation, the plasma and reaction products in the processing chamber are extracted using a piston to blow away all the gas. ⑥ Object disassembly: The activated support is disassembled from the processing chamber and the surface is cleaned again. ⑦ Inspection: The cleaned object is inspected to ensure that its surface is completely clean and free of residue.

[0039] Furthermore, the gradient layer preparation step specifically includes:

[0040] (1) Preparation of the first layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 5:95 using an electronic scale. Add the hydroxyapatite powder to the photosensitive resin solution and heat it in a constant temperature oil bath at 100°C. Stir it for 60 seconds at 500 rpm using a heat-collecting magnetic stirrer until it is uniform. Immerse S1 in the slurry to ensure that the rods inside the pore structure are wrapped by the slurry. Place the support in a centrifuge bucket and centrifuge to remove excess liquid from the surface, leaving only the slurry that is uniformly attached to the surface of the support. Place the support in a curing machine and cure the HA / PLA mixed slurry on the surface to form the first layer support S1 with a hydroxyapatite mass fraction of 5%.

[0041] (2) Preparation of the second layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 10:90 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a second scaffold S2 with a surface containing 10% hydroxyapatite by mass.

[0042] (3) Preparation of the third layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 15:85 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a third scaffold S3 with a surface containing 15% hydroxyapatite by mass.

[0043] (4) Preparation of the fourth layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 20:80 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a fourth scaffold S4 with a surface containing 20% ​​hydroxyapatite by mass.

[0044] (5) Preparation of the fifth layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 25:75 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a fifth layer scaffold S5 with a hydroxyapatite mass fraction of 25% on the surface.

[0045] (4) Preparation of the sixth layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 30:70 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a sixth layer scaffold S6 with a surface containing 30% hydroxyapatite by mass.

[0046] The advantages and beneficial effects of this invention are as follows:

[0047] The innovations of this invention are: ① The ceramic / polymer composite material has the properties of both materials. Compared with a single ceramic scaffold, this scaffold has better mechanical properties and complex molding capabilities; compared with a single polymer scaffold, this scaffold has better biocompatibility, hydrophilicity, and cell adhesion capabilities.

[0048] ② The continuous gradient design makes the scaffold different from directly bonding ceramic materials to the surface of the polymer scaffold. Although the inner polymer core provides mechanical properties and the outer ceramic improves biocompatibility, the large difference in mechanical properties can cause delamination. The gradient layer uses the same material and the gradual transition can avoid delamination.

[0049] ③ Existing gradient material preparation methods all involve layer-by-layer sintering or layer-by-layer deposition, resulting in scaffolds without complex structures (mostly rough-surfaced cylindrical scaffolds), and the internal pore structure cannot guarantee connectivity (currently, there is no way to prepare scaffolds by combining gradient materials with a three-period minimum surface design). However, the preparation method designed in this patent can effectively combine the three-period minimum surface and gradient materials, preparing continuous gradient materials that can be complexly shaped. The dual design of materials and structure improves the mechanical properties, pore connectivity, bone ingrowth ability, and bioactivity of the scaffold.

[0050] ④ Compared with the current methods of manufacturing gradient materials, the preparation method uses a photocurable solution to form a gradient layer, which results in gradient changes in all directions of the support rod structure, rather than a gradient change only in the horizontal or vertical direction.

[0051] ⑤ Process aspects: The oil bath heating process is used to solve the problem that the high ceramic mass fraction resin is too viscous and has poor fluidity, which can easily cause pore blockage; the spin drying process is used to solve the problem that excessive impregnation solution remains inside the pores and causes blockage; the plasma surface activation technology is used to solve the problem that the molecular chains of the previous layer may not be tightly bonded to the next layer after the curing is completed.

[0052] Furthermore, the advantages of this invention are:

[0053] 1. PLA scaffolds are easy to process, possess excellent mechanical properties, and have high impact strength. Ceramic scaffolds, on the other hand, are difficult to precisely control in shape during printing and exhibit brittleness under tension and shear, making them unsuitable for load-bearing environments in bone tissue. The scaffold is constructed entirely of PLA loaded with HA. The mechanical strength of polylactic acid can be enhanced by incorporating bioceramics, thereby increasing compressive strength and mineralization. Furthermore, PLA is easily processed and molded, enabling the printing of scaffolds with complex structures. This allows for precise control of the pore structure while ensuring sufficient mechanical strength.

[0054] 2. PLA lacks biological activity, and its hydrophobicity weakens cell adhesion, proliferation, and differentiation. The scaffold in this patent has the highest hydroxyapatite content on its surface. HA is bioabsorbable and bioactive, promoting osteogenic differentiation, exhibiting good biocompatibility and bone integration. Adding HA to the PLA matrix can improve cell adhesion, nutrient absorption, and promote cell activity.

[0055] 3: The scaffold is composed of a three-period minimal surface (TPMS) porous structure. Compared with traditional porous structures, the three-period minimal surface has better mechanical properties and higher permeability of the implant, which is conducive to the passage of fluid with low resistance. The TPMS structure plays a more significant role in promoting osteogenic differentiation of cells. The characteristic of the minimal surface with an average curvature of 0 also makes the whole structure relatively flat. The TPMS scaffold with a larger specific surface area and surface continuity greatly promotes cell adhesion and growth.

[0056] 4. The scaffold is fabricated using functionally graded materials (FGMs), which are composite materials with continuously varying compositions and structures. Compared to isotropic materials, the composition and structure of FGMs can be precisely designed. This patent uses a composite material with a gradient of HA concentration to fabricate the scaffold, thus avoiding delamination in multiphase scaffolds and poor adhesion between different materials.

[0057] 5. Additive manufacturing of conventional functionally graded materials (FJTs) is based on laser technology. This pre-powder-laying method limits the gradient to directions perpendicular to the powder layer, making variations in other directions extremely difficult. This patented method first uses stereolithography 3D printing to form a polymer scaffold, then uses ultraviolet light to cure the ceramic / polymer slurry, gradually increasing the ceramic content layer by layer. This results in a continuous material gradient, stronger composite material bonding, and a gradient change along the construction direction. The high-concentration ceramic particle-covered scaffold surface has a larger contact area with cells, facilitating cell adhesion and promoting tissue inward growth. Attached Figure Description

[0058] Figure 1This is a diagram of the preferred embodiment of the Diamond\Gyroid\I-WP scaffold single-cell structure provided by the present invention;

[0059] Figure 2 This is a structural diagram of a preferred embodiment of the Diamond\Gyroid\I-WP gradient porous scaffold provided by the present invention;

[0060] Figure 3 This is a flowchart illustrating the fabrication process of a preferred embodiment of the stent provided by the present invention;

[0061] Figure 4 This is a schematic diagram of the ceramic / polylactic acid material preparation process according to a preferred embodiment of the present invention;

[0062] Figure 5 This is a schematic diagram of a preferred embodiment of the present invention, showing the support being heated and immersed in HA / PLA solution;

[0063] Figure 6 This is a schematic diagram of a preferred embodiment of the bracket for centrifugal drying provided by the present invention;

[0064] Figure 7 This is a schematic diagram of a preferred embodiment of the UV-curing bracket provided by the present invention;

[0065] Figure 8 This is a schematic diagram of the plasma-activated surface treatment process according to a preferred embodiment of the present invention;

[0066] Figure 9 This is a schematic diagram of the gradient material of the I-WP support rod structure, a preferred embodiment of the present invention. Detailed Implementation

[0067] The technical solutions of the present invention will be clearly and thoroughly described below with reference to the accompanying drawings of the embodiments. The described embodiments are merely some embodiments of the present invention.

[0068] The technical solution of the present invention to solve the above-mentioned technical problems is:

[0069] This invention provides a functionally graded scaffold and its preparation method. This patent adopts a three-period minimal surface design for the scaffold, which effectively reduces stress concentration under load, improves the mechanical properties of the structure and increases fatigue life. On the other hand, the composite material can be complexly molded, and the high content of hydroxyapatite in the outer layer makes the scaffold biocompatible and has strong cell adhesion. At the same time, the radial and transverse gradients can meet the requirements of the complex mechanical environment in vivo, and the material has good bonding ability and is not prone to delamination.

[0070] This invention relates to a method for preparing a ceramic / polymer continuous gradient porous scaffold, belonging to the field of bone scaffold technology in bioengineering. The ceramic materials mainly include hydroxyapatite (HA), tricalcium phosphate (TCP), bioactive glass (BAG), or composites of the above ceramics; the polymer materials mainly include polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol (PEG), or copolymers of the above polymers. The porous scaffold structure employs a three-period minimal surface (TPMS) design, allowing for controllable scaffold structure and volume fraction. The continuous gradient material uses a mixture of hydroxyapatite powder and photosensitive PLA resin with different volume fractions as the material. From the inside out, a gradient polylactic acid layer containing 0% to 30% (e.g., 5%, 10%, 15%, 20%, 25%, 30%) nano-hydroxyapatite is set. The high volume fraction of HA / PLA on the outside promotes cell adhesion and improves bone ingrowth ability, while the pure PLA inside provides excellent mechanical properties. The pure PLA scaffold is prepared by 3D printing stereolithography. The scaffold surface is activated by plasma cleaning process. The outer layer of slurry with ceramic material components is attached to the scaffold surface by solution impregnation. Excess slurry in the pores is removed by centrifugation and cured by ultraviolet light (wavelength range 360-410nm). The bone scaffold not only possesses the excellent biocompatibility and osteogenic activity of ceramic materials, but also the excellent mechanical strength, toughness, and fatigue properties of polymer materials, and can slowly degrade in vivo. The scaffold composition gradually changes according to a predetermined pattern, overcoming the shortcomings of traditional composite materials where the properties change drastically at the material interface, leading to delamination. It improves the problems of easy delamination and insufficient interfacial bonding ability of multi-material scaffolds, and the heterogeneous material can better cope with the complex anisotropic mechanical environment in the human body.

[0071] Preferably, a method for fabricating a ceramic / polymer continuous gradient porous scaffold includes the following steps:

[0072] 1. Preparation of PLA photosensitive resin, the raw materials are shown in the table below:

[0073]

[0074]

[0075] Step 1: In a reaction flask, add the following amounts of the formulated methacrylic anhydride-modified 1,6-hexanediol carboxyl-terminated polylactic acid condensate, methacrylic anhydride-modified glycerol carboxyl-terminated polylactic acid condensate, and methacrylic anhydride-modified polyethylene glycol (600) carboxyl-terminated polylactic acid condensate in sequence to obtain a primary mixture.

[0076] Step 2: Add the free radical initiator (TPO) and ultraviolet absorber to the primary mixture in sequence, then heat to 40℃-50℃, turn on the mechanical stirrer to 500 rpm-800 rpm, stir at a constant speed for 1 hour to obtain a homogeneous mixed liquid, store it in the dark, and it is PLA photosensitive resin.

[0077] (1) Raw material one: The methacrylic anhydride modified 1,6-hexanediol carboxyl-terminated polylactic acid condensate requires L-lactic acid, 1,6-hexanediol, stannous chloride, p-hydroxyanisole and methacrylic anhydride with a mass concentration of 88% in the molar ratio of (2-8):1:(0.01-0.1):(0.01-0.1):(1.5-2.0) as raw materials.

[0078] (2) Raw material 2: The methacrylic anhydride modified glycerol carboxyl-terminated polylactic acid condensate requires L-lactic acid, glycerol, stannous chloride, p-hydroxyanisole and methacrylic anhydride with a mass concentration of 88% in the molar ratio of (1-6):1:(0.01-0.1):(0.01-0.1):(1.5-2.0).

[0079] (3) Raw material three: Among them, the molar ratio of L-lactic acid, polyethylene glycol (600), stannous chloride, p-hydroxyanisole and methacrylic anhydride modified polyethylene glycol (600) carboxyl-terminated polylactic acid condensate with a mass concentration of (3-9):1:(0.01-0.1):(0.01-0.1):(1.5-2.0) is required.

[0080] Preparation steps of modified polylactic acid raw materials: All three raw materials were prepared according to this procedure. An 88% (w / w) L-lactic acid aqueous solution was added to a 250 mL three-necked flask, magnetically stirred and heated. The temperature was gradually increased to 120 °C under normal pressure, and dehydrated for 2 hours. Then, the second solution and the catalyst stannous chloride were added, and the mixture was stirred magnetically until homogeneous. The mixture was then subjected to a 2×10⁻⁶ ppm reaction. 4 The product was dehydrated at 130°C for 2 hours under Pa, followed by dehydration at 150°C for 1 hour under 1000 Pa. It was then cooled to 100°C under vacuum, and the polymerization inhibitors p-hydroxyanisole and methacrylic anhydride were added. The temperature was then raised to 120°C and reacted at atmospheric pressure for 3 hours. Excess methacrylic anhydride was then removed under reduced pressure at 120°C, and the product was cooled to room temperature to obtain three different products.

[0081] 2. Design of Gradient Porous Structures: Using MATLAB to process three-period minimum surface functions, porous models of unit cell structures are generated. Diamond, Gyroid, and I-WP structures, which possess good comprehensive mechanical properties and facilitate liquid outflow, are selected for design. The function formulas for designing these three structures are as follows:

[0082]

[0083]

[0084]

[0085] in and These represent the functions of the Diamond, Gyroid, and I-WP structures on the coordinate axes, respectively. t is a constant, controlling the relative density (ρ) of each lattice structure. * The parameter t is used to generate different sizes of solid regions, resulting in porous structures with different relative densities.

[0086] The following formula is a relationship between parameter t and relative density ρ. * The relationship between them.

[0087]

[0088]

[0089]

[0090] Using functions, you can generate things like... Figure 1 The unit cell configuration of the gradient porous scaffold can be used to generate the unit cell configuration of the porous scaffold, which can be selected according to the design requirements, ensuring structural continuity, mechanical properties, and resistance to fatigue cracks.

[0091] After selecting the unit cell configuration, modifying the function can generate porous structures with varying volume fractions. Adjusting the value of 't' in the formula for the lattice structure can regulate the relative density of the structure. Figure 2 Diamond\Gyroid\I-WP gradient porous scaffold structure diagram, as shown Figure 2 Gradient porous scaffolds with G, D, I unit cell configurations generated using functions.

[0092] 3. Scaffold preparation and gradient layer fabrication method: The pure polylactic acid core inside the scaffold was printed using a prepared photocurable PLA. The final model generated by MSlattice was imported into the 3D printer, and the model infill rate was set to 100%. When slicing, the initial layer thickness was set to 0.05 mm, the exposure time was 3.5s to 7.5s, and the initial exposure duration was 35s to 45s. A base plate and a bottom support were added. After printing, the sample was cleaned with methanol and cured a second time to complete the fabrication of the core.

[0093] The outer gradient layer solution is a mixture of hydroxyapatite powder (within a range of 10 μm to 20 μm) and photosensitive resin, with a different mass fraction of hydroxyapatite powder in each layer. Figure 3 This is a flowchart of stent fabrication. Figure 3 This indicates a section of the rod-shaped structure within the support frame. Figure 4 A schematic diagram of the ceramic / polylactic acid (PLA) material preparation process, showing the attachment of gradient layers. Multiple layers of material are photocured to encapsulate the core, with the material composition changing layer by layer from the inside out. The gradient layer preparation method is as follows:

[0094] (1) Impregnation with HA / PLA solution

[0095] Figure 5 The diagram shows the process of heating and impregnating the scaffold with HA / PLA solution. Hydroxyapatite powder is added to the photosensitive resin solution and heated in a constant temperature oil bath at 100°C. The mixture is then stirred for 60 seconds at 300-500 rpm using a heat-collecting magnetic stirrer until homogeneous. The scaffold prepared in the previous step is then impregnated in the slurry to ensure that the internal connecting rod-like structures of the pore structure are completely encapsulated by the slurry.

[0096] (2) Centrifuge drying

[0097] Figure 6 This is a schematic diagram of a centrifugal drying rack. The rack is placed... Figure 6 Inside the centrifuge tank shown, centrifugation removes excess liquid from the surface, leaving only the HA / PLA mixed slurry uniformly attached to the surface of the support, while ensuring that the internal pore structure of the support is not blocked by liquid.

[0098] (3) Curing by ultraviolet light irradiation

[0099] Figure 7 This is a schematic diagram of a UV-curing support. The support is placed in a UV curing machine. The machine chassis rotates at a constant speed during curing to ensure uniform light exposure. At the same time, a small UV light source is placed inside the support to prevent the internal light from being blocked. Multiple light sources cure the newly impregnated HA / PLA mixed slurry on the surface of the support, forming a next gradient layer with a higher mass fraction of hydroxyapatite.

[0100] (4) Interlayer surface activation treatment

[0101] like Figure 8 The diagram shows a schematic of the plasma-activated surface treatment process. When the gradient layer is attached to the surface of the plasma-activated support, starting from the inner core, after each layer has cured, the surface of the new gradient layer undergoes plasma surface activation treatment. This decomposes and oxidizes the organic and inorganic substances on the surface, improving the material's adhesion, hydrophilicity, and bonding properties. The specific steps are as follows:

[0102] ① Pretreatment: Before activation treatment, large particles and other impurities on the surface of the support are removed to prevent the plasma from being unable to effectively act on the surface.

[0103] ② Processing equipment: Place the support to be processed in the plasma processing equipment, then seal the processing chamber and evacuate to a low pressure.

[0104] ③ Plasma injection: An electric arc discharge is generated through the electrodes, which converts inert gas (such as oxygen, argon, nitrogen, etc.) into plasma in the inert gas converter and injects it into the processing chamber.

[0105] ④ Discharge treatment: After the plasma is discharged by a high-voltage excitation power supply, high-temperature, high-pressure and high-energy plasma is generated, which activates the organic and inorganic matter on the surface of the support through plasma agents and chemical reactions.

[0106] ⑤ Exhaust gas flow: After plasma activation is completed, the plasma and reaction products in the processing chamber are extracted into the gas flow using a piston, and all the gas is blown away.

[0107] ⑥ Disassembling the object: The activated support is removed from the processing chamber and its surface is cleaned again.

[0108] ⑦ Inspection: Inspect the cleaned object to ensure that its surface is completely clean and free of residue.

[0109] 4. Gradient layer preparation:

[0110] (1) Preparation of the first layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 5:95 using an electronic scale. Add the hydroxyapatite powder to the photosensitive resin solution and heat it in a constant temperature oil bath at 100°C. Stir it for 60 seconds at 500 rpm using a heat-collecting magnetic stirrer until it is uniform. Immerse S1 in the slurry to ensure that the rods inside the pore structure are wrapped by the slurry. Place the support in a centrifuge bucket and centrifuge to remove excess liquid from the surface, leaving only the slurry that is uniformly attached to the surface of the support. Place the support in a curing machine and cure the HA / PLA mixed slurry on the surface to form the first layer support S1 with a hydroxyapatite mass fraction of 5%.

[0111] (2) Preparation of the second layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 10:90 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a second scaffold S2 with a surface containing 10% hydroxyapatite by mass.

[0112] (3) Preparation of the third layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 15:85 using an electronic scale, and repeat the preparation steps of layer S1: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a third scaffold S3 with a hydroxyapatite mass fraction of 15% on the surface.

[0113] (4) Preparation of the fourth layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 20:80 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a fourth scaffold S4 with a hydroxyapatite mass fraction of 20% on the surface.

[0114] (5) Preparation of the fifth layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 25:75 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a fifth layer scaffold S5 with a hydroxyapatite mass fraction of 25% on the surface.

[0115] (4) Preparation of the sixth layer: Weigh hydroxyapatite powder and PLA resin in a mass ratio of 30:70 using an electronic scale, and repeat the preparation steps of the S1 layer: impregnate the scaffold, centrifuge to remove excess slurry, and cure by ultraviolet light to form a sixth layer scaffold S6 with a surface containing 30% hydroxyapatite by mass.

[0116] like Figure 9 The diagram shows a gradient material arrangement for the I-WP support rod structure. Ultimately, taking I-WP as an example, the support forms a gradient from the inside out, as shown in the image. Figure 9 The material layers shown in the figure represent the gradient changes formed by the material on the support.

[0117] The ceramic / polymer continuous gradient porous scaffold prepared above can be applied to the clinical repair of bone defects. Figure 1 and Figure 2 The shape is only for illustration. Photocuring can produce scaffolds with multiple structures and shapes. When used for clinical repair, gradient scaffolds can be prepared in a personalized manner according to the specific defect location and shape of the patient. For example, CT scans can be performed on the defect to obtain the model structure. It is also necessary to combine some conventional technical means and equipment in the field of application to realize clinical application.

[0118] The systems, devices, modules, or units described in the above embodiments can be implemented by computer chips or entities, or by products with certain functions. A typical implementation device is a computer. Specifically, a computer can be, for example, a personal computer, laptop computer, cellular phone, camera phone, smartphone, personal digital assistant, media player, navigation device, email device, game console, tablet computer, wearable device, or any combination of these devices.

[0119] It should also be noted that the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0120] The above embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

Claims

1. A method for fabricating a ceramic / polymer continuous gradient porous scaffold, characterized in that, Includes the following steps: Preparation steps of modified polylactic acid raw materials; preparation steps of PLA photosensitive resin; design steps of gradient porous structure; scaffold preparation and gradient layer fabrication steps; The design steps for the gradient porous structure are as follows: MATLAB is used to process the three-period minimum surface function to generate a porous model of a unit cell structure. Diamond, Gyroid, and I-WP structures, which possess good comprehensive mechanical properties and facilitate liquid outflow, are used in the design. , and These represent the functions of the Diamond, Gyroid, and I-WP structures on the coordinate axes, respectively. As a control of the relative density of each lattice structure Parameters; parameters Different values ​​can generate different sizes of solid regions, resulting in porous structures with different relative densities; It is a constant; The unit cell configuration of the gradient porous scaffold is generated. A suitable unit cell structure is selected based on design requirements, and a function is used to generate the unit cell configuration of the porous scaffold. After selecting the unit cell configuration, the function is modified to generate porous structures with varying volume fractions. Adjusting the value of 't' in the formula for the lattice structure adjusts the relative density of the structure. Gradient porous scaffolds with G, D, and I unit cell configurations are generated using functions. The function formulas for the three designed structures are as follows: , and These represent the functions of the Diamond, Gyroid, and I-WP structures on the coordinate axes, respectively. ； parameter With relative density The specific relationship between them is as follows: ， ， ； The specific steps for preparing the stent are as follows: The pure polylactic acid core inside the support was printed using a formulated photocurable PLA resin. The final model generated by MSlattice was imported into the 3D printer, the model infill rate was set to 100%, the initial layer thickness was set to 0.05mm, the exposure time was 3.5s~7.5s, and the initial exposure duration was 35s~45s. A base plate and a bottom support were added. After printing, the sample was cleaned with methanol and cured a second time to complete the fabrication of the core. The outer gradient layer solution is a mixture of hydroxyapatite powder with an average particle size of 10μm~20μm and photosensitive resin. The mass fraction of hydroxyapatite powder in each layer is different. The rod-shaped structure in the scaffold is cut out and attached to the gradient layer. The multi-layer material is wrapped around the inner core by photocuring. The material composition changes from the inside to the outside. The PLA photosensitive resin preparation steps specifically include: Step 1: In a reaction flask, add methacrylic anhydride-modified 1,6-hexanediol carboxyl-terminated polylactic acid condensate, methacrylic anhydride-modified glycerol carboxyl-terminated polylactic acid condensate, and methacrylic anhydride-modified polyethylene glycol 600 carboxyl-terminated polylactic acid condensate in sequence to obtain a primary mixture. Step 2: Add free radical initiator TPO and UV absorber to the primary mixture in sequence, then heat to 40℃-50℃, turn on mechanical stirring to 500 rpm-800 rpm, stir at a constant speed for 1 hour to obtain a homogeneous liquid mixture, store it in the dark, which is PLA photosensitive resin. The raw materials for preparing the PLA photosensitive resin are as follows: Raw material 1: The methacrylic anhydride-modified 1,6-hexanediol-terminated carboxyl polylactic acid condensate requires L-lactic acid, 1,6-hexanediol, stannous chloride, p-hydroxyanisole, and methacrylic anhydride with a mass concentration of 88% in a molar ratio of (2-8):1:(0.01-0.1):(0.01-0.1):(1.5-2.0). Raw material 2: The methacrylic anhydride modified glycerol-terminated carboxyl polylactic acid condensate requires L-lactic acid, glycerol, stannous chloride, p-hydroxyanisole, and methacrylic anhydride with a mass concentration of 88% in a molar ratio of (1-6):1:(0.01-0.1):(0.01-0.1):(1.5-2.0). Raw material 3: The methacrylic anhydride modified polyethylene glycol 600 carboxyl-terminated polylactic acid condensate requires L-lactic acid, polyethylene glycol 600, stannous chloride, p-hydroxyanisole, and methacrylic anhydride with a molar ratio of (3-9):1:(0.01-0.1):(0.01-0.1):(1.5-2.0) and a mass concentration of 88%.

2. The method for fabricating a ceramic / polymer continuous gradient porous scaffold according to claim 1, characterized in that, The preparation steps of the modified polylactic acid raw material are as follows: All three raw materials are prepared according to this process. An 88% (w / w) L-lactic acid aqueous solution is added to a 250 mL three-necked flask, magnetically stirred and heated. The temperature is gradually increased to 120°C under normal pressure, and dehydrated for 2 hours. Then, the second solution and the catalyst stannous chloride are added, and the mixture is stirred magnetically until homogeneous. Then, the mixture is heated to 2 × 10⁻⁶ mm². 4 The product was dehydrated at 130°C for 2 hours under Pa, followed by dehydration at 150°C for 1 hour under 1000 Pa. It was then cooled to 100°C under vacuum, and the polymerization inhibitors p-hydroxyanisole and methacrylic anhydride were added. The temperature was then raised to 120°C and reacted at atmospheric pressure for 3 hours. Excess methacrylic anhydride was then removed under reduced pressure at 120°C, and the product was cooled to room temperature to obtain three different products.

3. The method for fabricating a ceramic / polymer continuous gradient porous scaffold according to claim 1, characterized in that, The steps for creating the gradient layer are as follows: (1) Impregnate with HA / PLA solution; (2) Centrifuge dry; (3) Curing by ultraviolet light irradiation; (4) Interlayer surface activation treatment.

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