WO2022170818A1 - 一种降解速度可调的骨组织梯度支架的3d打印成型方法 - Google Patents

一种降解速度可调的骨组织梯度支架的3d打印成型方法 Download PDF

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WO2022170818A1
WO2022170818A1 PCT/CN2021/132984 CN2021132984W WO2022170818A1 WO 2022170818 A1 WO2022170818 A1 WO 2022170818A1 CN 2021132984 W CN2021132984 W CN 2021132984W WO 2022170818 A1 WO2022170818 A1 WO 2022170818A1
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pores
gradient
contact surface
bone tissue
scaffold
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PCT/CN2021/132984
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English (en)
French (fr)
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张斌
殷晓红
洪忆榕
余晓雯
李琦
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浙江大学
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    • C—CHEMISTRY; METALLURGY
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    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
    • C04B35/447—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on phosphates, e.g. hydroxyapatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • B33Y70/10—Composites of different types of material, e.g. mixtures of ceramics and polymers or mixtures of metals and biomaterials
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
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    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/638—Removal thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
    • C04B2235/60—Aspects relating to the preparation, properties or mechanical treatment of green bodies or pre-forms
    • C04B2235/602—Making the green bodies or pre-forms by moulding
    • C04B2235/6026—Computer aided shaping, e.g. rapid prototyping
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
    • C04B2235/65—Aspects relating to heat treatments of ceramic bodies such as green ceramics or pre-sintered ceramics, e.g. burning, sintering or melting processes
    • C04B2235/656—Aspects relating to heat treatments of ceramic bodies such as green ceramics or pre-sintered ceramics, e.g. burning, sintering or melting processes characterised by specific heating conditions during heat treatment
    • C04B2235/6562—Heating rate
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2235/00—Aspects relating to ceramic starting mixtures or sintered ceramic products
    • C04B2235/65—Aspects relating to heat treatments of ceramic bodies such as green ceramics or pre-sintered ceramics, e.g. burning, sintering or melting processes
    • C04B2235/656—Aspects relating to heat treatments of ceramic bodies such as green ceramics or pre-sintered ceramics, e.g. burning, sintering or melting processes characterised by specific heating conditions during heat treatment
    • C04B2235/6567—Treatment time
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P10/00—Technologies related to metal processing
    • Y02P10/25—Process efficiency

Definitions

  • the invention belongs to the technical field of gradient scaffolds, in particular to a 3D printing and molding method for a bone tissue gradient scaffold with adjustable degradation speed.
  • HAp hydroxyapatite
  • TCP tricalcium phosphate
  • the porous structure of ceramic bone scaffolds is relatively simple, mostly with one or two pore sizes.
  • Natural bone tissue has a hierarchical porous structure, and cortical bone separates soft tissue cells from bone tissue cells, thereby providing the required different biological microenvironments; cancellous bone has abundant interconnected pores, which are the attachment and growth of bone tissue cells. It provides conditions that are conducive to the growth of blood vessels and other pipelines, and provides channels for the transportation of nutrients and metabolites; the hierarchical porous structure provides suitable mechanical properties, which can not only bear the corresponding environmental load, but also reduce the self-weight.
  • a bone tissue scaffold with a hierarchical porous structure is designed to simulate natural bone tissue, which can provide bone tissue cells with a biological microenvironment similar to that of natural bone tissue, prevent soft tissue from growing into defects, and facilitate blood vessel growth and new bone formation. Therefore, it is of great significance to prepare gradient scaffolds that mimic natural bone tissue with adjustable degradation rates.
  • the present invention provides a 3D printing and molding method for a bone tissue gradient scaffold with adjustable degradation speed.
  • the gradient scaffold provided by the present invention has a porous structure with gradient distribution, showing the characteristics of small pore size in the simulated cortical bone part and small to large pore size in the simulated cancellous bone part.
  • the gradient scaffold is made of TCP mixed photosensitive resin slurry, and is formed in the form of DLP light curing, and the resin is removed during sintering.
  • the nonlinear gradient pores inside the scaffold can adjust the mechanical properties and degradation rate of the scaffold on the basis of meeting the requirements of the surface pore size and the internal pore size of the scaffold, and the degradation process has no biological toxicity.
  • the bone tissue gradient scaffold with adjustable degradation rate provided by the present invention at least includes a first contact surface and a second contact surface, and the first contact surface and the second contact surface together form a closed outer surface of the gradient scaffold;
  • the interior of the gradient scaffold is a porous structure with gradient distribution;
  • the first contact surface is provided with first pores with a diameter of less than 100 microns, and the second contact surface is provided with second pores with a diameter of several hundreds of microns; adjacent first pores, second pores and The internal pores are connected by nonlinear transition.
  • the above-mentioned 3D printing method for the bone tissue gradient scaffold with adjustable degradation rate includes the following steps:
  • the TCP resin mixed slurry is photo-cured by DLP; in the photo-curing process, the porosity of DLP printing is set to be 5%-15% higher than the actual porosity;
  • the gradient scaffold of the present invention is biodegradable, and the degradation process has no biological toxicity.
  • the degradation rate can be adjusted in two ways: First, the microporosity of the scaffold can be adjusted by adjusting the solid content of the slurry, thereby adjusting the degradation rate of the scaffold. The lower the solid content, the higher the microporosity of the scaffold, and the faster the degradation rate of the scaffold; Second, the surface area of the scaffold can be changed by adjusting the pore size on the surface of the scaffold, thereby adjusting the degradation rate of the scaffold. The method of reducing the overall pore size increases the surface area of the scaffold and accelerates the degradation rate of the scaffold.
  • the nonlinear gradient pores used in the present invention can adjust the mechanical properties by adjusting the gradient function of the stent on the basis of meeting the requirements of the surface pore size and the internal pore size of the stent, which can not only play the role of replacing the support, but also Avoid stress shielding.
  • the six-order function transition is selected, the small hole of the stent quickly transitions to the large hole, the area of the small hole is small, and the mechanical properties of the stent are weak. Strong performance.
  • the gradient scaffold of the present invention can be used for the repair of various bone defects.
  • the surface of the stent includes at least a first contact surface and a second contact surface.
  • Different types of contact surfaces have different sizes of pores.
  • the small pores of the first contact surface can prevent the ingrowth of soft tissue, and the pores gradually increase in the normal direction of the first contact surface.
  • the pores of the second contact surface and the internal pores are favorable for the ingrowth of blood vessels and the exchange of nutrients and metabolites.
  • FIG. 1 is a schematic diagram of the three-dimensional structure of a bone tissue gradient scaffold for plate-shaped bone defects in the present embodiment
  • Fig. 2 is a side schematic view of the bracket shown in Fig. 1;
  • FIG. 3 is a schematic diagram of the three-dimensional structure of the bone tissue gradient scaffold for long bone defects in the present embodiment
  • FIG. 4 is a schematic side view of the bracket shown in FIG. 3 .
  • a bone tissue gradient scaffold with adjustable degradation rate comprising at least a first contact surface and a second contact surface, the first contact surface and the second contact surface together form a closed outer surface of the gradient scaffold; the gradient The inside of the scaffold is a porous structure with gradient distribution;
  • the first contact surface is provided with first pores with a diameter of less than 100 microns, and the second contact surface is provided with second pores with a diameter of several hundreds of microns; adjacent first pores, second pores and The internal pores are connected by nonlinear transition.
  • the bone tissue gradient scaffold proposed in the present invention has a porous structure with a gradient distribution, showing that the surface of the scaffold simulates cortical bone with numerous micron-sized pores and a small number of hundreds of micron-sized pores, and the inside of the scaffold simulates cancellous bone with hundreds of micron-sized pores.
  • the pore size on the surface of the scaffold is determined according to the needs in the design.
  • the pore size of the contact interface with soft tissue is less than 100 microns, and the pore size of hundreds of microns (300 microns to 600 microns) is selected for the contact interface with bone tissue, and the largest pore inside the scaffold is selected. size, and finally design the gradient function from the surface micropores to the inner macropores according to the mechanical requirements of the scaffold.
  • the gradient stent is made of TCP mixed photosensitive resin slurry, and the solid content of the slurry (30%-66% wt) is selected according to the degradation requirements of the stent, and is formed by DLP photocuring, and the resin is removed during sintering.
  • the scaffold is biodegradable, and its degradation rate can be adjusted in two ways: First, the microporosity of the scaffold can be adjusted by adjusting the solid content of the slurry, thereby adjusting the degradation rate of the scaffold. The lower the solid content, the higher the microporosity of the scaffold. The faster the degradation rate of the scaffold; the second is that the surface area of the scaffold can be changed by adjusting the macropore size of the second contact surface, thereby adjusting the degradation rate of the scaffold. The smaller the pore size of the scaffold, the larger the surface area of the scaffold, and the faster the degradation rate.
  • the mechanical properties of the scaffold can be adjusted. Under the condition that the external pore size and the internal pore size are constant, the mechanical properties of the scaffold can be adjusted by adjusting the gradient function of the scaffold, and the six-order function transition is selected. The smaller the area, the weaker the mechanical properties of the stent, the quadratic function transition is selected, the small hole of the stent slowly transitions to the large hole, the area of the small hole is large, and the mechanical performance of the stent is strong.
  • the surface of the scaffold can simulate cortical bone, with pores below 100 microns to prevent soft tissue ingrowth; the interior can be provided with pores of 200 to 600 microns according to the use environment, which is conducive to the ingrowth of blood vessels and the exchange of nutrients and metabolites.
  • the gradient scaffold of the present invention has adjustable degradation speed and mechanical properties. With the regeneration of bone tissue, the gradient scaffold gradually degrades, so it can provide stability and support in the early stage, while preventing the ingrowth of soft tissue, guide bone regeneration in the middle stage, and degrade and metabolize in the later stage.
  • the 3D printing forming method of the above gradient scaffold mainly includes the following steps:
  • the gradient functions include quadratic functions, cubic functions, quartic functions, quintic functions and hexadecimal functions. Each gradient function corresponds to different mechanical properties. As the power of the gradient function increases, the mechanical properties gradually weaken. .
  • TCP powder, resin, dispersant are mixed in proportion to obtain TCP resin mixed slurry; in the present embodiment, the average particle size of TCP powder is 1 micron, and the mass ratio of TCP powder, resin and dispersant is 66:29: 5 or 30:65:5, the resin type is SP700, and the dispersant type is BYK111.
  • the TCP resin mixed slurry is photo-cured by DLP. Since the curing time varies with the thickness of the model slice layer when using DLP photo-curing, in this embodiment, the bracket uses 20 Micron layer thickness slices, preferably the exposure power is 30mw/cm 2 and the curing time is 1.2s;
  • the actual printed line diameter produced by DLP printing is slightly larger than the design diameter, which easily leads to the actual porosity of the scaffold being lower than the designed porosity.
  • 56% of the designed porosity rate, and finally a 50% porosity scaffold can be obtained.
  • the present invention adopts the method of model compensation to increase the porosity in advance, which solves the problem of low porosity in DLP printing.
  • the porosity of DLP printing is set to be 5%-15% higher than the actual porosity.
  • the printed porosity is 10% higher than the actual porosity.
  • the threshold is set to 2%.
  • the diameter of the first pores on the surface is 10-90 microns; when the contact surface type is the second contact surface, the second contact surface on the surface has a diameter of 10-90 microns. Pore diameter is 300-600 microns.
  • the internal pore size of the bone tissue gradient scaffold is 200-600 microns.
  • the bone tissue gradient scaffold adjusts the microscopic porosity by adjusting the solid content of the printing paste, and the solid content of the printing paste is 30%-66% wt.
  • the specific solid content can be determined according to the actual situation. For example, a low solid content (such as 30% wt) can be selected for the position with fast regeneration speed to speed up the degradation speed of the stent, and a position with a slow regeneration speed can be selected with a high solid content (such as 66% wt) to slow down the degradation. speed.
  • low solid content increases porosity while reducing mechanical properties. Therefore, when the mechanical properties are high, the degradation rate cannot be adjusted by reducing the solid content, but a smaller pore size (such as 200 microns to 300 microns) should be set. Increase the scaffold surface area, thereby increasing the rate of degradation.
  • FIG. 1 and FIG. 3 are schematic diagrams of the three-dimensional structure of the bone tissue gradient scaffold for plate bone and long bone defects, respectively, and FIG. 2 and FIG. 4 are the side views of FIG. 1 and FIG. 3 , respectively.
  • Both include a first contact surface and a second contact surface, and the size and relative positions of pores on the two types of contact surfaces are different.
  • the upper and lower surfaces are the first contact surface, using small holes
  • the side surface is the second contact surface, using large holes.
  • the upper and lower surfaces are the second contact surfaces, using large holes
  • the side surfaces are the first contact surfaces, using small holes.
  • the bone tissue gradient scaffold prepared above can be applied to the clinical repair of bone defects.
  • the shapes of Figures 1 and 2 are only for illustration purposes. When used for clinical repair, individualized gradient preparations can be made for specific patient defect sites and shapes.
  • stents such as CT scanning of defects to obtain model structures, it is also necessary to combine some conventional technical means and equipment in the field of application to achieve clinical applications. The operations and treatment methods involved in the clinical repair process are not within the scope of protection of the present invention. .

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Abstract

一种降解速度可调的骨组织梯度支架的3D打印成型方法，属于梯度支架领域。至少包括一个第一接触面和一个第二接触面，形成梯度支架的封闭外表面；梯度支架的内部为呈梯度分布的多孔隙结构；第一接触面上设有直径小于100微米的第一孔隙，第二接触面上设有直径为数百微米的第二孔隙；相邻的第一孔隙、第二孔隙和内部孔隙之间采用非线性过渡方式连通。梯度支架具有呈梯度分布的多孔结构，采用TCP混合光敏树脂浆料为材料，利用DLP光固化形式成型，在烧结时除去树脂。支架内部的非线性梯度孔隙可以在满足支架表面孔隙尺寸要求与内部孔隙尺寸要求的基础上，调节支架的机械性能与降解速率，降解过程无生物毒性。

Description

一种降解速度可调的骨组织梯度支架的3D打印成型方法 技术领域
本发明属于梯度支架技术领域，具体为一种降解速度可调的骨组织梯度支架的3D打印成型方法。
背景技术
当肿瘤、创伤、感染等造成的骨缺损超过临界尺寸时，骨组织将无法自行修复，成为了临床上的难题。传统治疗方法中，对于处于或超过临界尺寸的骨缺损，通常植入金属骨支架或羟基磷灰石支架用于承载机械负载，但在使用中仍然存在一些问题，如支架移位、过敏反应、材料失效老化等。此外，由于该类支架通常无法降解，因此只能起替代骨组织作用，而无法真正实现骨组织的修复。
随着增材制造技术的发展，越来越多人对通过3D打印制备具有多孔结构的骨组织支架产生了兴趣。HAp(羟基磷灰石)与骨组织天然成分相似，因此率先被用于骨支架的制备，但其存在降解速率过慢的问题。TCP(磷酸三钙)也是天然人骨的成分之一，且可生物降解，因此被广泛用于骨支架的制备。但是至今为止，陶瓷骨支架的多孔结构相对简单，多为一种或两种孔隙尺寸。
天然骨组织具有分级多孔结构，皮质骨将软组织细胞与骨组织细胞分隔开，从而提供所需的不同生物微环境；松质骨具有丰富的相互连通的孔隙，为骨组织细胞的依附与生长提供了条件，有利于血管等管道的长入，为营养物质与代谢产物的运输提供了通道；分级多孔结构提供了合适的力学性能，既能承载相应的环境负荷，又降低了自重。
模拟天然骨组织设计同样具有分级多孔结构的骨组织支架，可以向骨组织细胞提供与天然骨组织相似的生物微环境，阻止软组织长入缺损，有利于血管长入，新骨形成。因此，制备降解速度可调的模拟天然骨组织的梯度支架具有重要意义。
发明内容
本发明为了解决现有的骨组织修复技术的不足，提供一种降解速度可调的骨组织梯度支架的3D打印成型方法。本发明提供的梯度支架具有呈梯度分布的多 孔结构，呈现出模拟皮质骨部分孔隙尺寸小、模拟松质骨部分孔隙尺寸由小到大的特征。该梯度支架采用TCP混合光敏树脂浆料为材料，利用DLP光固化形式成型，在烧结时除去树脂。
支架内部的非线性梯度孔隙可以在满足支架表面孔隙尺寸要求与内部孔隙尺寸要求的基础上，调节支架的机械性能与降解速率，降解过程无生物毒性。
本发明提供的降解速度可调的骨组织梯度支架，至少包括一个第一接触面和一个第二接触面，所述的第一接触面和第二接触面共同形成梯度支架的封闭外表面；所述梯度支架的内部为呈梯度分布的多孔隙结构；
所述的第一接触面上设有直径小于100微米的第一孔隙，所述的第二接触面上设有直径为数百微米的第二孔隙；相邻的第一孔隙、第二孔隙和内部孔隙之间采用非线性过渡的方式连通。
上述降解速度可调的骨组织梯度支架的3D打印成型方法，包括以下步骤：
1)根据需求获取骨组织梯度支架的尺寸和形状，以及获取骨组织梯度支架外表面的接触面类型；所述的接触面类型分为第一接触面和第二接触面；
2)根据接触面类型确定每一个接触面上的孔隙尺寸，并设计骨组织梯度支架的内部孔隙尺寸；
3)根据支架的力学要求选择接触面孔隙到内部孔隙之间的梯度函数，所述的梯度函数用于实现表面孔隙到内部孔隙之间、外表面相邻孔隙之间、以及内部相邻孔隙之间的非线性连通；
4)设计骨组织梯度支架的打印模型和模型支撑；
5)将TCP粉末、树脂、分散剂按比例混合，得到TCP树脂混合浆料；
6)根据设计好的打印模型和打印支撑，利用DLP将TCP树脂混合浆料光固化成型；在光固化成型过程中，设置DLP打印的孔隙率高于实际孔隙率的5％-15％；
7)脱脂烧结：首先在室温下以0.5-1.2℃/min的速率升温至400-500℃，在400-500℃下保温20-40min，随后从400-500℃以1.5-2.5℃/min的速率升温至1100-1300℃，在1100-1300℃下保温100-150min，取出骨组织梯度支架空冷，得到骨组织梯度支架。
与现有技术相比，本发明的优势在于：
(1)本发明的梯度支架可生物降解，降解过程无生物毒性。其降解速率可以通过两种途径调节：一是可通过调节浆料固含量以改变支架微孔隙率，从而调整支架降解速率，固含量越低，支架微孔隙率越高，支架降解速率越快；二是可通过调节支架表面孔隙大小来改变支架表面积，从而调整支架降解速率，支架孔隙尺寸越小，支架表面积越大，降解速率越快；在力学性能要求高的情况下(大于5MPa)，采用减小整体孔隙尺寸的方式增大支架表面积，加快支架降解速率。
(2)本发明采用的非线性梯度孔隙可以在满足支架表面孔隙尺寸要求与内部孔隙尺寸要求的基础上，通过调节支架梯度函数实现力学性能的调整，既能起到替代支撑的作用，也要避免应力屏蔽。选取六次函数过渡，支架小孔迅速过渡到大孔，小孔区域面积小，支架力学性能较弱，选取二次函数过渡，支架小孔缓慢过渡到大孔，小孔面积区域大，支架力学性能较强。
(3)传统的DLP打印技术由于光散射作用，实际打印线条的直径略大，容易导致支架实际孔隙率低于设计孔隙率的问题，本发明采用模型补偿的方式，预先提高孔隙率，解决了DLP打印中孔隙率偏低的问题。
(4)本发明的梯度支架可以用于各种骨缺损的修复。支架表面至少包括第一接触面和第二接触面，不同类型的接触面孔隙尺寸大小不同，例如第一接触面的小孔隙可以避免软组织长入，第一接触面法向向内孔隙逐渐增大以促进血管长入、骨组织再生。第二接触面孔隙和内部孔隙有利于血管长入以及营养物质与代谢产物的交换。
附图说明
图1为本实施例中的用于板状骨缺损的骨组织梯度支架三维结构示意图；
图2为图1所示支架中的一个侧面示意图；
图3为本实施例中的用于长骨缺损的骨组织梯度支架三维结构示意图；
图4为图3所示支架中的一个侧面示意图。
具体实施方式
这里将详细地对示例性实施例进行说明，其示例表示在附图中。下面的描述及附图时，除非另有表示，不同附图中的相同数字表示相同或相似的要素。以 下示例性实施例中所描述的实施方式并不代表与本申请相一致的所有的实施方式。相反，它们仅是与如所附中权利要求书中所详述的，本申请的一些方面相一致的装置的例子。本说明书的各个实施例均采用递进的方式描述。
需要说明，本申请实施例中所有方向性指示(诸如上、下、左、右、前、后……)仅用于解释在某一特定姿态(如附图所示)下各部件之间的相对位置关系、运动情况等，如果该特定姿态发生改变时，则该方向性指示也相应地随之改变。
另外，在本申请中涉及“第一”、“第二”等的描述仅用于描述目的，而不能理解为指示或暗示其相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。另外，各个实施例之间的技术方案可以相互结合，但是必须是以本领域普通技术人员能够实现为基础，当技术方案的结合出现相互矛盾或无法实现时应当认为这种技术方案的结合不存在，也不在本申请要求的保护范围之内。
一种降解速度可调的骨组织梯度支架，至少包括一个第一接触面和一个第二接触面，所述的第一接触面和第二接触面共同形成梯度支架的封闭外表面；所述梯度支架的内部为呈梯度分布的多孔隙结构；
所述的第一接触面上设有直径小于100微米的第一孔隙，所述的第二接触面上设有直径为数百微米的第二孔隙；相邻的第一孔隙、第二孔隙和内部孔隙之间采用非线性过渡的方式连通。
本发明提出的骨组织梯度支架具有呈梯度分布的多孔结构，呈现出支架表面模拟具有众多微米级孔隙与少量百微米级孔隙的皮质骨、支架内部模拟具有数百微米孔隙的松质骨。在设计时根据需要确定支架表面孔隙尺寸，与软组织接触界面选取小于100微米的孔隙尺寸，与骨组织接触界面选取数百微米的孔隙尺寸(300微米-600微米)，并选取支架内部最大孔隙的尺寸，最后根据支架的力学要求设计表面微孔隙到内部大孔隙之间的梯度函数。
该梯度支架采用TCP混合光敏树脂浆料为材料，根据支架的降解要求选取浆料固含量(30％-66％wt)，利用DLP光固化形式成型，在烧结时除去树脂。
该支架可以生物降解，其降解速率可以通过两种途径调节：一是可通过调节浆料固含量以改变支架微孔隙率，从而调整支架降解速率，固含量越低，支架微 孔隙率越高，支架降解速率越快；二是可通过调节第二接触面的大孔尺寸以改变支架表面积，从而调整支架降解速率，支架孔隙尺寸越小，支架表面积越大，降解速率越快。
该支架可以调整力学性能，在外部孔隙尺寸与内部孔隙尺寸一定的情况下，通过调节支架梯度函数，从而调整支架力学性能，选取六次函数过渡，支架小孔迅速过渡到大孔，小孔区域面积小，支架力学性能较弱，选取二次函数过渡，支架小孔缓慢过渡到大孔，小孔面积区域大，支架力学性能较强。
该支架表面可模拟皮质骨，设置100微米以下的孔隙以防止软组织长入；内部可根据使用环境设置200微米至600微米孔隙，有利于血管长入以及营养物质与代谢产物的交换。本发明的梯度支架具有可调的降解速度和力学性能。随着骨组织再生，该梯度支架逐步降解，因此可以起到早期提供稳定与支撑，同时防止软组织长入，中期引导骨再生，后期降解代谢的作用。
上述梯度支架的3D打印成型方法，主要包括以下步骤：
1)根据需求获取骨组织梯度支架的尺寸和形状，以及获取骨组织梯度支架外表面的接触面类型；所述的接触面类型分为第一接触面和第二接触面。
2)根据接触面类型确定每一个接触面上的孔隙尺寸，并设计骨组织梯度支架的内部孔隙尺寸。
3)根据支架的力学要求选择接触面孔隙到内部孔隙之间的梯度函数，所述的梯度函数用于实现表面孔隙到内部孔隙之间、外表面相邻孔隙之间、以及内部相邻孔隙之间的非线性连通。
所述的梯度函数包括二次函数、三次函数、四次函数、五次函数和六次函数，每一种梯度函数对应不同的力学性能，随着梯度函数的次方数增加，力学性能逐渐减弱。
4)设计骨组织梯度支架的打印模型和模型支撑；模型支撑为DLP打印中的公知概念，避免打印时支架脱落或支架底部孔隙堵塞。
5)将TCP粉末、树脂、分散剂按比例混合，得到TCP树脂混合浆料；本实施例中，TCP粉末平均粒径为1微米，TCP粉末、树脂、分散剂的质量比为66:29:5或者30：65：5，树脂型号为SP700，分散剂型号为BYK111。
6)根据设计好的打印模型和打印支撑，利用DLP将TCP树脂混合浆料光固化成型，由于使用DLP光固化成型时，固化时间因模型切片层厚而异，本实施例中，支架使用20微米层厚切片，优选为曝光功率为30mw/cm 2，固化时间为1.2s；
在光固化成型过程中，由于光散射作用，DLP打印产生实际打印线条直径略大于设计直径，易导致支架实际孔隙率低于设计孔隙率，在本发明的预实验中，采用56％的设计孔隙率，最终可获得50％孔隙率支架。本发明采用模型补偿的方式，预先提高孔隙率，解决了DLP打印中孔隙率偏低的问题，设置DLP打印的孔隙率高于实际孔隙率的5％-15％；本实施例中，设置DLP打印的孔隙率高于实际孔隙率的10％。
在一项具体实施中，若打印得到的孔隙率与实际孔隙率之间的误差低于阈值，则进入下一步骤；否则，降低设置的DLP打印的孔隙率，重复进行光固化成型过程。本实施例中，阈值设置2％。
7)脱脂烧结：首先在室温下以0.5-1.2℃/min的速率升温至400-500℃，在400-500℃下保温20-40min，随后从400-500℃以1.5-2.5℃/min的速率升温至1100-1300℃，在1100-1300℃下保温100-150min，取出骨组织梯度支架空冷，得到骨组织梯度支架。
本实施例中，优选为首先在室温下以1℃/min的速率升温至480℃，在480℃下保温30min，随后从480℃以2℃/min的速率升温至1240℃，在1240℃下保温2h，取出梯度支架空冷。
在本发明的一项具体实施中，当接触面类型为第一接触面时，其表面的第一孔隙直径为10-90微米；当接触面类型为第二接触面时，其表面的第二孔隙直径为300-600微米。所述的骨组织梯度支架内部孔隙尺寸为200-600微米。
步骤3)中所述的表面孔隙到内部孔隙之间、外表面相邻孔隙之间、以及内部相邻孔隙之间进行非线性过渡之后，在骨组织梯度支架内部形成三周期极小曲面孔隙，在三维空间中的三个坐标轴上均呈现出周期性(如图2和图4所示)。因此可以无限扩展，并可在参数方程中引入函数，使得TPMS在扩展中改变参数，实现梯度支架的设计。
所述的骨组织梯度支架通过调整打印浆料固含量来调整微观孔隙率，所述的打印浆料固含量为30％-66％wt。具体的固含量可以根据实际情况确定，例如再生速度快的位置可选择低固含量(例如30％wt)加快支架降解速度，再生速度缓慢的位置可选择高固含量(例如66％wt)减缓降解速度。特别地，低固含量提高孔隙率的同时降低了力学性能，因此力学性能要求高时，不能采取降低固含量的方式调节降解速度，而应当设置更小的孔隙尺寸(如200微米-300微米)增大支架表面积，从而提高降解速度。
在本发明的一项具体应用中，图1和图3给出了分别针对板状骨和长骨缺损的骨组织梯度支架立体结构示意图，图2和图4分别是图1和图3的侧面图。均包括第一接触面和第二接触面，两种类型的接触面上的孔隙大小和相对位置不同。根据板状骨的实际情况，上下面为第一接触面，采用小孔，侧面为第二接触面，采用大孔。根据长骨的实际情况，上下面为第二接触面，采用大孔，侧面为第一接触面，采用小孔。
可以将上述制备得到的骨组织梯度支架应用于骨缺损的临床修复，图1和图2的外形只起到示意作用，用于临床修复时可以针对具体的患者缺损部位和形状进行个性化制备梯度支架，例如对缺损处进行CT扫描等获取模型结构，还需结合所应用领域的一些常规技术手段和设备实现临床应用，在临床修复过程中涉及到的手术及治疗方法不在本发明的保护范围内。
附图和实施例中展示的梯度支架的结构或者基于3D打印的成型方法的过程只是若干优选实施方式中的一种，应当指出，本发明不限于上述结构和基于3D打印的成型方法。对于本领域的普通技术人员来说，依然可以对前述的技术方案进行修改，或者对其中部分技术特征进行等同替换。而这些修改或替换，在不脱离本发明技术方案本质的前提下，均应认为是本发明的保护范围。

Claims (7)

  1. 一种降解速度可调的骨组织梯度支架的3D打印成型方法，所述的降解速度可调的骨组织梯度支架至少包括一个第一接触面和一个第二接触面，所述的第一接触面和第二接触面共同形成梯度支架的封闭外表面；所述梯度支架的内部为呈梯度分布的多孔隙结构；
    所述的第一接触面上设有直径小于100微米的第一孔隙，所述的第二接触面上设有直径为数百微米的第二孔隙；相邻的第一孔隙、第二孔隙和内部孔隙之间采用非线性过渡的方式连通；
    其特征在于，所述的3D打印成型方法包括以下步骤：
    1)根据需求获取骨组织梯度支架的尺寸和形状，以及获取骨组织梯度支架外表面的接触面类型；所述的接触面类型分为第一接触面和第二接触面；
    2)根据接触面类型确定每一个接触面上的孔隙尺寸，并设计骨组织梯度支架的内部孔隙尺寸；
    3)根据支架的力学要求选择接触面孔隙到内部孔隙之间的梯度函数，所述的梯度函数用于实现表面孔隙到内部孔隙之间、外表面相邻孔隙之间、以及内部相邻孔隙之间的非线性连通；梯度函数包括二次函数、三次函数、四次函数、五次函数和六次函数，每一种梯度函数对应不同的力学性能，随着梯度函数的次方数增加，力学性能逐渐减弱；
    4)设计骨组织梯度支架的打印模型和模型支撑；
    5)将TCP粉末、树脂、分散剂按比例混合，得到TCP树脂混合浆料；
    6)根据设计好的打印模型和打印支撑，利用DLP将TCP树脂混合浆料光固化成型；在光固化成型过程中，设置DLP打印的孔隙率高于实际孔隙率的5％-15％；
    7)脱脂烧结：首先在室温下以0.5-1.2℃/min的速率升温至400-500℃，在400-500℃下保温20-40min，随后从400-500℃以1.5-2.5℃/min的速率升温至1100-1300℃，在1100-1300℃下保温100-150min，取出骨组织梯度支架空冷，得到骨组织梯度支架。
  2. 根据权利要求1所述的降解速度可调的骨组织梯度支架的3D打印成型方 法，其特征在于，当接触面类型为第一接触面时，其表面的第一孔隙直径为10-90微米；当接触面类型为第二接触面时，其表面的第二孔隙直径为300-600微米。
  3. 根据权利要求1所述的降解速度可调的骨组织梯度支架的3D打印成型方法，其特征在于，所述的骨组织梯度支架内部孔隙尺寸为200-600微米。
  4. 根据权利要求2或3所述的降解速度可调的骨组织梯度支架的3D打印成型方法，其特征在于，步骤3)中所述的表面孔隙到内部孔隙之间、外表面相邻孔隙之间、以及内部相邻孔隙之间进行非线性过渡之后，在骨组织梯度支架内部形成三周期极小曲面孔隙，在三维空间中的三个坐标轴上均呈现出周期性。
  5. 根据权利要求1所述的降解速度可调的骨组织梯度支架的3D打印成型方法，其特征在于，所述的骨组织梯度支架通过调整打印浆料固含量来调整微观孔隙率，所述的打印浆料固含量为30％-66％wt。
  6. 根据权利要求1所述的降解速度可调的骨组织梯度支架的3D打印成型方法，其特征在于，在所述的步骤6)之后还包括检测固化成型后的支架孔隙率的步骤，若打印得到的孔隙率与实际孔隙率之间的误差低于阈值，则进入下一步骤；否则，降低设置的DLP打印的孔隙率，重复进行光固化成型过程。
  7. 根据权利要求1所述的降解速度可调的骨组织梯度支架的3D打印成型方法，其特征在于，在步骤6)所述的光固化成型过程中，曝光功率为30mw/cm 2，固化时间为1.2s。
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